Treatment of Rheumatoid Arthritis With Methotrexate: Predictors of Response

The purpose of the study is to gather, in a prospective manner, information on patients with
early rheumatoid arthritis and their response to methotrexate therapy. Specific aims of this
study are:

- To evaluate the efficacy of methotrexate monotherapy as defined by attaining ACR 50
response after 16 weeks of therapy.

- To identify predictors of methotrexate response in patients with RA.

- Does presence of the shared epitope predict methotrexate response

- Does evidence of periodontal disease predict methotrexate response

A maximum of 120 RA patients will be consented for this protocol. This subject accrual will
include UNMC and the RAIN (Rheumatoid Arthritis Investigational Network). Investigators have
examined the discriminatory characteristics of several clinical and biologic parameters in
predicting treatment response (at least 50% improvement based on ACR criteria) in initial
analyses involving 54 participants with early RA treated with methotrexate monotherapy in
past RAIN clinical trials. In the initial analyses, factors showing discriminatory
characteristics have included rheumatoid factor (RF) isotypes (particularly IgA and IgM),
matrix metalloproteinase (MMP)-3, HLA-DRB1 shared epitope (SE)-containing alleles, C-reactive
protein, and interleukin (IL)-1. For instance, we have found that subjects with low serum
concentrations of RF-IgM (< 27 IU/ml) are more likely to be non-responders than those with
higher (> 27 IU/ml) serum concentrations (79% vs. 43%).

Males and females will participate in this protocol. As RA is approximately three times more
common in females, it is anticipated that a higher percentage of the study subjects will be
female. Subjects will be > 19 years of age. This age range was chosen because the age of
majority in Nebraska is 19. RA diagnosed before the age of 19 may not have the same disease
characteristics as defined by the American College of Rheumatology (ACR) criterion for RA.
Pediatric subjects will not be enrolled in this study. Rheumatoid arthritis occurs in all
races. No enrollment restrictions have been based on race or ethnic origin.

Inclusion Criteria:

- Diagnosed by physician with Rheumatoid Arthritis

- Any previous exposure that has occurred to Methotrexate must be discontinued at least
1 year prior to enrollment.

- Must be 19 years of age or older at time of diagnosis of RA.

- Must have active disease at the time of screening, defined as at least 4 swollen and 4
tender joints due to RA (using a 28 joint count)

- Screening Labs: Hemoglobin > 9g/dL, WBC > 3.5, neutrophils > 1.0, Platelets > 100, ALT
or AST not exceeding 1.2 the upper limit of normal, Serum creatinine <1.6, Albumin up
to 1.0g/dL less than lower limit of normal

- Prior monotherapy with any of the following DMARDs is permissible, provided that the
patient has stopped this therapy at least 2 weeks prior to randomization:
hydroxychloroquine, sulfasalazine, minocycline, leflunomide, azathioprine. Prior
combination therapy with 2 or more DMARDs or a biologic agent (i.e. etanercept,
adalimumab, infliximab, abatacept, or rituximab) is not allowed.

- use of oral glucocorticoids, then they must be on a stable dose (≤ 10 mg of prednisone
per day or equivalent) for at least 2 weeks prior to screening. Patient may be
considered if on a titrating dose of 10mg or less.

- If using non-steroidal anti-inflammatory drugs (NSAIDs), then they must be on a stable
dose for at least 1 week prior to screening.

- must be capable of giving informed consent and able to adhere to study visit schedule.

Exclusion Criteria:

- Pregnant or lactating women.

- Women and men of childbearing potential who are not practicing a successful method of
contraception.

- a known history of alcohol use should be excluded unless willing to limit or abstain
from alcohol consumption as allowed per physician discretion.