Ankylosing Spondylitis & Psoriatic Arthritis

Ankylosing Spondylitis &

Psoriatic Arthritis

A Focus on Morbidity and Mortality

John D. Carter, MD

Associate Professor of Medicine Division of Rheumatology

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Clinical Features of AS

Skeletal Axial arthritis (eg, sacroiliitis and spondylitis) Arthritis of ‘girdle joints’ (hips and shoulders) Peripheral arthritis uncommon

Others: enthesitis, osteoporosis, vertebral, fractures, spondylodiscitis, pseudoarthrosis Extraskeletal Acute anterior uveitis

Cardiovascular involvement Pulmonary involvement

Cauda equina syndrome Enteric mucosal lesions

Natural History of AS

• Highly variable

• Early stages: spontaneous remissions and exacerbations

• Spectrum of severity

– Mild with limited sacroiliac or lumbar joint involvement to severe, debilitating disease

• “Pre-spondylitic” phase – unrecognized period of progressive structural damage over a

5-to-10-year period

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Genetic Predisposition for Development

of Ankylosing Spondylitis (AS)

• AS and HLA-B27 – strong association

• Ethnic and racial variability in presence and expression of HLA-B27 HLA-B27 positive AS and HLA-B27 positive Western European Whites 8% 90% African Americans 2% to 4% 48%

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Modified New York Criteria for the

Diagnosis of AS (1984)

• Clinical Criteria

– Low back pain, > 3 months, improved by exercise, not relieved by rest

– Limitation of lumbar spine motion, sagittal and frontal planes – Limitation of chest

expansion relative to normal values for age and sex • Radiologic Criteria – Sacroiliitis grade ≥ 2 bilaterally or grade 3 – 4 unilaterally • Grading – Definite AS if radiologic

criterion present plus at least one clinical criteria

– Probable AS if:

• Three clinical criterion • Radiologic criterion

present, but no signs or symptoms satisfy clinical criteria

Non-radiographic axial

spondyloarthritis

Pathogenesis of AS

• Incompletely understood, but knowledge increasing

• Interaction between HLA-B27 and T-cell response

• Increased concentration of T-cells,

macrophages, and proinflammatory cytokines

– Role of TNF

• Inflammatory reactions  produce hallmarks of disease

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Burden of Illness

• Functional disability

• Potential complications • Quality-of-life issues

– Pain, stiffness, fatigue, sleep problems

• Healthcare costs • Co-morbidities

Obstacles to Desirable Outcomes in

AS Until Recently

• Diagnostic and classification limitations

• Lack of universally accepted instruments to assess AS

• Until recently, limited treatment options

– NSAIDs, DMARDs

• Mostly symptomatic relief only

• However, recent data suggest a long-term radiographic protective effect with NSAIDs

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Advances in Medicine:

Hope for Patients With AS

• Increased understanding of pathophysiologic processes

• Advent of Anti-TNF agents

• International meetings by ASAS (ASsessment in

AS working group) to address need for universal

standards

• Development of ASAS guidelines

– US modifications to the ASAS International

Guidelines to meet realities of clinical practice in the United States

Disease Activity Assessment

Index Metric BASFI Disability level

BASDAI Disease activity level

ASAS - IC Composite sum of disease activity

BASFI = Bath Ankylosing Spondylitis Functional Index

BASDAI = Bath Ankylosing Spondylitis Disease Activity Index

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Bath Ankylosing Spondylitis

Functional Index (BASFI)

• Visual analog scale (VAS) – 10 cm • Mean score of 10 questions

• Questions level of functional disability, including:

– Ability to bend at the waist and perform tasks

– Looking over your shoulder without turning your body – Standing unsupported for 10 minutes without discomfort – Rising from a seated position without the use of an aid – Exercising and performing strenuous activity

– Performing daily activities of living – Climbing 12 to 15 steps without aid

Bath Ankylosing Spondylitis

Disease Activity Index (BASDAI)

• A self-administered instrument (using 10-cm horizontal visual analog scales) that comprises 6 questions:

Over the last one week, how would you describe the overall level of:

– Fatigue/tiredness

– AS spinal (back, neck) or hip pain

– Pain/swelling in joints other than above – Level of discomfort from tender areas

– Morning stiffness from the time you awake – How long does morning stiffness last?

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ASsessment in Ankylosing

Spondylitis (ASAS)

• ASAS 20: An improvement of > 20% and absolute

improvement of > 10 units on a 0–100 scale in > 3 of the following 4 domains:

– Patient global assessment (by VAS global assessment) – Pain assessment (the average of VAS total and nocturnal

pain scores)

– Function (represented by BASFI)

– Inflammation (the average of the BASDAI’s last two VAS concerning morning stiffness intensity and duration)

• Absence of deterioration in the potential remaining domain

Pathogenesis of Joint Destruction

Bone Erosions Macrophages Endothelium Synoviocytes Proinflammatory cytokines Chemokines Adhesion molecules Metalloproteinase synthesis Articular Cartilage Degradation Increased Cell Infiltration Increased Inflammation Osteoclast

progenitors RANKL expression TNF

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Contraindications for

Anti-TNF Therapy

• Current or recurrent infections • Tuberculosis

• Multiple sclerosis • Lupus

• Malignancy

Anti-TNF Agents

• Etanercept (Enbrel) • Infliximab (Remicade) • Adalimumab (Humira) • Golimumab (Simponi) • Certolizumab (Cimzia)

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Anti-TNF Agents: Summary

• Anti-TNF agents target underlying inflammatory process

– Alter disease progression – Provide symptomatic relief

• Recommended treatment after trial of chronic daily NSAIDs, physical therapy, and regular exercise

• Good safety and tolerability profiles

• Still unclear if they truly delay radiographic progression • Implement treatment guidelines to ensure proper

Figure 1. Cumulative incidence of ischemic heart disease (IHD) in the ankylosing spondylitis group (dotted line) and non-AS group (solid line).

Cardiac Conduction Abnormalities

in Ankylosing Spondylitis

• Cross-sectional study; 210 participants • Mean age: 49 years (16-77 years)

– All received questionnaires, PE, ECG, lab tests

• Cardiac conduction disturbances 10-33%

(depending conservative or less conservative predetermined criteria)

– Mostly 1st _{Degree AV block and prolonged QRS; 7}

with complete bundle branch blocks; one pacemaker

– Associated with age, male gender and weight; not with labs (including B27) or markers of inflammation

Bone Mineral Density in early AS

• Decreased BMD is common in AS

– Prevalence range 19-63%; these data mostly from patients with long disease duration

• Review of BMD in AS patients with disease duration of ≤ 10 years

• Decreased BMD T-score < -1.0

• Overall prevalence of 54% L-spine and 51% in femoral neck

Vertebral Fractures (VF’s) in AS

• Study the prevalence and risk factors of VF’s in AS

– 204 patients; mean age 50 and disease duration 15 years

• VF’s diagnosed in 24 (12%)

• Only previously noted clinically in 3 of the 24

• VF’s were significantly associated with older age, longer disease duration, higher disease activity, syndesmophytes, and smoking

• Strongly associated with BMD

Increased Mortality in AS

• 677 patients followed for 24 years • Crude mortality rate: 14.5%

• CVD, malignant, infectious: 40%, 26.8%,23.2% • Factors associated with reduced survival:

– Diagnostic delay: OR 1.05 – Increased CRP: OR 2.68 – Work disability: OR 3.65

Ankylosing Spondylitis: Healthcare

Costs and Productivity Losses

• Study in UK; cross-sectional study of 612 patients

• Mean 3 month healthcare cost £2,802

– BASDAI <4, 4-6, >6: £1331, £2790, £4840

• Direct healthcare costs were just 15% of total costs

• Unemployment, absenteeism, reduced work productivity: 63.2%, 1.4%, 19%

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Trends of Long-Term Disability and

Sick leave in AS

• 1993: 91 patients; mean age 35 years

– 31% on permanent disability

– 67% of workers had missed at least one day in the preceding 12 months

– 3%/yr went on permanent disability over the ensuing 5 years

• 2007: 185 patients; mean age 42 years

– 39% on permanent disability

Psoriatic Arthritis (PsA): Basic Facts

• As many as 7.5 million Americans have psoriasis

• Common, chronic, inflammatory disease of skin and joints

• Auto-immune disease caused by both genetic and environmental influences

Plaque psoriasis is the most common form

Other forms of psoriasis

Guttate: Small, red,

individual spots on skin. Usually appears on trunk and limbs.

Inverse: Found in skin

folds. Lesions are very red and usually lack scale.

Pustular: White

pustules surrounded by red skin.

Erythrodermic: Fiery

redness on large areas of skin. Often

accompanied by severe itching and pain.

Nail psoriasis

 Pitting  Peeling

 Discoloration

 Lifting up from the nail bed

Psoriatic arthritis

 Inflammatory joint disease found in 10-30% of patients with psoriasis

 Stiffness, pain, swelling and tenderness of the joints and surrounding ligaments and tendons  Early recognition, diagnosis and treatment can

help prevent progressive joint involvement and damage

 Skin symptoms usually appear before joint symptoms, but not always

Psoriatic arthritis

Early diagnosis and treatment is the key to preventing long-term joint damage

Psoriatic arthritis

Psoriatic arthritis

Symptoms to be aware of

 Back pain/stiffness

 Pain in heel or bottom of foot

 _{Morning stiffness lasting longer than 30} minutes

 _{Generalized fatigue}

 Reduced range of motion  _{Swollen fingers and/or toes}

Diagnosing psoriatic arthritis

There is no one test that can

diagnose psoriatic arthritis

 Physical exam looking for signs of psoriasis and/or psoriatic arthritis

– Skin, joints, tendon insertion sites

 Other tests include

– X-rays or other imaging tests – Blood test

Treatments for psoriatic arthritis

 Disease-modifying antirheumatic drugs

(DMARDs) may relieve more severe symptoms and attempt to slow or stop joint/tissue damage and the progression of psoriatic arthritis.

 Methotrexate (oral and injection)  Leflunomide (oral)

Treatments for psoriatic arthritis

 Nonsteroidal anti-inflammatory drugs (NSAIDs)

– Over-the-counter (OTC) medications such as naproxen and ibuprofen

– Prescription strength products

These will help with pain and inflammation

Treatments for psoriatic arthritis

 Biologics approved by FDA for psoriatic

arthritis:

 Etanercept (Enbrel®)  Adalimumab (Humira®)  Infliximab (Remicade®)  Golimumab (Simponi®)  Certolizumab (Cimzia)  Ustekinumab (Stelara)

Most advanced drugs in pipeline

for psoriatic arthritis

Name Sponsor Mechanism Route Developmen

t phase

Apremilast Celgene Anti-inflammatory

(PDE4 inihibitor)

Oral III

Tofacitinib Pfizer Anti-inflammatory

(JAK3 inhibitor)

Oral III

Secukinumab (AIN457)

Psoriasis and heart attacks

 Recent studies show that psoriasis, in and of itself, can cause cardiovascular risk

 The greater the psoriasis severity, the greater the risk  Controlling psoriasis with

certain medications shows promising results for

Psoriasis is associated with increased risk of:

 Ischemic heart disease - 78%

 Cerebrovascular disease - 70%

 Peripheral vascular disease - 98%

* after controlling for age, sex, hypertension,

diabetes mellitus, dyslipidemia, and tobacco

Atherosclerosis and Other

Vascular Diseases

Mortality in PsA, RA, Ps

• Longitudinal cohort study from UK; 1994-2010 • PsA (n=8706); RA (n=41,752); Ps (n=138,424);

controls (n=82,258)

• PsA: no increased risk of mortality [OR: 0.8-1.19] – regardless of DMARD use

• RA: increased risk of mortality [OR: 1.47-1.66] – regardless of DMARD use

• Ps: increased risk of mortality [OR: 1.04 – 1.12; 1.56 – 1.95]

– regardless of DMARD use, but even higher in those prescribed DMARDs

CV and All Cause Morbidity in PsA

• Large systematic review of 28 articles from 1966 to 2011

• Studies on all cause mortality were mixed • CV mortality more consistent

• Increased CV mortality and morbidity overall

• Surrogate markers increased, arterial stiffness, etc. • CV risk factors more prominent (HTN, Dyslipidemia,

Obesity) in PsA

• Suppression of inflammation linked to more favorable effect on CV surrogate markers

Work Disability in PsA

• Systematic review of 19 publications • Unemployment ranged from 20-50% • Work Disability 16-39%

• Predictors: longer disease duration, worse physical function, high joint count, low

educational level, female gender, erosive disease, manual work

• Sparse low-quality evidence that disability is

worse in those with PsA compared to Ps alone.

Work Disability in PsA treated with

anti-TNF therapy

• Population based Swedish Cohort Study; 2003-2007 • 191 patients with PsA (mean age 43)

• 67% were work disabled at treatment initiation (sick leave or disability pension)

• Avg # of work disabled days/month 12.5 to 10.6 (after 3 years of therapy)

• Control population 2.5 and 3.0 days

• Significant predictors of disability: prior work disability, anti-TNF failure, higher age, female gender, longer disease duration

Conclusions

• AS and PsA are both types of spondyloarthritis and share common features

• Both AS and PsA are associated with increased risk of CV disease

• AS, and possibly PsA, are associated with increased all-cause mortality

• Work disability is more common in both