Ankylosing spondylitis is an inflammatory disorder that primarily affects the axial skeleton including the spine and sacroiliac joints. It has a strong genetic association with the HLA-B27 gene. The disease begins in the second or third decade of life and is more common in males. It is characterized by inflammation of the joints of the spine which can lead to bony fusion and stiffness over time if left untreated. Symptoms include lower back pain and stiffness that improves with movement and worsens with inactivity.

1. Ankylosing SpondilitisAnkylosing Spondilitis
Dr Biplave KarkiDr Biplave Karki
ResidentResident
Dhulikhel HospitalDhulikhel Hospital

2. Spondylo-arthritidesSpondylo-arthritides
 A group of overlapping disorders that shareA group of overlapping disorders that share
certain clinical features and genetic associationscertain clinical features and genetic associations
 Ankylosing spondylitis (AS)Ankylosing spondylitis (AS)
 Reactive arthritisReactive arthritis
 Psoriatic arthritis and spondylitisPsoriatic arthritis and spondylitis
 Enteropathic arthritis and spondylitisEnteropathic arthritis and spondylitis
 Juvenile onset spondyloarthritis (SpA)Juvenile onset spondyloarthritis (SpA)
 Undifferentiated SpAUndifferentiated SpA

3. INTRODUCTIONINTRODUCTION
 AS is an inflammatory disorder of unknown cause thatAS is an inflammatory disorder of unknown cause that
primarily affects theprimarily affects the Axial skeletonAxial skeleton
 Peripheral joints and extra-articular structuresPeripheral joints and extra-articular structures
 Begins in the 2Begins in the 2ndnd
or 3or 3rdrd
decadedecade
 Male-to-female prevalence is between 2:1 and 3:1Male-to-female prevalence is between 2:1 and 3:1
 Axial spondylo-arthritisAxial spondylo-arthritis
 definite ASdefinite AS
 early stages that do not yet meet classical criteria for ASearly stages that do not yet meet classical criteria for AS

4. EPIDEMIOLOGYEPIDEMIOLOGY
 HLA-B27HLA-B27
 North American whitesNorth American whites
 prevalence of B27 is 7%prevalence of B27 is 7%
 90% in patients with AS, independent of disease severity90% in patients with AS, independent of disease severity
 AS is present in 1–6% of adults inheriting B27, whereasAS is present in 1–6% of adults inheriting B27, whereas
the prevalence is 10–30% among B27+ adult first-the prevalence is 10–30% among B27+ adult first-
degree relatives of ASdegree relatives of AS
 Concordance rate in identical twins is about 65%Concordance rate in identical twins is about 65%

5. PATHOLOGYPATHOLOGY
 SacroiliitisSacroiliitis
 earliest manifestation of ASearliest manifestation of AS
 Synovitis and myxoid marrowSynovitis and myxoid marrow
 Pannus and subchondral granulation tissuePannus and subchondral granulation tissue
 Marrow edema, enthesitis, and chondroid differentiationMarrow edema, enthesitis, and chondroid differentiation
 SyndesmophyteSyndesmophyte
 Bony ankylosisBony ankylosis
 Spine changesSpine changes
 Bamboo spineBamboo spine
 Diffuse osteoporosisDiffuse osteoporosis
 Erosion of vertebral bodies at the disk marginErosion of vertebral bodies at the disk margin
 Squaring” or “barreling” of vertebrae,Squaring” or “barreling” of vertebrae,

6. PATHOGENESISPATHOGENESIS
 Immune-mediatedImmune-mediated
 Autoinflammatory pathogenesis >Antigen-specificAutoinflammatory pathogenesis >Antigen-specific
autoimmunityautoimmunity
 Dramatic response to therapeutic blockade ofDramatic response to therapeutic blockade of
tumor necrosis factor α (TNF-α)tumor necrosis factor α (TNF-α)
 Other genes related to TNF pathways showOther genes related to TNF pathways show
association with ASassociation with AS
 TNFRSF1A, LTBR, and TBKBP1TNFRSF1A, LTBR, and TBKBP1

7. PATHOGENESIS contd..PATHOGENESIS contd..
 Interleukin (IL-23/IL-17) cytokine pathwayInterleukin (IL-23/IL-17) cytokine pathway
 IL23R, PTER4, IL12B, CARD9, and TYK2IL23R, PTER4, IL12B, CARD9, and TYK2
 Also associated withAlso associated with
 Inflammatory bowel disease (IBD)Inflammatory bowel disease (IBD)
 PsoriasisPsoriasis
 Serum levels of IL-23 and IL-17 are elevated inSerum levels of IL-23 and IL-17 are elevated in
AS patientsAS patients

8. PATHOGENESIS contd..PATHOGENESIS contd..
 Peripheral arthritisPeripheral arthritis
 Mast cells / Neutrophils are major IL-17-producing cellsMast cells / Neutrophils are major IL-17-producing cells
 Neutrophils producing IL-17 are prominent in apophysealNeutrophils producing IL-17 are prominent in apophyseal
jointsjoints
 Inflamed sacroiliac jointInflamed sacroiliac joint
 Infiltrated with CD4+ and CD8+ T cells and macrophagesInfiltrated with CD4+ and CD8+ T cells and macrophages
andand
 Shows high levels of TNF-α (early) in the diseaseShows high levels of TNF-α (early) in the disease
 Abundant transforming growth factor β (TGF- β) inAbundant transforming growth factor β (TGF- β) in
advanced lesionsadvanced lesions

9. PATHOGENESIS contd..PATHOGENESIS contd..
 Peripheral synovitis in ASPeripheral synovitis in AS
 neutrophils, macrophages expressing CD68 and CD163neutrophils, macrophages expressing CD68 and CD163
 CD4+ and CD8+ T cellsCD4+ and CD8+ T cells
 B cellsB cells
 Prominent staining forProminent staining for
 Intercellular adhesion molecule 1 (ICAM-1)Intercellular adhesion molecule 1 (ICAM-1)
 Vascular cell adhesion molecule 1 (VCAM-1)Vascular cell adhesion molecule 1 (VCAM-1)
 Matrix metalloproteinase 3 (MMP-3), andMatrix metalloproteinase 3 (MMP-3), and
 Myeloid-related proteins 8 and 14 (MRP-8 and MRP-14)Myeloid-related proteins 8 and 14 (MRP-8 and MRP-14)
 Unlike RA synoviumUnlike RA synovium
 citrullinated proteins and cartilage gp39 peptide–MHCs arecitrullinated proteins and cartilage gp39 peptide–MHCs are
absentabsent

10. PATHOGENESIS contd..PATHOGENESIS contd..
 HLA-B27HLA-B27
 ERAP1, which strongly influences the MHC class IERAP1, which strongly influences the MHC class I
peptide repertoire, is only found in B27+ patientspeptide repertoire, is only found in B27+ patients
 The pairs of ERAP1 alleles found in AS patients showThe pairs of ERAP1 alleles found in AS patients show
diminished peptidase activitydiminished peptidase activity
 The B27 heavy chain has an unusual tendency toThe B27 heavy chain has an unusual tendency to
misfoldmisfold
 ProinflammatoryProinflammatory
 Role for natural killer (NK) cellsRole for natural killer (NK) cells
 Interaction with B27 heavy chain homodimersInteraction with B27 heavy chain homodimers

11. HLA class I moleculeHLA class I molecule

12. HLA-B27 peptide presentationHLA-B27 peptide presentation
• A peptide (green) intimately interacts with
the groove through hydrogen bonds.
• Each of six pockets (A-F) can bind the
side chain of an individual amino acid
• The side-chains of peptide "anchor" residues
P2, P3 and P9 (C-terminal) are bound in
pockets.
• The side-chains of P1, P4 and P8, which
extend out of the peptide-binding groove, are
critical for T-cell recognition

13. HLA B27 induces ASHLA B27 induces AS
 HLA-B27 are first generatedHLA-B27 are first generated
as free heavy chains, whichas free heavy chains, which
inside the cells becomeinside the cells become
associated and folded with theassociated and folded with the
β2-microglobulin andβ2-microglobulin and
antigenic peptide, and thenantigenic peptide, and then
become expressed on the cellbecome expressed on the cell
surface as a trimolecularsurface as a trimolecular
complex.complex.
 It can also be expressed on theIt can also be expressed on the
cell surface as homodimers ofcell surface as homodimers of
heavy chains without the β2heavy chains without the β2
microglobulinmicroglobulin..

14. PATHOGENESIS contd..PATHOGENESIS contd..
 New bone formation in ASNew bone formation in AS
 enchondral bone formation (periostealenchondral bone formation (periosteal
compartment)compartment)
 lack of regulation of thelack of regulation of the Wnt signalingWnt signaling
pathwaypathway
 controls the differentiation of mesenchymal cells intocontrols the differentiation of mesenchymal cells into
osteophytes, by the inhibitors (DKK-1 and sclerostin)osteophytes, by the inhibitors (DKK-1 and sclerostin)

15. PATHOGENESIS contd..PATHOGENESIS contd..
 Recent magnetic resonance imaging (MRI)Recent magnetic resonance imaging (MRI)
studiesstudies
 it is vertebral inflammatory lesionsit is vertebral inflammatory lesions
 that undergo metaplasia to fat (increased T1-that undergo metaplasia to fat (increased T1-
weighted signal)weighted signal)
 that are the predominant site of subsequentthat are the predominant site of subsequent
syndesmophytes despite anti-TNF-α therapy,syndesmophytes despite anti-TNF-α therapy,
whereas early acute inflammatory lesions resolvewhereas early acute inflammatory lesions resolve
 Rate of syndesmophyte formation decreasesRate of syndesmophyte formation decreases
after >4 years of anti-TNF-α therapyafter >4 years of anti-TNF-α therapy

16. CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS
 First noticed in late adolescence or earlyFirst noticed in late adolescence or early
adulthoodadulthood
 Median age (Western countries) ~ 23 yearsMedian age (Western countries) ~ 23 years
 5% of patients after 40 years5% of patients after 40 years
 Initial symptomsInitial symptoms
 dull pain, insidious in onset, felt deep in the lowerdull pain, insidious in onset, felt deep in the lower
lumbar or gluteal region,lumbar or gluteal region,
 accompanied by low-back morning stiffness of up toaccompanied by low-back morning stiffness of up to
a few hours’ durationa few hours’ duration
 improves with activity and returns followingimproves with activity and returns following
inactivityinactivity

17. CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS
cont..cont..
 Within a few monthsWithin a few months
 Pain becomes persistent and bilateralPain becomes persistent and bilateral
 Nocturnal exacerbation of painNocturnal exacerbation of pain
 Bony tenderness (enthesitis or osteitis)Bony tenderness (enthesitis or osteitis)
 Costosternal junctions,Costosternal junctions,
 Spinous processes,Spinous processes,
 Iliac crests,Iliac crests,
 Greater trochanters,Greater trochanters,
 Ischial tuberosities,Ischial tuberosities,
 Tibial tubercles, andTibial tubercles, and
 HeelsHeels

18. CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS
cont..cont..
 Hip and shoulder (“root” joint) arthritisHip and shoulder (“root” joint) arthritis
 Part of the axial diseasePart of the axial disease
 Hip arthritisHip arthritis 25–35% of patients25–35% of patients
 Shoulder arthritisShoulder arthritis less commonless common
 Arthritis of peripheral jointsArthritis of peripheral joints
 AsymmetricAsymmetric
 ~30% of patients~30% of patients
 Neck pain and stiffness (cervical spine)Neck pain and stiffness (cervical spine)
 relatively late manifestationsrelatively late manifestations

19. Cervical flexion deformity in ASCervical flexion deformity in AS
• The severity of cervical
flexion deformity in
ankylosing spondylitis can be
assessed by measuring the
occiput to wall distance
(Flesche test)

20. CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS
cont..cont..
 Most specific findingsMost specific findings
 Loss of spinal mobilityLoss of spinal mobility
 Limitation of anterior and lateral flexion and extension of the lumbar spineLimitation of anterior and lateral flexion and extension of the lumbar spine
 Limitation of chest expansionLimitation of chest expansion
 Limitation of motion is usually out of proportion to the degreeLimitation of motion is usually out of proportion to the degree
of bony ankylosisof bony ankylosis
 muscle spasm secondary to pain and inflammationmuscle spasm secondary to pain and inflammation
 Pain in the sacroiliac jointsPain in the sacroiliac joints
 direct pressure or with stress on the jointsdirect pressure or with stress on the joints
 Modified Schober test is a useful measure of lumbar spineModified Schober test is a useful measure of lumbar spine
flexionflexion
 Lateral bending testLateral bending test

21. Testing for low back flexion (SchoberTesting for low back flexion (Schober
test)test)

22. CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS
cont..cont..
 In a typical severe untreated case withIn a typical severe untreated case with
progression of the spondylitis to syndesmophyteprogression of the spondylitis to syndesmophyte
formationformation
 Posture changes, with obliterated lumbar lordosis,Posture changes, with obliterated lumbar lordosis,
buttock atrophy, and accentuated thoracic kyphosisbuttock atrophy, and accentuated thoracic kyphosis
 Forward stoop of the neck or flexion contractures atForward stoop of the neck or flexion contractures at
the hips, compensated by flexion at the kneesthe hips, compensated by flexion at the knees

23. CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS
cont..cont..
 In women,In women,
 AS tends to progress less frequently to total spinalAS tends to progress less frequently to total spinal
ankylosis,ankylosis,
 Although there may be an increased prevalence ofAlthough there may be an increased prevalence of
 Isolated cervical ankylosisIsolated cervical ankylosis
 Peripheral arthritisPeripheral arthritis

24. ComplicationComplication
 Spinal fractureSpinal fracture
 Lower cervical spine is most commonly involvedLower cervical spine is most commonly involved
 Fracture through a diskovertebral junction andFracture through a diskovertebral junction and
adjacent neural arch (pseudoarthrosis)adjacent neural arch (pseudoarthrosis)
 Most common in the thoraco-lumbar spineMost common in the thoraco-lumbar spine
 Unrecognized source of persistent localized painUnrecognized source of persistent localized pain
and/or neurologic dysfunction.and/or neurologic dysfunction.
 Wedging of thoracic vertebraeWedging of thoracic vertebrae
 Accentuated kyphosis.Accentuated kyphosis.

25. Extraarticular manifestationExtraarticular manifestation
 Acute anterior uveitisAcute anterior uveitis 40%40%
 Inflammation in the colon or ileumInflammation in the colon or ileum 60%60%
 Frank IBDFrank IBD 5–10%5–10%
 psoriasispsoriasis 10%10%
 Aortic insufficiencyAortic insufficiency (early)(early)
 Third-degree heart blockThird-degree heart block
 Subclinical pulmonary lesionsSubclinical pulmonary lesions
 Upper pulmonary lobe fibrosisUpper pulmonary lobe fibrosis (late)(late)
 Cauda equina syndromeCauda equina syndrome (late)(late)
 Retroperitoneal fibrosis, Prostatitis, AmyloidosisRetroperitoneal fibrosis, Prostatitis, Amyloidosis

26. Measures of disease activityMeasures of disease activity
 Bath Ankylosing Spondylitis Disease ActivityBath Ankylosing Spondylitis Disease Activity
Index (BASDAI)Index (BASDAI)
 Ankylosing Spondylitis Disease Activity ScoreAnkylosing Spondylitis Disease Activity Score
(ASDAS)(ASDAS)
 Bath Ankylosing Spondylitis Functional IndexBath Ankylosing Spondylitis Functional Index
(BASFI)(BASFI)
 The Harris hip scoreThe Harris hip score

31. PrognosisPrognosis
 Some but not all studies of survival in AS haveSome but not all studies of survival in AS have
suggested that AS shortens life spansuggested that AS shortens life span
 MortalityMortality
 Spinal traumaSpinal trauma
 Aortic insufficiencyAortic insufficiency
 Respiratory failureRespiratory failure
 Amyloid nephropathyAmyloid nephropathy
 Complications of therapyComplications of therapy
 upper gastrointestinal hemorrhageupper gastrointestinal hemorrhage

32. LABORATORY FINDINGSLABORATORY FINDINGS
 HLAB27HLAB27
 80–90% of patients in some ethnic groups80–90% of patients in some ethnic groups
 ESR and CRPESR and CRP
 often, but not always, elevatedoften, but not always, elevated
 Mild anemiaMild anemia
 Alkaline phosphatase levelAlkaline phosphatase level
 Elevated in severe casesElevated in severe cases
 Serum IgA levelsSerum IgA levels
 ElevatedElevated
 Rheumatoid factor, anti-CCP (cyclic citrullinated peptide), andRheumatoid factor, anti-CCP (cyclic citrullinated peptide), and
ANAs (antinuclear antibodies)ANAs (antinuclear antibodies)
 Largely absentLargely absent

33. LABORATORY FINDINGS cont..LABORATORY FINDINGS cont..
 Circulating levels of CD8+ T cellsCirculating levels of CD8+ T cells
 LowLow
 Serum matrix metalloproteinase 3 levelsSerum matrix metalloproteinase 3 levels
 correlate with disease activitycorrelate with disease activity
 Synovial fluid from peripheral jointsSynovial fluid from peripheral joints
 nonspecifically inflammatorynonspecifically inflammatory
 In cases with restriction of chest wall motionIn cases with restriction of chest wall motion
 decreased vital capacity and increased functional residualdecreased vital capacity and increased functional residual
capacitycapacity
 airflow is normal and ventilatory function is usually wellairflow is normal and ventilatory function is usually well
maintainedmaintained

34. RADIOGRAPHIC FINDINGSRADIOGRAPHIC FINDINGS
 Sacroiliitis, usually symmetricSacroiliitis, usually symmetric
 Blurring of the cortical margins of the subchondralBlurring of the cortical margins of the subchondral
bonebone
 Erosions and sclerosisErosions and sclerosis
 ““pseudowidening” of the joint spacepseudowidening” of the joint space
 As fibrous and then bony ankylosis supervene,As fibrous and then bony ankylosis supervene,
the joints may become obliterated.the joints may become obliterated.

35. RADIOGRAPHIC FINDINGSRADIOGRAPHIC FINDINGS
cont..cont..
 Lumbar spineLumbar spine
 straightening, caused by loss of lordosisstraightening, caused by loss of lordosis
 reactive sclerosis, caused by osteitis of the anteriorreactive sclerosis, caused by osteitis of the anterior
corners of the vertebral bodies with subsequentcorners of the vertebral bodies with subsequent
erosionerosion
 ““squaring” or “barreling” of one or more vertebralsquaring” or “barreling” of one or more vertebral
bodiesbodies
 Progressive ossificationProgressive ossification
 Marginal syndesmophytes (anteriorly and laterally)Marginal syndesmophytes (anteriorly and laterally)

36. Bamboo spine in ASBamboo spine in AS
Ankylosis of the sacroiliac joint in
advanced ankylosing spondylitis with
complete obliteration of the joint space
"bamboo spine" with
vertebral fusion

37. RADIOGRAPHIC FINDINGSRADIOGRAPHIC FINDINGS
cont..cont..
 Active sacroiliitis is best visualized by dynamic MRIActive sacroiliitis is best visualized by dynamic MRI
with fat saturation, eitherwith fat saturation, either
 T2-weighed turbo spin-echo sequence orT2-weighed turbo spin-echo sequence or
 Short tau inversion recovery (STIR) with high resolutionShort tau inversion recovery (STIR) with high resolution
 T1-weighted images with contrast enhancementT1-weighted images with contrast enhancement
 These techniques sensitively identifyThese techniques sensitively identify
 early intraarticular inflammation, cartilage changes, andearly intraarticular inflammation, cartilage changes, and
underlying bone marrow edema in sacroiliitisunderlying bone marrow edema in sacroiliitis
 Reduced bone mineral density can be detected byReduced bone mineral density can be detected by
 dual-energy x-ray absorptiometry of the femoral neck and thedual-energy x-ray absorptiometry of the femoral neck and the
lumbar spine.lumbar spine.

38. MRI (active sacroiliitis)MRI (active sacroiliitis)
Panel A shows the T1 sequence
The bright white areas in STIR, which are not seen in
the T1, are the areas of bone edema (arrows)
Panel B shows the STIR sequence

39. DIAGNOSISDIAGNOSIS
 Modified New York criteria (1984)Modified New York criteria (1984)
 Too insensitive in early or mild casesToo insensitive in early or mild cases
 In 2009, new criteria for axial SpA wereIn 2009, new criteria for axial SpA were
proposed by the “Assessment ofproposed by the “Assessment of
Spondyloarthritis International Society” (ASAS)Spondyloarthritis International Society” (ASAS)

40. Modified New York criteria (1984)Modified New York criteria (1984)

41. ASAS Criteria for Classification of Axial Spondyloarthritis
(Back Pain ≥3 Months and Age of Onset <45 Years) 2009
Sensitivity 83%, specificity 84%.
≥≥4 of the following characteristic features:4 of the following characteristic features:
1.1. Age of onset <40 years oldAge of onset <40 years old
2.2. Insidious onsetInsidious onset
3.3. Improvement with exerciseImprovement with exercise
4.4. No Improvement with restNo Improvement with rest
5.5. Pain at night with improvement upon getting upPain at night with improvement upon getting up
Inflammatory back pain

42. Other causes of back painOther causes of back pain
 Mechanical or degenerativeMechanical or degenerative
 MetabolicMetabolic
 InfectiousInfectious
 Infectious spondylitis, spondylodiskitis, andInfectious spondylitis, spondylodiskitis, and
sacroiliitissacroiliitis
 MalignantMalignant
 Primary or metastatic tumorPrimary or metastatic tumor
 OchronosisOchronosis

43.  Diffuse idiopathic skeletal hyperostosis (DISH)Diffuse idiopathic skeletal hyperostosis (DISH)
 Calcification and ossification of paraspinous ligamentsCalcification and ossification of paraspinous ligaments
 Middle-aged and elderlyMiddle-aged and elderly
 Usually not symptomatic.Usually not symptomatic.
 Ligamentous calcificationLigamentous calcification
 appearance of “flowing wax” on the anterior bodies of the vertebraeappearance of “flowing wax” on the anterior bodies of the vertebrae
 Intervertebral disk spaces are preservedIntervertebral disk spaces are preserved
 (vs spondylosis)(vs spondylosis)
 Sacroiliac and apophyseal joints appear normalSacroiliac and apophyseal joints appear normal
 (vs AS)(vs AS)

44. TREATMENTTREATMENT
 Exercise programExercise program
 to maintain posture and range of motionto maintain posture and range of motion
 Nonsteroidal anti-inflammatory drugs (NSAIDs)Nonsteroidal anti-inflammatory drugs (NSAIDs)
 11stst
line of pharmacologic therapy for ASline of pharmacologic therapy for AS
 Anti-TNF-α therapyAnti-TNF-α therapy
 InfliximabInfliximab
 (chimeric human/mouse anti-TNF-α monoclonal antibody)(chimeric human/mouse anti-TNF-α monoclonal antibody)
 EtanerceptEtanercept
 (soluble p75 TNF-α receptor–IgG fusion protein)(soluble p75 TNF-α receptor–IgG fusion protein)
 Adalimumab, or golimumabAdalimumab, or golimumab
 (human anti-TNF-α monoclonal antibodies)(human anti-TNF-α monoclonal antibodies)
 Certolizumab pegolCertolizumab pegol
 (humanized mouse anti-TNF-α monoclonal antibody)(humanized mouse anti-TNF-α monoclonal antibody)

45. Anti TNF-Anti TNF-αα therapytherapy
 About one-half of the patients achieve a ≥50% reduction in theAbout one-half of the patients achieve a ≥50% reduction in the
BASDAI.BASDAI.
 The response tends to be stable over time, and partial or fullThe response tends to be stable over time, and partial or full
remissions are commonremissions are common
 Predictors of the best responses includePredictors of the best responses include
 younger age,younger age,
 shorter disease duration,shorter disease duration,
 higher baseline inflammatory markers, andhigher baseline inflammatory markers, and
 lower baseline functional disability.lower baseline functional disability.
 Nonetheless, some patients with long-standing disease and evenNonetheless, some patients with long-standing disease and even
spinal ankylosis can obtain significant benefitspinal ankylosis can obtain significant benefit
 Increased bone mineral density is found as early as 24 weeksIncreased bone mineral density is found as early as 24 weeks
after onset of therapy.after onset of therapy.

46. Anti TNF-Anti TNF-αα therapytherapy
 There is evidence that anti-TNF therapy does notThere is evidence that anti-TNF therapy does not
prevent syndesmophyte formation, although this mayprevent syndesmophyte formation, although this may
apply mainly during the early years of therapy.apply mainly during the early years of therapy.
 A mechanism for this has been proposed based on theA mechanism for this has been proposed based on the
observation that TNF-α inhibits new bone formationobservation that TNF-α inhibits new bone formation
by upregulating DKK-1, a negative regulator of theby upregulating DKK-1, a negative regulator of the
wingless (Wnt) signaling pathway that promoteswingless (Wnt) signaling pathway that promotes
osteoblast activityosteoblast activity
 Serum DKK-1 levels are inappropriately low in ASSerum DKK-1 levels are inappropriately low in AS
patients and are also suppressed by anti-TNF therapy.patients and are also suppressed by anti-TNF therapy.

47. Anti TNF-Anti TNF-αα therapytherapy
 Infliximab is given intravenously, 3–5 mg/kg bodyInfliximab is given intravenously, 3–5 mg/kg body
weight, and then repeated 2 weeks later, again 6 weeksweight, and then repeated 2 weeks later, again 6 weeks
later, and then at 8-week intervals.later, and then at 8-week intervals.
 Etanercept is given by subcutaneous injection, 50 mgEtanercept is given by subcutaneous injection, 50 mg
once weekly.once weekly.
 Adalimumab is given by subcutaneous injection, 40 mgAdalimumab is given by subcutaneous injection, 40 mg
biweekly.biweekly.
 Golimumab is given by subcutaneous injection, 50 orGolimumab is given by subcutaneous injection, 50 or
100 mg every 4 weeks.100 mg every 4 weeks.
 Certolizumab pegol is given by subcutaneous injection,Certolizumab pegol is given by subcutaneous injection,
400 mg every 4 weeks..400 mg every 4 weeks..

48. Side effects of Anti TNF-Side effects of Anti TNF-αα therapytherapy
 Disseminated tuberculosisDisseminated tuberculosis
 Hypersensitivity infusion or injection site reactionsHypersensitivity infusion or injection site reactions
 Anti-TNF-induced psoriasisAnti-TNF-induced psoriasis
 Systemic lupus erythematosus–related diseaseSystemic lupus erythematosus–related disease
 Hematologic disorders such as pancytopeniaHematologic disorders such as pancytopenia
 Demyelinating disordersDemyelinating disorders
 Exacerbation of congestive heart failure, andExacerbation of congestive heart failure, and
 Severe liver diseaseSevere liver disease
 Isolated cases of hematologic malignancyIsolated cases of hematologic malignancy

49. Anti TNF-Anti TNF-αα therapy -Indicationtherapy -Indication
 Because of the expense, potentially serious side effects,Because of the expense, potentially serious side effects,
and unknown long-term effects of these agents, theirand unknown long-term effects of these agents, their
use should be restricted touse should be restricted to
 patients with a definite diagnosis and active disease (BASDAIpatients with a definite diagnosis and active disease (BASDAI
≥4 out of 10 and expert opinion) that is inadequately≥4 out of 10 and expert opinion) that is inadequately
responsive to therapy with at least two different NSAIDs.responsive to therapy with at least two different NSAIDs.
 Before initiation of anti-TNF therapy, all patientsBefore initiation of anti-TNF therapy, all patients
should be tested for tuberculin (TB) reactivityshould be tested for tuberculin (TB) reactivity
 Reactors (≥5 mm on PPD testing or a positive quantiferonReactors (≥5 mm on PPD testing or a positive quantiferon
test)test)
 should be treated with anti-TB agents.should be treated with anti-TB agents.

50. Anti TNF-Anti TNF-αα therapy - CItherapy - CI
 Active infection or high risk of infectionActive infection or high risk of infection
 Malignancy or premalignancyMalignancy or premalignancy
 History of systemic lupus erythematosus,History of systemic lupus erythematosus,
multiple sclerosis, or related autoimmunity.multiple sclerosis, or related autoimmunity.
 Pregnancy and breast-feeding are relativePregnancy and breast-feeding are relative
contraindicationscontraindications

51. How long ?How long ?
 Continuation beyond 12 weeks of therapyContinuation beyond 12 weeks of therapy
requiresrequires
 either a 50% reduction in BASDAI oreither a 50% reduction in BASDAI or
 absolute reduction of ≥2 out of 10, andabsolute reduction of ≥2 out of 10, and
 favorable expert opinionfavorable expert opinion
 Switching to a second anti-TNF agent may beSwitching to a second anti-TNF agent may be
effectiveeffective
 especially if there was a response to the first that wasespecially if there was a response to the first that was
lost rather than primary failure.lost rather than primary failure.

52. Other drugs ?Other drugs ?
 SulfasalazineSulfasalazine
 2–3 g/d2–3 g/d
 Modest benefitModest benefit
 Primarily for peripheral arthritisPrimarily for peripheral arthritis
 A therapeutic trial of this agent should precedeA therapeutic trial of this agent should precede
any use of anti-TNF agents in patients withany use of anti-TNF agents in patients with
predominantly peripheral arthritispredominantly peripheral arthritis

53. Other drugs ?Other drugs ?
 Methotrexate, gold or oral glucocorticoidsMethotrexate, gold or oral glucocorticoids
 No any therapeutic role in ASNo any therapeutic role in AS
 ThalidomideThalidomide
 200 mg/d200 mg/d
 Potential benefit in AS reportedPotential benefit in AS reported
 Perhaps acting through inhibition of TNF-α.Perhaps acting through inhibition of TNF-α.

54. Other drugs ?Other drugs ?
 Uste-kinumab (anti-IL-12/23)Uste-kinumab (anti-IL-12/23)
 Secu-kinumab (anti-IL-17)Secu-kinumab (anti-IL-17)
(monoclonal antibodies)(monoclonal antibodies)
 have shown promising efficacy in clinical trialshave shown promising efficacy in clinical trials
 not yet been approved for use in ASnot yet been approved for use in AS

55. Surgery in ASSurgery in AS
 Total hip arthroplastyTotal hip arthroplasty
 Severe hip joint arthritisSevere hip joint arthritis
 Surgical correction ofSurgical correction of
 Extreme flexion deformities of the spineExtreme flexion deformities of the spine
 Atlantoaxial subluxationAtlantoaxial subluxation

56. Attacks of uveitis in ASAttacks of uveitis in AS
 Local glucocorticoid+mydriatic agentsLocal glucocorticoid+mydriatic agents
 Although systemic glucocorticoids, immunosuppressiveAlthough systemic glucocorticoids, immunosuppressive
drugs or anti-TNF therapy may be requireddrugs or anti-TNF therapy may be required
 TNF inhibitorsTNF inhibitors
 Reduce the frequency of attacks of uveitis in patients with ASReduce the frequency of attacks of uveitis in patients with AS
 Although cases of new or recurrent uveitis after use of a TNFAlthough cases of new or recurrent uveitis after use of a TNF
inhibitor have been observed, especially with etanercept.inhibitor have been observed, especially with etanercept.

57.  Coexistent cardiac diseaseCoexistent cardiac disease
 Pacemaker implantation and/or aortic valvePacemaker implantation and/or aortic valve
replacementreplacement
 Management of axial osteoporosisManagement of axial osteoporosis
 similar to that used for primary osteoporosissimilar to that used for primary osteoporosis

58. THANK YOUTHANK YOU
ReferencesReferences
 Harrison's Principles of Internal Medicine (19thHarrison's Principles of Internal Medicine (19th
Ed)Ed)
 Uptodate 2013Uptodate 2013