1. Guidelines for Care Needs a team approach of rheumatologists, dermatologists and patients (NPF, ?AF) Combination of Cost and Evidence Based Criteria will be likely determinants –Some rationing is inevitable.

2. Access to Biologics Fact: Cost determines access –How do we optimize patient care in a cost conscious environment? –How do we prevent inappropriate placement of biologics as last drugs of choice?

3. Role of Methotrexate Rheumatologists think MTX is safe long term for use (RA use predominates); Rheumatologists used biologics first therefore guidelines in place for RA. Dermatologists think MTX is not safe long term and requires stringent monitoring (Psoriasis predominates). Third party payers chose MTX first because of cost. How can we work together to make evidence-based recommendations for PSA and PSO on use of MTX?

4. Liver Toxicity Compared

5. Role of non-alcoholic steatohepatitis in methotrexate- induced liver injury. Langman G, Hall PM, Todd G.J: Gastroenterol Hepatol. 2001 Dec;16(12):1395-401. The histological features of MTX liver toxicity are non-specific and resemble those of non-alcoholic steatohepatitis (NASH). Most of the risk factors of MTX-induced liver injury are also associated with NASH. 24 Psoriasis patients on long-term, low dose MTX studied with liver biopsies: 13/17 psoriasis patients on MTX, and who had a NASH-like pattern of liver injury, also had the risk factors for NASH obesity and/or diabetes, and all had progressive liver injury. 4/17 psoriasis patients on MTX, and who had a NASH-like pattern of liver injury, had no risk factors, but a mean cumulative dose of 6.5 g. 7/24 patients, who did not have a NASH-like pattern of injury, had a mean cumulative dose of 3.8 g. There was a positive correlation between the cumulative dose, risk factors and progression.

6. Methotrexate-induced liver cirrhosis. Clinical, histological and serological studies--a further 10-year follow-up. Zachariae H, Sogaard H, Heickendorff L. Dermatology. 1996;192(4):343-6 Studies on 25 patients with MTX-induced liver cirrhosis indicated that this type of cirrhosis was not of an aggressive nature. Patients studied for a further 10 years. Investigations were carried out on 186 liver biopsies and 5 autopsies. 13 patients had died; 1 of these died of liver failure. The remaining deaths were non-MTX related, but all 5 autopsies showed some degree of cirrhosis. The remaining deaths were non-MTX related, but all 5 autopsies showed some degree of cirrhosis. 13 patients had no histologically verified liver cirrhosis in their latest biopsy in spite of total cumulative MTX doses from 1,120 to 18,645 mg (mean 7,171 mg). This study confirmed that in most patients MTX-induced liver cirrhosis is not aggressive. However, continued low-dose MTX led, in spite of normal liver tests, 8 years after the last biopsy to liver failure and death in 1 of our patients. Data support the continued use of liver biopsies in the surveillance of MTX-treated psoriatics.

7. Methotrexate revisited: effects of long-term treatment in psoriasis. Van Dooren-Greebe RJ, Kuijpers AL, Mulder J, De Boo T, Van de Kerkhof PC. Br J Dermatol. 1994 Feb;130(2):204-10 113 psoriasis patients rx’d w/ MTX over 22 years; mean cumulative dose 4,803 mg; mean duration 8 yrs. 11 mos. Liver biopsies in 55 patients Fibrosis in 7 patients Cirrhosis in 2 patients No deaths or life threatening side-effects from MTX rx.

8. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Whiting-O'Keefe QE, Fye KH, Sack KD. Am J Med. 1991 Jun;90(6):711-6. A meta-analysis of 15 studies (636 patients) examined the relationship between long-term, low- dose methotrexate administration and biopsy evidence of liver fibrosis. The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9%. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0%

9. Whiting-O'Keefe QE, Fye KH, Sack KD. Am J Med. 1991 Jun;90(6):711-6. The rate of progression of liver disease in 15 studies was associated with the cumulative dose of MTX (p= 0.01). Patients on average had a 6.7% chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. Patients with psoriasis were more likely than patients with rheumatoid arthritis to have –advanced changes (7.7% versus 2.7%, p = 0.003) and –histologic progression (33.1% versus 24.3%, p = 0.02)

10. Whiting-O'Keefe QE, Fye KH, Sack KD. Am J Med. 1991 Jun;90(6):711-6. The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.

11. Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotexate therapy in 88 patients. A blind study. Nyfors A, Poulsen H Acta Pathol Microbiol Scand [A]. 1976 May;84(3):262-70. 88 patients with severe, recalcitrant psoriasis had liver biopsies performed before and after MTX therapy. MTX was given for an average of 26 months as a single, weekly, oral dose of 25 mg maximum. The mean cumulative dose was 1733 mg (range 175-4590 mg). An increase in the number of pathological post-MTX liver biopsies was found (p < 0.0001). Of the 88 patients 6 developed cirrhosis and another 5 developed fibrosis, during MTX therapy (12.5%). A multifactorial index comprising: cumulative dose of MTX, admitted alcoholic intake during MTX therapy, age, obesity and, if available, pre-MTX liver histology gave an estimate of the probability of developing cirrhosis or fibrosis during treatment of psoriasis with weekly, oral doses of MTX.

12. Methotrexate-induced cirrhosis requiring liver transplantation in three patients with psoriasis. A word of caution in light of the expanding use of this 'steroid-sparing' agent. Gilbert SC, Klintmalm G, Menter A, Silverman A. Arch.Int.Med. 1990 150:733-4. Three cases of methotrexate-induced cirrhosis requiring orthotopic liver transplantation are presented to emphasize the importance of strict adherence to published criteria for patient selection, monitoring of cumulative drug dosages, and the performance of serial liver biopsies.

13. Low-dose methotrexate treatment of rheumatoid arthritis. Long- term observations. Weinstein A, Marlowe S, Korn J, Farouhar F. Am J Med. 1985 Sep;79(3):331-7. Liver toxicity assessed in 21 RA patients and four others receiving long-term methotrexate therapy revealed Acute hepatitis in one and elevated transaminase levels in 12 (48 percent). Liver biopsy specimens in 17 patients after a mean of 1,950 mg of methotrexate (range: 915 to 3,125) revealed mild fibrosis in six and no cirrhosis. Hepatic fibrosis and cirrhosis due to methotrexate may be less common in rheumatoid arthritis than has been reported in psoriasis.

14. RA vs PSA on TNF Blockade: The CORRONA Database Prospective cohort of 5596 (2722 pt-years) RA; 524 (399 pt-years) PSA PSA have more liver AEs than RA Liver disease in PSA correlated with weight, male sex, past/present DMARD use and h/o liver disease Cassell et.al., Arthr.Rheum. 52(suppl.), abstract 491, 2005

15. Infliximab Liver toxicity in psoriasis patients in phase III trials No significant liver toxicity in rheumatoid arthritis patients in phase III trials