Ankylosing SpondylitisAnkylosing SpondylitisJohn K. John K. BotsonBotson, MD, , MD, RPhRPh, CCD, CCD

October 9, 2014October 9, 2014

DisclosuresDisclosuresDisclosuresDisclosuresDisclosuresDisclosuresDisclosuresDisclosures

•• No financial relationships to disclose No financial relationships to disclose

ObjectivesObjectivesObjectivesObjectivesObjectivesObjectivesObjectivesObjectives•• Understand the definition of ankylosing Understand the definition of ankylosing

d liti f thd liti f th titispondylitis as one of the spondylitis as one of the seronegativeseronegativespondyloarthropathiesspondyloarthropathies..L h th di i f k l iL h th di i f k l i•• Learn how the diagnosis of ankylosing Learn how the diagnosis of ankylosing spondylitis is made.spondylitis is made.L t t t tiL t t t ti•• Learn treatment options.Learn treatment options.

•• Understand the longUnderstand the long--term outcome of term outcome of treated and untreated disease.treated and untreated disease.

SpondyloarthopathiesSpondyloarthopathies ((SpAsSpAs))SpondyloarthopathiesSpondyloarthopathies ((SpAsSpAs))•• Definition: group of inflammatory arthropathies Definition: group of inflammatory arthropathies g p y pg p y p

that share distinctive clinical, radiographic, and that share distinctive clinical, radiographic, and genetic features and include:genetic features and include:

Ankylosing spondylitis (AS)Ankylosing spondylitis (AS)–– Ankylosing spondylitis (AS)Ankylosing spondylitis (AS)–– Reactive arthritis (Reactive arthritis (ReAReA, Reiter’s syndrome), Reiter’s syndrome)–– Psoriatic arthritisPsoriatic arthritisso at c a t t sso at c a t t s–– EnteropathicEnteropathic arthritis (Crohn’s, ulcerative arthritis (Crohn’s, ulcerative

colitis) colitis)

Khan MA. Khan MA. Ann Intern Med.Ann Intern Med. 2002;136:8962002;136:896--907.907.

SpondyloarthopathiesSpondyloarthopathies ((SpAsSpAs))SpondyloarthopathiesSpondyloarthopathies ((SpAsSpAs))•• Patients not fulfilling individual criteria but Patients not fulfilling individual criteria but gg

possessing overlapping features may be possessing overlapping features may be classified as having undifferentiated classified as having undifferentiated SpASpA((uSpAuSpA).).((uSpAuSpA).).

•• Prevalence of all Prevalence of all SpAsSpAs ~1% to 2%, similar to ~1% to 2%, similar to rheumatoid arthritis (RA ).rheumatoid arthritis (RA ).

•• Associated with presence of HLAAssociated with presence of HLA--B27.B27.

Khan MA. Khan MA. Ann Intern Med.Ann Intern Med. 2002;136:8962002;136:896--907.907.

HLAHLA B27B27HLAHLA B27B27HLA HLA -- B27B27HLA HLA -- B27B27

•• Human Leukocyte AntigenHuman Leukocyte AntigenHuman Leukocyte Antigen.Human Leukocyte Antigen.•• MHC class I MHC class I -- participates in antigen participates in antigen

presentation.presentation.•• Genetic marker with disease association.Genetic marker with disease association.•• >90 % of patient with ankylosing spondylitis.>90 % of patient with ankylosing spondylitis.•• 5050--75% of patients with other 75% of patients with other

spondyloarthropathiesspondyloarthropathies..•• Present in 5Present in 5--15% of general population15% of general populationPresent in 5Present in 5 15% of general population.15% of general population.••

SpondyloarthropathiesSpondyloarthropathies: : SeronegativeSeronegativeinflammatory back arthritisinflammatory back arthritis

SpondyloarthropathiesSpondyloarthropathies: : SeronegativeSeronegativeinflammatory back arthritisinflammatory back arthritisinflammatory back arthritisinflammatory back arthritisinflammatory back arthritisinflammatory back arthritis

FEATUREFEATURE SERONEGATIVESERONEGATIVE SEROPOSITIVESEROPOSITIVEPeripheral ArthritisPeripheral Arthritis Usually asymmetric Usually asymmetric

Large jointsLarge jointsLower extremityLower extremity

Usually symmetricUsually symmetricSmall and medium sized jointsSmall and medium sized jointsUpper and lower extremitiesUpper and lower extremities

Axial InvolvementAxial Involvement SI jointsSI jointsApophysealApophyseal joints of the spinejoints of the spine

Almost neverAlmost neverRarely Rarely

Enthesitis Enthesitis (tendon insertion)(tendon insertion) CommonCommon UncommonUncommon

PeriostitisPeriostitis CommonCommon UncommonUncommon

TendinitisTendinitis Achilles, plantar fasciaAchilles, plantar fascia Finger tendonsFinger tendons

Rheumatoid nodulesRheumatoid nodules NeverNever OftenOften

IritisIritis CommonCommon UncommonUncommon

Aortic root dilitationAortic root dilitation CommonCommon UncommonUncommon

Scaly skin rashScaly skin rash CommonCommon UnusualUnusualScaly skin rashScaly skin rash CommonCommon UnusualUnusual

Bowel inflammation Bowel inflammation CommonCommon UnusualUnusual

UretheritisUretheritis CommonCommon UnusualUnusual

SpondyloarthropathiesSpondyloarthropathies::SpondyloarthropathiesSpondyloarthropathies::p y pp y pDifferentiating Inflammatory vs. Differentiating Inflammatory vs.

Mechanical Back PainMechanical Back Pain

p y pp y pDifferentiating Inflammatory vs. Differentiating Inflammatory vs.

Mechanical Back PainMechanical Back Pain

Features Inflammatory Back Pain

Mechanical Back Pain

AM Stiffness Usually prolonged >60 min.

Minor

SpAsSpAs: Axial Features: Axial Features

•• SpineSpine inflammation stiffening andinflammation stiffening and ankylosisankylosis

SpAsSpAs: Axial Features: Axial Features

•• Spine Spine –– inflammation, stiffening, and inflammation, stiffening, and ankylosisankylosis–– CervicalCervical–– ThoracicThoracic–– LumbarLumbar

•• SI joints SI joints –– sacroiliitis and fusionsacroiliitis and fusion•• Hips Hips –– synovitis and cartilage degenerationsynovitis and cartilage degeneration

SpAsSpAs: Extra: Extra axial Featuresaxial Features

•• CutaneousCutaneous keratodermakeratoderma blennorrhagicumblennorrhagicum andand

SpAsSpAs: Extra: Extra--axial Featuresaxial Features

•• CutaneousCutaneous——keratodermakeratoderma blennorrhagicumblennorrhagicum and and psoriasis or nail lesions (psoriasis or nail lesions (onycholysisonycholysis, dystrophy, , dystrophy, pitting) pitting)

•• PeriarticularPeriarticular——dactylitisdactylitis, , enthesitisenthesitis, tendonitis, tendonitis•• OcularOcular——uveitis, conjunctivitisuveitis, conjunctivitis

G t i t ti lG t i t ti l•• Gastrointestinal Gastrointestinal –– Painless oral ulcerations Painless oral ulcerations –– Asymptomatic gut inflammationAsymptomatic gut inflammationAsymptomatic gut inflammation Asymptomatic gut inflammation –– Symptomatic colitisSymptomatic colitis

•• GenitourinaryGenitourinary——urethritis, vaginitis, balanitisurethritis, vaginitis, balanitis•• CardiacCardiac——aortitisaortitis, , valvularvalvular insufficiency, heart blockinsufficiency, heart block

FeatureFeature Ankylosing Ankylosing SpondylitisSpondylitis

PsoriaticPsoriatic Reactive ArthritisReactive Arthritis IBD associatedIBD associated

Gender (M:F)Gender (M:F) 9:19:1 1:11:1 8:18:1 1:11:1

Age of onsetAge of onset 20s20s 3535--45 yrs45 yrs 20s20s Any ageAny age

Peripheral ArthritisPeripheral Arthritis 25%25% 96%96% 90%90% CommonCommon

DistributionDistribution Axial, lower Axial, lower limbslimbs

Any jointAny joint Lower limbsLower limbs Lower limbsLower limbslimbslimbs

DactylitisDactylitis UncomonUncomon 35%35% CommonCommon UncommonUncommon

EnthesitisEnthesitis CommonCommon CommonCommon CommonCommon Less CommonLess Common

SacroiliitisSacroiliitis 100%100% 40%40% 80%80% 20%20%SacroiliitisSacroiliitis 100%100% 40%40% 80%80% 20%20%

Skin LesionsSkin Lesions RareRare 100%100% CommonCommon OccasionalOccasional

Type of skin lesionsType of skin lesions Nil specificNil specific Psoriasis vulgarisPsoriasis vulgarisPsoriasis Psoriasis guttateguttate

KeratodermiaKeratodermiaBlenorrhagica,Blenorrhagica,

PyodermaPyoderma grangrenosumgrangrenosum,,E. E. NodosumNodosum

Nail lesionsNail lesions Circinate balanitisCircinate balanitisNail changesNail changes

Mucous membranesMucous membranes UncommonUncommon UncommonUncommon CommonCommon UncommonUncommon

ConjunctivitisConjunctivitis RareRare OccasionalOccasional CommonCommon RareRareConjunctivitisConjunctivitis RareRare OccasionalOccasional CommonCommon RareRare

UveitisUveitis OccasionalOccasional OccasionalOccasional CommonCommon OccasionalOccasional

UrethritisUrethritis RareRare OccasionalOccasional CommonCommon RareRare

AorticAortic OccasionalOccasional RareRare OccasionalOccasional Occasional regurgitationOccasional regurgitationAorticAortic OccasionalOccasional RareRare OccasionalOccasional Occasional regurgitationOccasional regurgitation

Familial AggregationFamilial Aggregation CommonCommon CommonCommon CommonCommon CommonCommon

HLAHLA--B27B27 90%90% 40%40% 80%80% 30%30%

Etiology FactorsEtiology FactorsEtiology FactorsEtiology Factors•• Interplay between genetic, environmental, and Interplay between genetic, environmental, and

immunological immunological factors.factors.

•• Increase in HLA Increase in HLA B27:B27:–– Concordance rate of 67% for monozygotic twins, 23% Concordance rate of 67% for monozygotic twins, 23%

for dizygoticfor dizygotic twinstwinsfor dizygotic for dizygotic twins.twins.–– Molecular mimicry theory based on similarity Molecular mimicry theory based on similarity

between bacterial epitopes and HLA between bacterial epitopes and HLA B27.B27.–– ArthritogenicArthritogenic peptidespeptides preferentially presentedpreferentially presentedArthritogenicArthritogenic peptides peptides preferentially presented.preferentially presented.

•• Oxidation of cysteine 67 in Oxidation of cysteine 67 in recognition pocket.recognition pocket.–– Free B27 heavy chains bind as Free B27 heavy chains bind as homodimerhomodimer to activate to activate

CD4CD4+.+.

•• Chromosome 4 and chromosome 14 may also be Chromosome 4 and chromosome 14 may also be important.important.

Prevalence of Prevalence of SpAsSpAs Varies With Varies With Geographic RegionGeographic Region

Prevalence of Prevalence of SpAsSpAs Varies With Varies With Geographic RegionGeographic RegionGeographic RegionGeographic RegionGeographic RegionGeographic Region

S AS A HLAHLA B27B27SpASpA HLAHLA--B27B27•• Japan (total population)Japan (total population) 0.0095%0.0095% 20.0%

Hukuda S, et al. Hukuda S, et al. J Rheumatol.J Rheumatol. 2001;28:5542001;28:554--559.559.Khan MA. Khan MA. Curr Opin Rheumatol.Curr Opin Rheumatol. 1995;7:2631995;7:263--269.269.Khan MA. Khan MA. Ann Intern Med.Ann Intern Med. 2002;136:8962002;136:896--907.907.

Ankylosing SpondylitisAnkylosing SpondylitisAnkylosing SpondylitisAnkylosing Spondylitisy g p yy g p yy g p yy g p y•• Men: women affected 9:1Men: women affected 9:1•• Usually axial disease, including shoulder, Usually axial disease, including shoulder, hips.hips.•• Inflammatory back Inflammatory back pain at night (awaken 2AM to 5AMpain at night (awaken 2AM to 5AM).).•• Peripheral Peripheral arthritis usually occurs late in the illness:arthritis usually occurs late in the illness:

–– Early is a predictor of progressionEarly is a predictor of progression–– Usually Usually asymmetric asymmetric in LEin LE

•• EnthesitisEnthesitis, arthritis is , arthritis is aggravated aggravated by rest and improved with by rest and improved with activity.activity.

•• ExtraExtra--articulararticular::–– IritisIritis, particularly , particularly acute anterior acute anterior uveitis (20uveitis (20--30 % of patients)30 % of patients)–– Cardiac manifestations, including Cardiac manifestations, including dilatation of aortic dilatation of aortic root and root and

conductionconduction deficitsdeficitsconduction conduction deficitsdeficits–– AApical pical fibrosis of the fibrosis of the lungslungs–– AmyloidosisAmyloidosis–– AAspergillomaspergilloma

C dC d ii dd–– CaudaCauda equinaequina syndromesyndrome

Ankylosing Spondylitis in USAnkylosing Spondylitis in USAnkylosing Spondylitis in USAnkylosing Spondylitis in USAnkylosing Spondylitis in USAnkylosing Spondylitis in USAnkylosing Spondylitis in USAnkylosing Spondylitis in US

AS325,000

Diagnosed and treated146,000

Undiagnosed/untreated179,000

Mild disease Moderate disease Severe disease FusedMild disease55,000

Moderate disease44,000

Severe disease25,000

Fused23,000

Amgen Inc. Data on file. 2003.Amgen Inc. Data on file. 2003.

Age at Onset and Diagnosis of ASAge at Onset and Diagnosis of ASAge at Onset and Diagnosis of ASAge at Onset and Diagnosis of ASAge at Onset and Diagnosis of ASAge at Onset and Diagnosis of ASAge at Onset and Diagnosis of ASAge at Onset and Diagnosis of AS

Symptom Onset Symptom Onset DiagnosisDiagnosis

GermanyGermany(N 1486)(N 1486)

28.5 years 28.5 years 33.7 years*33.7 years*(N=1486)(N=1486)

yy

E (t iE (t i ti )ti ) 22 722 7 31 931 9Europe (triEurope (tri--nation)nation)(N=210)(N=210)

22.7 years22.7 years 31.9 years31.9 years

*Age when first seen by rheumatologist.*Age when first seen by rheumatologist.

Zink A, et al. Zink A, et al. Ann Rheum Dis. Ann Rheum Dis. 2001;60:1992001;60:199--206. 206. Boonen ABoonen A, , et al.et al. Ann Rheum Dis. Ann Rheum Dis. 2002;61:4292002;61:429--437.437.

HLAHLA B27 d Di E iB27 d Di E iHLAHLA--B27 and Disease ExpressionB27 and Disease Expression

HLAHLA B27+ individuals more likely to have earlierB27+ individuals more likely to have earlier•• HLAHLA--B27+ individuals more likely to have earlier B27+ individuals more likely to have earlier onset, sacroiliitis, spondylitis, acute anterior onset, sacroiliitis, spondylitis, acute anterior uveitis, and more severe clinical course.uveitis, and more severe clinical course.

•• HLAHLA--B27B27-- patients more likely to develop patients more likely to develop peripheral arthritis, skin and nail disease, or peripheral arthritis, skin and nail disease, or inflammatory bowel diseaseinflammatory bowel diseaseinflammatory bowel disease.inflammatory bowel disease.

•• Thus, HLAThus, HLA--B27+ increases risk of spondylitis and B27+ increases risk of spondylitis and uveitis.uveitis.

Cush JJ, Lipsky PE. In: Bennett JC, et al, eds. Cush JJ, Lipsky PE. In: Bennett JC, et al, eds. Cecil Textbook of Internal Cecil Textbook of Internal Medicine. Medicine. 20th ed20th ed. . Philadelphia, Pa: WB Saunders, 1996:1466Philadelphia, Pa: WB Saunders, 1996:1466--1472. 1472.

NY Criteria 1968 Modified NY Criteria 1984

ASAS 2009(Assessment of SpondyloarthritisInternational Society)

Clinical:1. Limitation of LS motion in all

planes2. Pain in the thoracolumbar

junction or the lumbar spine

Clinical:1. Low back pain of at least 3

months duration improved by exercise and not relieved by rest

Back pain >3 months andAge of onset

AS & ASAS Classification CriteriaAS & ASAS Classification Criteria5

•• AS CriteriaAS Criteria11

5

–– Modified New York CriteriaModified New York Criteria11•• Relies mainly on detection of radiologic sacroiliitis.Relies mainly on detection of radiologic sacroiliitis.

•• ASAS CriteriaASAS Criteria–– Assessment of Assessment of SpondyloArthritisSpondyloArthritis International International

SocietySocietySocietySociety•• Allows classification BEFORE radiographic changes occur.Allows classification BEFORE radiographic changes occur.

1. van der Linden S, et al. Arthritis Rheum. 1984;27:361-368.

Radiologic Changes in ASRadiologic Changes in ASRadiologic Changes in ASRadiologic Changes in AS•• SI joints commonly initial sites of inflammationSI joints commonly initial sites of inflammation

–– NY criteria:NY criteria:•• Grade 1: suspiciousGrade 1: suspicious•• Grade 1: suspiciousGrade 1: suspicious•• Grade 2: erosions and sclerosisGrade 2: erosions and sclerosis•• Grade 3: erosions, sclerosis, Grade 3: erosions, sclerosis, ankylosisankylosis•• Grade 4: total Grade 4: total ankylosisankylosis

•• Thoracolumbar junction with subsequent caudal and distal Thoracolumbar junction with subsequent caudal and distal progression.progression.

•• Squaring of vertebra is followed by development of Squaring of vertebra is followed by development of syndesmophytessyndesmophytes..

•• Total Total ankylosisankylosis occurs with ossification of the longitudinal occurs with ossification of the longitudinal ligaments.ligaments.yy gg gg

•• EnthesitisEnthesitis can be detected as spurs at the insertion of plantar can be detected as spurs at the insertion of plantar fascia.fascia.

Bony Progression in ASBony Progression in ASBony Progression in ASBony Progression in AS

http://www.nature.comhttp://www.nature.com

AnkylosingAnkylosing SpondylitisSpondylitisAnkylosingAnkylosing SpondylitisSpondylitisAnkylosingAnkylosing SpondylitisSpondylitisDisease ProgressionDisease Progression

AnkylosingAnkylosing SpondylitisSpondylitisDisease ProgressionDisease Progression

PrognosisPrognosisPrognosisPrognosisgggg•• First symptoms generally occur in the First symptoms generally occur in the

early 30’s (average age 26)early 30’s (average age 26)early 30 s (average age 26).early 30 s (average age 26).•• Rare to present after age 40.Rare to present after age 40.

D f itiD f iti d di bilit ithi thd di bilit ithi th•• Deformities Deformities and disability occur within the and disability occur within the first 10 first 10 years.years.

•• Work disability is associated with olderWork disability is associated with older•• Work disability is associated with older Work disability is associated with older age, longer disease, coage, longer disease, co--morbidity, severe morbidity, severe functional functional disability.disability.yy

•• Survival is reduced by RR Survival is reduced by RR 1.93 vs non1.93 vs non--affected population.affected population.

Treatment in ASTreatment in ASTreatment in ASTreatment in AS

•• Physical therapyPhysical therapy•• Regular Regular exercise programexercise program•• Patient educationPatient education•• Pharmacological treatmentPharmacological treatment

NonNon--pharmacologic Treatmentpharmacologic TreatmentNonNon--pharmacologic Treatmentpharmacologic Treatment•• Hospital vs home program.Hospital vs home program.•• Spa therapySpa therapy•• Spa therapy.Spa therapy.•• Group physical therapy.Group physical therapy.

–– Advantage cost savings.Advantage cost savings.•• Individualized exercise programIndividualized exercise program--important.important.•• Sleeping in a straight position with thin pillow Sleeping in a straight position with thin pillow

preferredpreferredpreferred.preferred.•• Avoid:Avoid:

–– Prolonged immobilityProlonged immobility–– Poor posturePoor posture–– SmokingSmoking–– Excessive spinal manipulationExcessive spinal manipulationp pp p

Nonsteroidal Nonsteroidal AntiinflammatoryAntiinflammatoryDrugs (NSAIDs)Drugs (NSAIDs) in ASin ASDrugs (NSAIDs) Drugs (NSAIDs) in ASin AS

•• NSAIDs are firstNSAIDs are first--line treatment for ASline treatment for ASDi l f t i t d i iDi l f t i t d i i–– Diclofenac, enteric coated aspirin, Diclofenac, enteric coated aspirin, indomethacin, naproxen, indomethacin, naproxen, phenylbutazonephenylbutazone, , sulindacsulindac, and , and celecoxibcelecoxib. .

•• Relieve back pain and stiffness.Relieve back pain and stiffness.•• Rapid response (48 hours) has been included in Rapid response (48 hours) has been included in

classification criteriaclassification criteriaclassification criteria.classification criteria.•• As the disease progresses, these drugs may be As the disease progresses, these drugs may be

less effective.less effective.•• Some evidence that Some evidence that NSAIDs (CoxNSAIDs (Cox--2) inhibit 2) inhibit

disease progression.disease progression.

GlucocorticoidsGlucocorticoids in ASin ASGlucocorticoids Glucocorticoids in ASin AS•• Oral glucocorticoids limited efficacy.Oral glucocorticoids limited efficacy.

A i l d i h l j i t i d iA i l d i h l j i t i d i–– Axial and peripheral joint pain may respond in Axial and peripheral joint pain may respond in short term, however longshort term, however long--term use with term use with significant side effects.significant side effects.

•• Local glucocorticoid injections of joints and Local glucocorticoid injections of joints and enthesesentheses may be helpful temporarily.may be helpful temporarily.

–– Particularly into SI joints.Particularly into SI joints.Particularly into SI joints.Particularly into SI joints.•• Topical glucocorticoids for acute anterior uveitis Topical glucocorticoids for acute anterior uveitis

is effective.is effective.

Traditional DMARDs in theTraditional DMARDs in theTraditional DMARDs in theTraditional DMARDs in theTraditional DMARDs in the Traditional DMARDs in the Treatment of Treatment of SpASpA

Traditional DMARDs in the Traditional DMARDs in the Treatment of Treatment of SpASpA

•• DiseaseDisease--modifying modifying antirheumaticantirheumatic drugs drugs (DMARDs) are sometimes used in (DMARDs) are sometimes used in SpAsSpAs when when NSAIDs are inadequate.NSAIDs are inadequate.

•• Recommendations to fail 2 NSAIDs.Recommendations to fail 2 NSAIDs.•• None of the DMARDs are FDA approved for None of the DMARDs are FDA approved for

the the SpAsSpAs..•• Few controlled clinical trials address the use Few controlled clinical trials address the use

of traditional DMARDs in of traditional DMARDs in SpAsSpAs..

Sulfasalazine in ASSulfasalazine in ASSulfasalazine in ASSulfasalazine in ASSulfasalazine in ASSulfasalazine in ASSulfasalazine in ASSulfasalazine in AS

Ankylosing SpondylitisAnkylosing Spondylitis•• Ankylosing SpondylitisAnkylosing Spondylitis–– 264 pts/placebo/36weeks/SSZ 2000mg/d264 pts/placebo/36weeks/SSZ 2000mg/d

N li i l i t/d d ESRN li i l i t/d d ESR–– No clinical improvement/decreased ESRNo clinical improvement/decreased ESR–– Trend for SSZ in peripheral arthritisTrend for SSZ in peripheral arthritis

Mi i l t i itMi i l t i it–– Minimal toxicityMinimal toxicity

Sulfasalazine inSulfasalazine in SpAsSpAsSulfasalazine inSulfasalazine in SpAsSpAsSulfasalazine in Sulfasalazine in SpAsSpAsSulfasalazine in Sulfasalazine in SpAsSpAs

•• 619 patients (AS psoriatic arthritis and619 patients (AS psoriatic arthritis and ReAReA))•• 619 patients (AS, psoriatic arthritis, and 619 patients (AS, psoriatic arthritis, and ReAReA))–– Axial disease (n=187) Axial disease (n=187) –– Peripheral articular (n=432)Peripheral articular (n=432)–– Placebo or 2 g/day sulfasalazinePlacebo or 2 g/day sulfasalazine–– 36 weeks36 weeks

A i lA i l lf l ilf l i•• AxialAxial——no sulfasalazine responseno sulfasalazine response•• PeripheralPeripheral——sulfasalazine response (sulfasalazine response (PP=0.0007)=0.0007)•• Conclude sulfasalazine effective for peripheralConclude sulfasalazine effective for peripheral•• Conclude sulfasalazine effective for peripheral Conclude sulfasalazine effective for peripheral

arthritis of arthritis of SpAsSpAs

Clegg DO, et al. Clegg DO, et al. Arthritis Rheum.Arthritis Rheum. 1999;42:23251999;42:2325--2329.2329.

Methotrexate (MTX) in ASMethotrexate (MTX) in ASMethotrexate (MTX) in ASMethotrexate (MTX) in ASMethotrexate (MTX) in ASMethotrexate (MTX) in ASMethotrexate (MTX) in ASMethotrexate (MTX) in AS

•• ASAS11•• ASAS–– 51 patients, 7.5 mg/week for 12 months, placebo 51 patients, 7.5 mg/week for 12 months, placebo

controlledcontrolled–– Negative results/improved peripheral joints (?)Negative results/improved peripheral joints (?)Negative results/improved peripheral joints (?)Negative results/improved peripheral joints (?)

•• ASAS22–– 31 patients, 7.5 mg/week for 6 months, placebo 31 patients, 7.5 mg/week for 6 months, placebo

controlledcontrolledcontrolledcontrolled–– Significantly more patients had good response with Significantly more patients had good response with

MTX than placebo (53% vs 13%, MTX than placebo (53% vs 13%, PP=0.019)=0.019)

11Altan L, et al. Altan L, et al. ScandScand J J RheumatolRheumatol.. 2001;30:2552001;30:255--259.259.22GonzalezGonzalez--Lopez L, et al. Lopez L, et al. Arthritis Rheum. 2002;Arthritis Rheum. 2002;46(46(supplsuppl). Abstract 1134.). Abstract 1134.

Oral Gold in ASOral Gold in ASOral Gold in ASOral Gold in ASOral Gold in ASOral Gold in ASOral Gold in ASOral Gold in AS

•• AuranofinAuranofin•• AuranofinAuranofin•• 238 patients238 patients

–– 6 mg/day6 mg/day–– 6 mg/day 6 mg/day –– 6 months, placebo controlled6 months, placebo controlled

•• Improvements in physician global and dailyImprovements in physician global and dailyImprovements in physician global and daily Improvements in physician global and daily function scores.function scores.

•• No effect on axial skeleton.No effect on axial skeleton.•• 10% withdrawal due to adverse effects or toxicity.10% withdrawal due to adverse effects or toxicity.

Grasedyck K, et al. Grasedyck K, et al. Z Rheumatol.Z Rheumatol. 1990;49:981990;49:98--99.99.

PamidronatePamidronate in ASin ASPamidronatePamidronate in ASin ASPamidronatePamidronate in ASin ASPamidronatePamidronate in ASin AS

Bi h h t bBi h h t b ti i hibitti i hibit•• Bisphosphonate boneBisphosphonate bone--resorption inhibitor.resorption inhibitor.•• 84 AS patients with active disease refractory to 84 AS patients with active disease refractory to

NSAIDs.NSAIDs.–– Randomized, doubleRandomized, double--blinded assignment.blinded assignment.–– Infusions of 60 mg vs 10 mg Infusions of 60 mg vs 10 mg pamidronatepamidronate/month /month

for 6 monthsfor 6 monthsfor 6 months.for 6 months.•• Significant improvement in axial symptoms in the Significant improvement in axial symptoms in the

6060--mg group vs 10mg group vs 10--mg group.mg group.•• No significant difference in joint pain or CNo significant difference in joint pain or C--reactive reactive

protein (CRP)/erythrocyte sedimentation rate (ESR)protein (CRP)/erythrocyte sedimentation rate (ESR)Well tolerated lo ithdra al rateWell tolerated lo ithdra al rate•• Well tolerated, low withdrawal rateWell tolerated, low withdrawal rate

Maksymowych WP, et al. Maksymowych WP, et al. Arthritis Rheum.Arthritis Rheum. 2002;46:7662002;46:766--773. 773.

LeflunomideLeflunomide in ASin ASLeflunomideLeflunomide in ASin ASLeflunomideLeflunomide in ASin ASLeflunomideLeflunomide in ASin AS

•• OpenOpen--label 24label 24--week study of 20 NSAIDweek study of 20 NSAID--refractoryrefractory•• OpenOpen--label, 24label, 24--week study of 20 NSAIDweek study of 20 NSAID--refractory refractory patientspatients

–– Primary outcome Primary outcome 25% BASDAI reduction25% BASDAI reduction50% di ti d f l k f ffi id50% di ti d f l k f ffi id–– 50% discontinued for lack of efficacy, side 50% discontinued for lack of efficacy, side effects, or noncomplianceeffects, or noncompliance

–– No significant change in BASDAI or a number No significant change in BASDAI or a number g gg gof other component measuresof other component measures

–– Peripheral symptoms showed significant Peripheral symptoms showed significant improvement with improvement with leflunomideleflunomidepp

Haibel H, et al. Haibel H, et al. Ann Rheum DisAnn Rheum Dis. 2003;62(suppl 1). Abstract FRI0173.. 2003;62(suppl 1). Abstract FRI0173.

Thalidomide in ASThalidomide in ASThalidomide in ASThalidomide in ASThalidomide in ASThalidomide in ASThalidomide in ASThalidomide in AS•• Despite wellDespite well--known teratogenic effects, useful in known teratogenic effects, useful in

l diff t dil diff t diseveral different diseases.several different diseases.•• 26 AS patients 26 AS patients

–– 1212--month openmonth open--label triallabel trial1212 month, openmonth, open label triallabel trial–– 200 mg/day200 mg/day

•• 80% had improvement >20% in 4 of 7 indices.80% had improvement >20% in 4 of 7 indices.•• 9 patients became pain free.9 patients became pain free.•• Appears to act by decreasing expression of tumor Appears to act by decreasing expression of tumor

i f t (TNF) d thi f t (TNF) d th i fl ti fl tnecrosis factor (TNF) and other necrosis factor (TNF) and other proinflammatoryproinflammatorycytokines.cytokines.

Huang F, et al. Huang F, et al. Arthritis RheumArthritis Rheum. 2002;47:249. 2002;47:249--254.254.

Summary: Traditional DMARDs in ASSummary: Traditional DMARDs in ASSummary: Traditional DMARDs in ASSummary: Traditional DMARDs in ASSummary: Traditional DMARDs in ASSummary: Traditional DMARDs in ASSummary: Traditional DMARDs in ASSummary: Traditional DMARDs in AS

•• Few wellFew well designed studies existdesigned studies exist•• Few wellFew well--designed studies exist.designed studies exist.•• No evidence of true “disease modification”.No evidence of true “disease modification”.•• Response generally favors peripheral disease Response generally favors peripheral disease

over axial disease.over axial disease.PamidronatePamidronate is an exceptionis an exception–– PamidronatePamidronate is an exceptionis an exception

•• Preliminary data suggest oral agents that Preliminary data suggest oral agents that potentially affect TNF expression (potentially affect TNF expression (leflunomideleflunomidepotentially affect TNF expression (potentially affect TNF expression (leflunomideleflunomideand thalidomide) may be beneficial.and thalidomide) may be beneficial.

Rationale for TNF Inhibition in ASRationale for TNF Inhibition in ASRationale for TNF Inhibition in ASRationale for TNF Inhibition in ASRationale for TNF Inhibition in ASRationale for TNF Inhibition in ASRationale for TNF Inhibition in ASRationale for TNF Inhibition in AS

•• Overexpression of TNF in mouse modelOverexpression of TNF in mouse model•• Overexpression of TNF in mouse model Overexpression of TNF in mouse model produces an ASproduces an AS--like diseaselike disease11

•• Serum and joint fluid/tissue of AS patientsSerum and joint fluid/tissue of AS patients•• Serum and joint fluid/tissue of AS patients Serum and joint fluid/tissue of AS patients have elevated levels of TNFhave elevated levels of TNF2,32,3

•• Success with TNF inhibitors in psoriaticSuccess with TNF inhibitors in psoriaticSuccess with TNF inhibitors in psoriatic Success with TNF inhibitors in psoriatic arthritis, which is an SpAarthritis, which is an SpA4,54,5

11Crew MD, et al. Crew MD, et al. J Interferon Cytokine Res.J Interferon Cytokine Res. 1998;18:2191998;18:219--225.225.22Gratacos J, et al. Gratacos J, et al. Br J Rheumatol.Br J Rheumatol. 1994:33:9271994:33:927--931.931.33Braun J, et al. Braun J, et al. Arthritis RheumArthritis Rheum. 1995;38:499. 1995;38:499--505.505.44Mease PJ, et al. Mease PJ, et al. Arthritis RheumArthritis Rheum. 2001;44(suppl):S90. Abstract 226.. 2001;44(suppl):S90. Abstract 226.55Antoni C, et al. Antoni C, et al. Arthritis RheumArthritis Rheum. 2002;47(suppl):S381. Abstract 985.. 2002;47(suppl):S381. Abstract 985.

TNF inhibitors in ASTNF inhibitors in ASTNF inhibitors in ASTNF inhibitors in AS

•• FDA approved TNF inhibitors for ASFDA approved TNF inhibitors for AS–– EtanerceptEtanercept (Enbrel)(Enbrel)–– Infliximab (Infliximab (RemicadeRemicade))–– AdalimumabAdalimumab ((HumiraHumira))–– GolimumabGolimumab ((SimponiSimponi))

MRI of Sacroiliac and SpinalMRI of Sacroiliac and SpinalInflammation of an AS Patient Inflammation of an AS Patient

Before and After TherapyBefore and After TherapyBefore and After Therapy Before and After Therapy With InfliximabWith Infliximab

3535--yearyear--old AS patient, 6old AS patient, 6--y disease durationy disease duration

Braun J, et al. Ann Rheum Dis. 2002;61(suppl 3):iii51-iii60.

TNF Inhibitor SafetyTNF Inhibitor SafetyTNF Inhibitor SafetyTNF Inhibitor SafetyTNF Inhibitor SafetyTNF Inhibitor SafetyTNF Inhibitor SafetyTNF Inhibitor Safety•• Safer than traditional DMARDs:Safer than traditional DMARDs:

–– Less osteoporosis; less bone marrow, hepatic Less osteoporosis; less bone marrow, hepatic and renal toxicity; less infection and neoplasm.and renal toxicity; less infection and neoplasm.

•• TNF inhibition is associated with some safety TNF inhibition is associated with some safety issues.issues.

–– Common: upper respiratory infectionCommon: upper respiratory infection–– Common: upper respiratory infection.Common: upper respiratory infection.–– Rare: tuberculosis and other opportunistic Rare: tuberculosis and other opportunistic

infections.infections.–– Extremely rare: demyelination, drugExtremely rare: demyelination, drug--induced induced

lupus, possibly lymphoma.lupus, possibly lymphoma.

Summary: TNF Inhibitors in ASSummary: TNF Inhibitors in ASSummary: TNF Inhibitors in ASSummary: TNF Inhibitors in ASSummary: TNF Inhibitors in ASSummary: TNF Inhibitors in ASSummary: TNF Inhibitors in ASSummary: TNF Inhibitors in AS

•• Biologic rationale based on human and animal Biologic rationale based on human and animal studies.studies.

•• TNF inhibitors are effective in AS disease activity TNF inhibitors are effective in AS disease activity and show significant impact on spinal symptomsand show significant impact on spinal symptomsand show significant impact on spinal symptoms.and show significant impact on spinal symptoms.

•• Differences among individual agents, but TNF Differences among individual agents, but TNF inhibitors are generally safe in AS.inhibitors are generally safe in AS.g yg y

•• TNF inhibitors offer great symptomatic and TNF inhibitors offer great symptomatic and functional benefits as measured by mobility.functional benefits as measured by mobility.

•• True disease modification is under study with True disease modification is under study with longlong--term imaging studies.term imaging studies.

AS Treatment SummaryAS Treatment SummaryAS Treatment SummaryAS Treatment Summary•• Regular Regular exercise exercise program.program.•• NSAIDs (fail at least 2)NSAIDs (fail at least 2)•• NSAIDs (fail at least 2).NSAIDs (fail at least 2).•• Sulfasalazine or MTX for Sulfasalazine or MTX for peripheral peripheral arthritis.arthritis.•• AntiAnti TNFTNF forfor purely axial disease or concomitantpurely axial disease or concomitant•• AntiAnti--TNF TNF for for purely axial disease or concomitant purely axial disease or concomitant

inflammatory bowel disease.inflammatory bowel disease.•• Corticosteroid injections for SI joint pain.Corticosteroid injections for SI joint pain.j j pj j p•• No treatment modality treats all aspects of No treatment modality treats all aspects of

disease.disease.•• Conventional therapies do not halt disease Conventional therapies do not halt disease

progression.progression.•• Combinations of modalities are required.Combinations of modalities are required.

ConclusionsConclusionsConclusionsConclusionsConclusions Conclusions Conclusions Conclusions

•• New therapies are available to reduce New therapies are available to reduce t d h th t ti l t dift d h th t ti l t difsymptoms and have the potential to modify symptoms and have the potential to modify

disease progression.disease progression.E li di i d f l ill blE li di i d f l ill bl•• Earlier diagnosis and referral will enable Earlier diagnosis and referral will enable eligible patients to receive the appropriate eligible patients to receive the appropriate therapy.therapy.pypy

•• New studies are underway to determine effect New studies are underway to determine effect of new therapies on structural progression of of new therapies on structural progression of AS.AS.

New Approaches to AS TreatmentNew Approaches to AS TreatmentNew Approaches to AS TreatmentNew Approaches to AS TreatmentNew Approaches to AS Treatment New Approaches to AS Treatment New Approaches to AS Treatment New Approaches to AS Treatment

Old ApproachOld Approach New ApproachNew ApproachOld ApproachOld Approach

•• Emphasis onEmphasis on

New ApproachNew Approach

•• Emphasis on limitingEmphasis on limitingEmphasis on Emphasis on symptomssymptoms

•• Less aggressiveLess aggressive

Emphasis on limiting Emphasis on limiting progressionprogression

•• Earlier aggressive Earlier aggressive

•• Single agentsSingle agentstherapytherapy

•• Use of biologic agents Use of biologic agents or combination therapyor combination therapy

•• Toxicity frequentToxicity frequentor combination therapyor combination therapy

•• Limit toxicityLimit toxicity

How to Refer a PatientHow to Refer a PatientHow to Refer a PatientHow to Refer a PatientHow to Refer a PatientHow to Refer a PatientHow to Refer a PatientHow to Refer a Patient•• Consider rheumatologic diseaseConsider rheumatologic disease

Classic presentationsClassic presentations–– Classic presentationsClassic presentations•• Appropriate XAppropriate X--rays and lab studies helpful rays and lab studies helpful

prior to referraprior to referrallprior to referraprior to referrall•• Call or Fax referralCall or Fax referral

–– Phone (907) 562Phone (907) 562--22772277–– Phone (907) 562Phone (907) 562--22772277–– Fax (907) 563Fax (907) 563--34603460

•• All referrals are reviewedAll referrals are reviewed•• All referrals are reviewedAll referrals are reviewed•• We will contact patient to schedule if We will contact patient to schedule if

appropriateappropriateappropriateappropriate

QUESTIONS?QUESTIONS?QUESTIONS?QUESTIONS?QUESTIONS?QUESTIONS?QUESTIONS?QUESTIONS?