QOL/Function/Participation Committee 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 GRAPPA PsA Treatment Guidelines

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? GRAPPA PsA Treatment Guidelines

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 GRAPPA PsA Treatment Guidelines

GRAPPA PsA Treatment Guidelines Establish Diagnosis of Psoriatic Arthritis Reassess Response to Therapy and Toxicity Initiate Therapy NSAID PT Biologics (anti-TNF) Axial Disease Peripheral Arthritis Initiate Therapy NSAIDs, IA steroids, DMARDs (MTX, CsA, SSZ, LEF), Biologics (anti-TNF) Skin and Nail Disease Initiate Therapy Topicals PUVA/UVB DMARDs (MTX,CsA,etc) Biologics (anti-TNF, etc) Dactylitis Initiate Therapy NSAID Injection Biologics (anti-TNF) Enthesitis Initiate Therapy NSAID Injection Biologics (anti-TNF)

Methods GRAPPA PsA Treatment Guidelines 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

Methods Principles 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 assessed 1 GRAPPA PsA Treatment Guidelines 1 Ann Intern Med 1997; 126:

GRAPPA PsA Treatment Guidelines 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

GRAPPA PsA Treatment Guidelines 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 GRAPPA PsA Treatment Guidelines d = x 1 -x c s pooled 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 & 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 GRAPPA PsA Treatment Guidelines

Peripheral Arthritis (Enrique Soriano, Neil McHugh) Strength of Recommendation:Level evidence; Effect size, side effect profile SS Z MT X CyALFNOGIMGAZAETNINF Evidenc e sympto m control 1A2B1B -1A 2B1B Effect size SENEMELESE HE - Evidenc e x-Ray B- ToxicityLo w Hig h? LowMed LowLow? Recom m. Grade? A- B? B- C ? A- B? A-A BAA 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) Summary of Clinical Trials: Psoriasis: Conventional Systemic Agents, Bruce Strober, MD, PhD Data: Studies CsA: 2 placebo (effect size 1.5  4.6), 2 c/w MTX Lef: 1 placebo (effect size 0.33) SSZ: 1 placebo (effect size 2.01) Acitretin: 2 placebo Hydroxyurea: 1 open label 6-TG: 2 open label Fumaric acid esters: 2 placebo MTX: 2 c/w CsA Issues remaining: Gaps in data!! (efficacy and toxicity)

Dactylitis – Philip Helliwell DrugStudy # Pt s Type Dactylitis Outcome measure ResultsP valueEffect SizeComments SASClegg et al 1996 (10) 22 1 DBRP C Simple count of digits Change at 36 wks: P: -0.9  4.1 S: -0.5  LEFLKaltwasser et al 2004 (12) 18 6 DBRP C Dactylitis scored 1- 4* Change at 24 wks: P: -0.2  2.4 L: -0.9  * Data not included in paper (courtesy of Dr P Nash) CYCA/ SAS/S T Salvarani et al 2001 (13) 99OLNumber of dactylitic digits Only 4 Ss developed dactylitis (2 CYCA, 1 SAS, 1 ST) Not enough data to make meaningful comparison DrugStudy # Pt s Type Dactylitis Outcome measure ResultsP valueEffect SizeComments INFAntoni et al 2005 IMPACT1 (11) 10 4 DBRPC+ dactylitis score Change at 16 wks: P:  0.28 I:  0.35 < Effect size estimated from Table 2 (%) INFAntoni et al 2005 IMPACT2 (14) 20 0 DBRPCPercentag e of patients with dactylitis of hands/feet Change at 14 weeks: P: -13 patients I: - 23 patients 0.025N/AFigures 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 % 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 Moderate Severe Peripheral ArthritisSkinEnthesitisDactylitisSpine 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

GRAPPA PsA Treatment Guidelines Establish Diagnosis of Psoriatic Arthritis Reassess Response to Therapy and Toxicity Initiate Therapy NSAID (continuous) PT, CS injections Biologics(anti-TNF) MTX, Pamidronate Axial Disease Peripheral Arthritis Initiate Therapy NSAIDs, IA steroids, DMARDs (MTX, CsA, SSZ, LEF), Biologics (anti-TNF) Skin and Nail Disease Initiate Therapy Topicals PUVA/UVB DMARDs (MTX,CsA,etc) Biologics (anti-TNF, etc) Dactylitis Initiate Therapy NSAID Injection Biologics (anti-TNF) Enthesitis Initiate Therapy NSAID Injection Biologics (anti-TNF)

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 AgentEvidenceGradeComments alefacept1BA efalizumab1BA etanercept1BA underestimation of Ps in PsA trials infliximab1BA underestimation of Ps in PsA trials adalimuma b 1BA 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 Moderate Severe Peripheral ArthritisSkinEnthesitisDactylitisSpine 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

GRAPPA PsA Treatment Guidelines Establish Diagnosis of Psoriatic Arthritis Reassess Response to Therapy and Toxicity Initiate Therapy NSAID PT Biologics (anti-TNF) Axial Disease Peripheral Arthritis Initiate Therapy NSAIDs, IA steroids, DMARDs (MTX, CsA, SSZ, LEF), Biologics (anti-TNF) Skin and Nail Disease Initiate Therapy Topicals PUVA/UVB DMARDs (MTX,CsA,etc) Biologics (anti-TNF, etc) Dactylitis Initiate Therapy NSAID Injection Biologics (anti-TNF) Enthesitis Initiate Therapy NSAID Injection Biologics (anti-TNF)