Treatment of Rheumatoid Arthritis With Methotrexate: Predictors of Response

Study Purpose

This is an open-label, prospective study of methotrexate in patients with early rheumatoid arthritis (RA) designed to characterize the subset of RA patients that respond best to methotrexate monotherapy. Eligible patients will be adults with RA who are naïve to prior methotrexate or combination disease-modifying antirheumatic drug (DMARD) therapy. Patients will be started on methotrexate at 15 mg once weekly, with the dose escalated to 20 mg once weekly at 8 weeks for patients not in remission. Patients will be assessed with joint counts and laboratory monitoring at study entry, 8 weeks, and 16 weeks. Primary endpoint will be achievement of ACR 50 (American College of Rheumatology 50) criteria. Investigators will collect serum for rheumatoid factor (RF) and anti-CCP antibody isotyping and, in patients who sign a separate consent, DNA for genotype analysis. This should allow Investigators not only to evaluate the efficacy of methotrexate monotherapy but also to identify predictors of a good therapeutic response and evaluate the tolerability of a more aggressive dosing regimen.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.

An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.

Searching Both is inclusive of interventional and observational studies.

Eligible Ages 19 Years and Over
Gender All
More Inclusion & Exclusion Criteria

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.

Trial Details

Trial ID:

This trial id was obtained from, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.


Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 3
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

University of Nebraska
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

James R O'Dell, MD
Principal Investigator Affiliation University of Nebraska
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Overall Status Recruiting
Countries United States

The disease, disorder, syndrome, illness, or injury that is being studied.

Rheumatoid Arthritis
Additional Details

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.#46; 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.

Arms & Interventions


Other: Single arm Methotrexate

This study is a 16-week, open-label study designed to identify the subset of RA patients that respond to methotrexate monotherapy. All patients will receive methotrexate at a starting dose of 15 mg once weekly plus folic acid 1 mg daily. If a patient is not in remission by 8 weeks, then the dose will be escalated as tolerated to 20 mg once weekly. Both oral and injectable methotrexate are acceptable. If the patient is unable to tolerate the Methotrexate at 15 mg, it is allowed to titrate the dose as tolerated as long as patient remains on Methotrexate.


Drug: - Methotrexate

Starting dose of Methotrexate of 15 mg once a week plus folic acid 1mg. daily.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

University of Nebraska Medical Center, Omaha, Nebraska




University of Nebraska Medical Center

Omaha, Nebraska, 68198

Site Contact

Cindy Marr, LPN

[email protected]