QOL/Function/Participation Committee

1. 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)

2. GRAPPA PsA Treatment Guidelines 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

3. 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

4. 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?

5. 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

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

7. GRAPPA PsA Treatment Guidelines 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 1Shiffman et al; Ann Intern Med 2003; 139:493

8. GRAPPA PsA Treatment Guidelines 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

9. 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

10. 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

11. GRAPPA PsA Treatment Guidelines Effect Size x1-xc = d spooled d = Cohen’s d effect size x = Mean (average of treatment or comparison conditions) s = Standard deviation

12. How to Use a Clinical Practice Guideline.Hayward et al (evidenced based working group). JAMA 1995;274:570-4 & 1630-2. • 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? • 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?

13. GRAPPA PsA Treatment Guidelines 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

14. 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 Peripheral Arthritis (Enrique Soriano, Neil McHugh) 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.

15. 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)

16. Summary of Clinical Trials: Psoriasis: Conventional Systemic Agents, Bruce Strober, MD, PhD Skin – Synthetics (Bruce Strober, Kimberly Siu, Kavi Menon) 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)

17. Drug Study # Pts Type Dactylitis Outcome measure 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  4.1 S: -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  2.4 L: -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 Type Dactylitis Outcome measure Results P value Effect Size Comments INF Antoni et al 2005 IMPACT1 (11) 104 DBRPC + dactylitis score Change at 16 wks: P: -0.58  0.28 I: -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 patients I: - 23 patients 0.025 N/A Figures estimated from Table 2 Dactylitis – Philip Helliwell

18. International Guidelines PSA AXIAL DISEASE

19. 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%)

20. 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

21. 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

22. 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

23. Bisphosphonates • Pamidronate IV 60 mgs monthly x 6 - 60% responders , - 40% BASDAI decreased 50% - level of evidence A

24. 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)

25. 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

26. Anti-TNFs in axPsA • Etanercept trials - 4% SpA - no difference response • Infliximab - no data • Adalimumab - no data

27. 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

28. Peripheral Arthritis Skin Enthesitis Dactylitis Spine < 3% BSA • 1-3 tender and/or swollen joints • No erosive disease on plain film • Function not significantly impaired • No signs or symptoms of spinal inflammation • Normal Schoeber scrore and normal AP pelvis film None None Mild Moderate • 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 > 3% and < 10% BSA 1-3 entheseal sites inflamed 1-3 inflamed digits Inflammatory back pain with a normal AP pelvis film • > 5 tender/swollen joints w/ evidence of joint damage on exam • Arthritis mutilans • Oligo- or polyarticular disease that limits ADLs • > 3 sites • Entheseal involvement in foot that prevents ambulation • Tendon rupture • > 3 inflamed digits • Evidence of ankylosis in a dactylitic joint Symptomatic inflammatory back pain with radiographic changes on plain films > 10% BSA Severe

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

30. Enthesitis-Ritchlin 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.

31. Enthesitis: Comments These recommendations should be viewed with caution, however, because the underlying data is incomplete and in many cases severely flawed. • Several different outcome measures were used in the studies examined in this review and none of them have been validated. • With the exception of azulfidine, large controlled trials examining the effect of traditional DMARDs on enthesitis have not been carried out. • 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.

32. Biologics in Psoriasis-Boehncke

33. 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.

34. 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

35. Peripheral Arthritis Skin Enthesitis Dactylitis Spine < 3% BSA • 1-3 tender and/or swollen joints • No erosive disease on plain film • Function not significantly impaired • No signs or symptoms of spinal inflammation • Normal Schoeber scrore and normal AP pelvis film None None Mild Moderate • 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 > 3% and < 10% BSA 1-3 entheseal sites inflamed 1-3 inflamed digits Inflammatory back pain with a normal AP pelvis film • > 5 tender/swollen joints w/ evidence of joint damage on exam • Arthritis mutilans • Oligo- or polyarticular disease that limits ADLs • > 3 sites • Entheseal involvement in foot that prevents ambulation • Tendon rupture • > 3 inflamed digits • Evidence of ankylosis in a dactylitic joint Symptomatic inflammatory back pain with radiographic changes on plain films > 10% BSA Severe

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