GRAPPA Evidence-Based Treatment Guidelines for Psoriatic Arthritis. Peripheral joint disease Dr. Enrique R. Soriano Dr. Neil J. McHugh

Peripheral joint disease Objective: present the best scientific evidence as it relates to the treatment of peripheral joint involvement in PsA. Literature search included: – EBD: Medline, Embase, Ovid, and Lilacs back to 1966; and – SRD: Cochrane (CDSR; CCTR) – Manual search of references – Recently published BSR guideline for anti-TNF alpha therapy in PsA (: Key words: psoriatic arthritis, psoriasis treatment, and each one of the treatments and psoriasis and/ or psoriatic arthritis

Categories of evidence: AHCPR Evidence 1A Meta-analysis of RCT 1B One or more RCT 2A One or more CT 2B well designed studies 3 non experimental studies 4 Expert opinions, clinical experience Grade A Grade B Grade C Grade D Recommendation

What is the evidence regarding efficacy of NSAIDs, systemic steroids and intraarticular steroids in treating peripheral arthritis of PsA?" NSAIDs: evidence grade 1B for : (recommendation grade A) indomethacin, diclofenac, azapropazone, acemetacin and ibuprofen to improve symptoms in PsA. (Nimesulide not recommended) There is lack of sufficient data to support recommendations for the use of Cox-2 specific NSAIDs in psoriatic arthritis. There have been reports of exacerbations of psoriasis with NSAIDs, (evidence grade 4). Systemic corticosteroids: Evidence grade 4, recommendation grade D. Intraarticular corticosteroids: Evidence grade 4, (evidence grade 3?) recommendation grade D (recommendation grade C?).

What is the evidence regarding efficacy of DMARDs on symptom improvement on peripheral arthritis of PsA? Methotrexate: Only parenteral methotrexate at a unacceptably high toxic dose has well demonstrated published efficacy Data for oral MTX suggest it may be beneficial but conclusive proof of its efficacy is still lacking. (evidence grade 2B) Sulphasalazine: Evidence grade 1A Cyclosporine: Evidence grade 1B Leflunamide: Evidence grade 1B efficacy for symptom control and improving functional status and quality of life

What is the evidence regarding efficacy of DMARDs on symptom improvement on peripheral arthritis of PsA? Gold (Oral, IM): Evidence grade 1A, that intramuscular or oral gold are no better than placebo Azathioprine: Not well demonstrated published efficacy. The magnitude of the effect seen in one RCT suggests that it may be effective. Antimalarials: Evidence grade 3

What is the evidence regarding DMARDs on radiogrpaphic progression on peripheral arthritis of PsA? Methotrexate: Evidence grade 3 MTX does not prevent radiographic progression Sulphasalazine: Evidence grade 3 that SSZ does not prevent radiographic progression Cyclosporine: Evidence grade 3 that CyA is able to control radiographic progression defined as the development of less than two new eroded joints Leflunamide: Evidence grade 4 that leflunomide might prevent radiographic progression Gold (Oral, IM): Evidence grade 3 IM Gold does not prevent radiographic progression

What is the evidence regarding DMARDs toxicity on patients treated for PsA? Methotrexate: Liver toxicity: more likely in PsA than in RA (evidence 2B) Histopathologic changes not predicted by abnormal LFT (evidence 2B). The risk of liver fibrosis: related to methotrexate cumulative dose. Progression to clinically significant cirrhosis: uncertain and may be low (evidence 2B). Liver biopsy considered in patients exceeding 1.5g of cumulative dose of methotrexate (evidence 2B, recommendation grade B). Evidence grade 3 that serial evaluations of amino-terminal propeptide of type III procollagen levels are useful for selecting patients for liver re-biopsies Sulphasalazine: There is a high withdrawal rate in patients due to adverse events. (evidence grade 3). Cyclosporine: less well tolerated than other DMARDs (evidence grade 3), significant renal toxicity (evidence grade 2B). Close monitoring of patient’s blood pressure and renal function should be done before and during treatment (recommendation grade B).

What is the evidence regarding DMARDs toxicity on patients treated for PsA? Leflunamide: Diarrhea and elevated ALT levels: higher frequencies in patients treated with leflunomide compared with placebo (evidence grade 1B). Long term data from patients with PsA treated with leflunomide are not yet available. Gold (Oral, IM): Gold is well tolerated in most patients with PsA. Follow up studies showed lower treatment survival rate with gold than with other DMARDs. (evidence grade 3) Antimalarials: Evidence grade 3 that they may exacerbate psoriasis.

Anti TNF alpha Therapy. Etanercept Two controlled randomized trirals (60 and 205 patients). Summary: Efficacy. Toxicity There is evidence grade 1B, that etanercept has efficacy in symptom, disability and quality of life improvement in PsA patients. There is evidence grade 1B that etanercept is able to control radiographic progression in the short term in PsA There is evidence grade 1B, that etanercept is safe in the short term in patients with PsA

Anti TNF alpha Therapy. Infliximab A randomized, double blind trial of infliximab, 5 mg/Kg, or placebo (102 patients) Summary: Efficacy. Toxicity There is evidence grade 1B, that infliximab has efficacy in symptom improvement in PsA patients. There is no evidence that infliximab stop radiographic progression There is evidence grade 1B that infliximab is safe in the short term in patients with PsA

SSZMTXCyALFNOGIMGAZAEtanarcept Combe 1996 *Gupta 1995 Clegg 1996 Willkens 1984 Salvarani 2001 Kaltwass er 2004 Carrete 1989 Palit 1990 Levy 1972 Mease 2000 n patients 117; * Weeks follow up 24;* Tender joint score 0,160,120,060,440,650,220,782,682,29 & Swollen Joint score 0,18*0,02 0,46 #0,17 0,33 --1,32# Pain (VAS) 0, ,533,640,03 - Cohen´s d effect size calculated on mean changes between baseline and final visit of selected outcomes variables for different DMARDs. medium effect (>=.40 and =.75 and <1.10); very large effect (>=1.10 and 1.45

SSZMTXCyALFNOGIMGAZAETNINF Evidence symptom control 1A2B1B -1A 2B1B Effect size SENEMELESE HE - Evidence x-Ray B- ToxicityLow High ? LowMed LowLow ? Recomm. Grade? A- B? B- C ? A-B?A-A BAA -: Means evidence against. NE: negligible effect;SE: Small effect; ME: Medium effect ; LE: Large effect; HE: Huge effect Strength of Recommendation:Level evidence; Effect size, side effect profile

Should all patients with PsA receive DMARDs? There is evidence grade 2A that psoriatic arthritis is a progressive disease that can inflict severe damage. Clinical subgroups appears to change over time and the mode of onset does not predict outcome (evidence grade 2B). Patients with a higher number of inflamed joints are at greater risk of progressive damage (evidence grade 2B). There is no evidence other than expert opinion that early aggressive treatment can prevent disease progression (evidence grade 4)

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