qol/function/participation committee projects to be done –validation of current measures: haq, sf-...

QOL/Function/ParticipationCommittee

• Projects to be done– Validation of current measures: HAQ, SF-36,

DLQI, PsAQOL– Development of MCID – need to validate (or

not) the HAQ MCID of 0.3 derived from etanercept phase III study

– Analysis of fatigue measures

• Participation project (Taylor and Boehncke)

Guidelines Mission Statement

“To develop guidelines, based upon the best scientific evidence, for the optimal treatment of patients with psoriatic arthritis (PsA).”

Guidelines: “Systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” IOM

GRAPPA PsA Treatment Guidelines

Considerations Relevant to Guideline Creation in PsA

• PsA may follow heterogeneous, variable clinical course• More research needed on important prognostic factors

(e.g. oligo vs poly) to allow optimal stratification• PsA multifaceted (axial/periph joints, skin, etc): Work is

progressing on classification criteria (CASPAR)• How appropriate is extrapolation of efficacy/safety data

from similar conditions (psoriasis, AS, RA, etc)?• Determine most appropriate outcome measures

(signs/symptoms, structural integrity, QOL/functional status)

• Guideline exigency driven by introduction of novel immunomodulatory therapies


If Guidelines Are Based on Best Available Evidence, How Do We Handle:

• When “state of the art” outstrips peer-reviewed published medical literature?

• That quality of newer studies is superior to older studies?• The variable diagnostic criteria / outcomes in trials?• Absence of studies for certain therapies (e.g. steroids)?• The absence of head-to-head trials?• Aphorism: “The absence of evidence of an effect is not equivalent to

evidence of absence of an effect” (e.g. MTX• When there is no data, what is the role of “expert” opinion?

How can treatment approaches to divergent aspects of PsA (skin, joints, enthesitis, dactylitis, spondylitis) with various levels of activity) be optimally synthesized?


Methods• Determine areas of interest for obtaining data (axial disease,

peripheral arthritis, skin, enthesitis, dactylitis)• Formulate questions for the systematic review; for the different

manifestations (and based on disease characteristics…)– What is the effect of a given therapy on clinical

manifestations (including signs/symptoms, QOL/Fx, structural integrity)? What is the effect size

– What is the effect of a given therapy as regards safety? What is the effect size?

• Systematic literature review; excerpting data• Identify key areas for research (i.e. lacking data)• Re-assemble into unifying guideline



Establish Diagnosis of Psoriatic Arthritis

Reassess Response to Therapy and Toxicity

Initiate TherapyNSAIDPTBiologics(anti-TNF)

Axial Disease

Peripheral Arthritis

Initiate TherapyNSAIDs,IA steroids,DMARDs(MTX, CsA, SSZ, LEF),Biologics(anti-TNF)

Skin and Nail Disease

Initiate TherapyTopicalsPUVA/UVBDMARDs (MTX,CsA,etc)Biologics (anti-TNF, etc)

Dactylitis

Initiate TherapyNSAIDInjectionBiologics(anti-TNF)

Enthesitis


Methods


After considerations of relevant characteristics of PsA, the best available evidence is collected, graded and utilized to formulate recommendations. An important task is the identification of areas lacking sufficient data to support recommendations.

In an attempt to produce guidelines of the highest quality, as guidelines are developed, we will adhere to the Conference on Guideline Standardization recommendations.1

1 Shiffman et al; Ann Intern Med 2003; 139:493

MethodsPrinciples of Systemic Review of Published Medical Literature

• Review addresses a focused clinical question• Literature search strategy is explicit and reproducible• Literature review is comprehensive• Criteria for selection of articles for review are described• Criteria for selection of patients/patient groups w/in each article for

analysis are described• Criteria for outcome assessments of patients/patient groups are

defined• Articles and patients are assessed by multiple reviewers using a

standard form; differences of interpretation resolved by consensus• Assembled data are quantitatively assessed1


1 Ann Intern Med 1997; 126: 376-80


GRAPPA is using a systematic review of the literature, including languages other than English, using established principles for such reviews.1 Retrieved articles are graded according to the categories of evidence suggested by the Agency for Health Care Policy Research (AHCPR). Categories Include:

1A Evidence from meta-analysis of randomized controlled trials (RCT)

1B Evidence from one or more RCTs

2A Evidence from 1 or more controlled trials (without randomization)

2B Evidence obtained through other well-designed studies (quasi-experimental)

3 Evidence from non-experimental studies (e.g. comparative, correlation or case-control)

4 Expert committee opinions, clinical experience

1 Cook et al; Ann Intern Med 1997: 126:376


When the best evidence is extracted from published literature, recommendations are graded accordingly:

Grade A: Based on category 1 evidence

Grade B: Category 2 evidence

Grade C: Category 3 evidence

Grade D: Category 4 evidence

Effect Size


d =x1-xc

spooled

d = Cohen’s d effect size

x = Mean (average of treatment or comparison conditions)

s = Standard deviation

How to Use a Clinical Practice Guideline.Hayward et al (evidenced based working group). JAMA

1995;274:570-4 & 1630-2. I. Are the results of the study valid?

- Were all important options and outcomes clearly specificied?- Was an explicit and sensible process used to identify, select and combine the evidence? To consider the value of different outcomes?- Is the guideline likely to account for important recent developments?- Has the guideline been subject to peer review and testing?

II. What were the results?- Are practical, clinically important recommendations made?- How strong are the recommendations?- What is the impact of uncertainty associated with the evidence and

the values used in the guidelines?III. Will the results help me in caring for my patients?

- Is the primary objective consistent with your objective- Are the recommendations applicable to your patients?

Synopses of Evidence• Peripheral Arthritis (Enrique Soriano, Neil

McHugh)• Axial Involvement (Peter Nash)• Skin – Biologics (Wolf-Henning Boehncke)• Skin – Synthetics (Bruce Strober, Kimberly Siu,

Kavi Menon)• Enthesitis – Chris Ritchlin• Dactylitis – Philip Helliwell

Discussion and Synthesis


Peripheral Arthritis (Enrique Soriano, Neil McHugh)

Strength of Recommendation:Level evidence; Effect size, side effect profile

SSZ

MTX

CyA LFN OG IMG AZA ETN INF

Evidence symptom control

1A 2B 1B 1B -1A -1A 2B 1B 1B

Effect size

SE NE ME LE SE SE HE HE -

Evidence x-Ray

-3 -3 3 4 - -3 - 1B -

Toxicity Low

Low

High?

Low Med Med Low Low? Low?

Recomm. Grade?

A-B?

B-C ?

A-B?

A -A -A B A A

SSZ: sulphazalacine; MTX: metothrexate; CyA: cyclosporine; LFN: leflunomide; OG: Oral gold; IMG: Intramuscular gold; AZA: azathioprine; ETN: etanercept; INF: infliximab.SE: Small effect; NE: Negligible effect ; ME : Medium effect ; HE : Huge effect. A negative value indicates evidence against.

-Peripheral Arthritis (Enrique Soriano, Neil McHugh)

Issues remaining: incorporate newer data on infliximab, adalimumab MTX study in progress evaluate functional status (e.g. HAQ) ? How to standardize toxicity data? (NNH, etc)

BSR guidelines have been published (Rheumatology 2005;44:390-7)

Skin – Synthetics(Bruce Strober, Kimberly Siu, Kavi Menon)

Data: StudiesCsA: 2 placebo (effect size 1.54.6), 2 c/w MTXLef: 1 placebo (effect size 0.33)SSZ: 1 placebo (effect size 2.01)Acitretin: 2 placeboHydroxyurea: 1 open label 6-TG: 2 open labelFumaric acid esters: 2 placeboMTX: 2 c/w CsAIssues remaining: Gaps in data!! (efficacy and toxicity)

Dactylitis – Philip Helliwell

Drug Study# Pts

TypeDactylitis Outcomemeasure

Results P value Effect Size Comments

SAS Clegg et al 1996 (10)

221

DBRPC

Simple count of digits

Change at 36 wks:P: -0.9 4.1S: -0.5 4.2

0.43 0.20

LEFL Kaltwasser et al 2004 (12)

186

DBRPC

Dactylitis scored 1-4*

Change at 24 wks:P: -0.2 2.4L: -0.9 2.7

0.2 0.33 * Data not included in paper (courtesy of Dr P Nash)

CYCA/ SAS/ST

Salvarani et al 2001 (13)

99 OL Number of dactylitic digits

Only 4 Ss developed dactylitis (2 CYCA, 1 SAS, 1 ST)

Not enough data to make meaningful comparison

Drug Study# Pts

TypeDactylitis Outcomemeasure

Results P value Effect Size Comments

INF Antoni et al 2005 IMPACT1 (11)

104

DBRPC + dactylitis score

Change at 16 wks:P: -0.58 0.28I: -1.94 0.35

< 0.001 0.57 Effect size estimated from Table 2 (%)

INF Antoni et al 2005 IMPACT2 (14)

200

DBRPC Percentage of patients with dactylitis of hands/feet

Change at 14 weeks:P: -13 patientsI: - 23 patients

0.025 N/A Figures estimated from Table 2

International Guidelines PSA

AXIAL DISEASE

PsA Axial disease

• Symptomatic inflammatory spinal pain prevalence 40% , 25% plain radiological evidence of sacroiliitis in PsA

• Less symptomatic, less severe• Often assymetrical• Less caudocranial progression• In PsA, clinical tests for sacroiliac

involvement sens. (38%) spec. (67%)

Caveats

• Inadequate studies in PSA axial disease• Unvalidated outcome measures• Using Ankylosing Spondylitis criteria may

not be appropriate eg Taylor et al BASDAI studies

• Cannot assume BASFI, BASMI , minimally clinically significant differences comparable AS & PSA with axial disease

Axial disease PSA

• Physiotherapy - Supervised group physical therapy level of evidence A

• NSAID- symptom and sign relief - level of evidence A- continuous NSAID usage may reduce radiological progression- level of evidence

A

Corticosteroids

• Intra-articular corticosteroid injection - level of evidence C

• Fluoroscopic or CT guided sacroiliac joint injection - level of evidence A

• Intravenous pulse methylprednisolone 1gr for 3 days - level of evidence B

Bisphosphonates

• Pamidronate IV 60 mgs monthly x 6 - 60% responders ,

- 40% BASDAI decreased 50%

- level of evidence A

• Sulphasalazine- benefit peripheral arthritis - level of evidence A

- no axial benefit - level of evidence A Methotrexate

- benefit in peripheral arthritis - level of evidence A

- benefit in axial disease - level of evidence A (1B)

• No evidence of benefit Anti-malarials, Gold salts, Azathioprine, D-penicillamine

• Small 1 year open study of Thalidomide showed significant benefit - level B

• Leflunomide - no benefit - level A

• Cyclosporine - no benefit - level A

Anti-TNFs in axPsA

• Etanercept trials

- 4% SpA - no difference response

• Infliximab - no data

• Adalimumab - no data

Anti-TNFs in AS

• Etanercept & Infliximab- symptoms, signs, function ,

quality of life, radiological progression - level of evidence A

• Use ASAS Consensus - disease definitons,

contraindications, assessment of disease activity and response

Mild

Mod

erat

eS

ever

ePeripheral Arthritis Skin Enthesitis Dactylitis Spine

• 1-3 tender and/or swollen joints

• No erosive disease on plain film

• Function not significantly impaired

• 5+ tender/swollen joints

• Normal x-rays but oligoarticular or polyarticular disease that interferes w/ normal function

• Or less than 5 T/S Joints but w/ erosions or JSN on x-ray

• > 5 tender/swollen joints w/ evidence of joint damage on exam

• Arthritis mutilans

• Oligo- or polyarticular disease that limits ADLs

< 3%

BSA

> 3%

and

< 10%

BSA

> 10%

BSA

None

1-3 entheseal sites inflamed

• > 3 sites

• Entheseal involvement in foot that prevents ambulation

• Tendon rupture

None

1-3 inflamed digits

• > 3 inflamed digits

• Evidence of ankylosis in a dactylitic joint

•No signs or symptoms of spinal inflammation

•Normal Schoeber scrore and normal AP pelvis film

Inflammatory back pain with a normal AP pelvis film

Symptomatic inflammatory back pain with radiographic changes on plain films




Initiate TherapyNSAID (continuous)PT , CS injectionsBiologics(anti-TNF)MTX, Pamidronate

Axial DiseasePeripheral Arthritis




Dactylitis


Enthesitis


1. NSAIDs, physiotherapy and corticosteroid injections improve entheseal symptoms in PsA and SpA (level 4) grade D

2. Azulfidine is not effective for Rx of enthesitis in PsA (level 1b) Grade A.

3. Mesalamine is effective for the Rx of enthesitis in SpA (level 3) grade C.

4. Infliximab is effective for the Rx of enthesitis in PsA (level 1b) Grade A.

5. Etanercept is effective for the Rx of enthesitis in SpA (level 1b) Grade A.

Enthesitis-Ritchlin

Enthesitis: Comments

These recommendations should be viewed with caution, however, because the underlying data is incomplete and in many cases severely flawed.

1. Several different outcome measures were used in the studies examined in this review and none of them have been validated.

2. With the exception of azulfidine, large controlled trials examining the effect of traditional DMARDs on enthesitis have not been carried out.

3. Most of the studies did not state how many patients in the total population actually had enthesitis, which may result in overestimation of effect size.

Biologics in Psoriasis-Boehncke

Agent Evidence Grade Comments

alefacept 1B A

efalizumab 1B A

etanercept 1B A underestimation of Ps in PsA trials

infliximab 1B A underestimation of Ps in PsA trials

adalimumab

1B A underestimation of Ps in PsA trials

Comments on “the Grid”

• Signs and symptoms of disease activity at present have to be distinguished from signs of residual damage of the past.

• A composition severity score for PsA of peripheral arthritis, skin, enthesitis, dactylitis and spine should be avoided for treatment purposes as every item on its own can be severe enough to start or intensify treatment, outcomes are different and the most appropriate treatment can be different for each item.

• A “severity” score for PsA has to be oriented to its aim (treatment? trial? quantification of physical damage, ...).

• A “severity” score for PsA should not (at least not exclusively) rely on numbers of peripheral joints or numbers of digits with dactylitis but on the functional consequences of the joint or digit involvement.

• A “severity” score for skin involvement for treatment decisions, next to the total area should take into account the location of the lesions.

• Treatment decisions considering the spine can be adopted from ankylosing spondylitis.

Comments on “the Grid”

• We must consider function i.e link # inflamed joints to function

• Have derm generate skin boxes

• What is the rationale for looking at BSA?

• Beware! “can of worms, circular approach” “consensus should be limited to the steering committee”

• Separate “process” (activity) from “outcome” (cumulation of process)

• Define what you are treating: symptoms vs prevention of damage

• Please, don’t build rigid guidelines

• Combine disease activity score with a disability score

Mild

Mod

erat

eS

ever

ePeripheral Arthritis Skin Enthesitis Dactylitis Spine

• 1-3 tender and/or swollen joints

• No erosive disease on plain film

• Function not significantly impaired

• 5+ tender/swollen joints

• Normal x-rays but oligoarticular or polyarticular disease that interferes w/ normal function

• Or less than 5 T/S Joints but w/ erosions or JSN on x-ray

• > 5 tender/swollen joints w/ evidence of joint damage on exam

• Arthritis mutilans

• Oligo- or polyarticular disease that limits ADLs

< 3%

BSA

> 3%

and

< 10%

BSA

> 10%

BSA

None

1-3 entheseal sites inflamed

• > 3 sites

• Entheseal involvement in foot that prevents ambulation

• Tendon rupture

None

1-3 inflamed digits

• > 3 inflamed digits

• Evidence of ankylosis in a dactylitic joint

•No signs or symptoms of spinal inflammation

•Normal Schoeber scrore and normal AP pelvis film

Inflammatory back pain with a normal AP pelvis film

Symptomatic inflammatory back pain with radiographic changes on plain films




Initiate TherapyNSAIDPTBiologics(anti-TNF)

Axial Disease

Peripheral Arthritis




Dactylitis


Enthesitis


qol/function/participation committee projects to be done –validation of current measures: haq, sf-...

Documents

treatment approaches

absence of evidence

evidence of absence

psoriatic arthritis

divergent aspects of

optimal treatment of

absence of studies

effect sizewhat