Q: Should
methotrexate be a first-line
treatment for rheumatoid arthritis?
William S. Wilke, MD
Department of Rheumatic and Immunologic
Diseases,
Cleveland Clinic; associate editor, Cleveland Clinic Journal of Medicine
A: Not only must an agent used to treat rheumatoid arthritis
be beneficial in the short term, it must both be relatively safe and maintain its
effectiveness over the long term. Because methotrexate has a rapid onset of action
(3–6 weeks) and works better than most other drugs, some experts felt, as early as
the mid-1980s, that it should be considered as a first-line disease-modifying drug for
rheumatoid arthritis.1 However, in an essay published in 1990, Furst2
argued that methotrexate should not be the first disease-modifying drug chosen because
many questions remained to be answered, among them:
• Was methotrexate capable of slowing
radiographic progression?
• What was the true frequency and impact of
long-term liver toxicity?
• How did methotrexate compare with other
disease-modifying agents?
• What drug reactions might occur when
methotrexate was combined with other agents?
Since that time, these questions have been
addressed and answered.
Methotrexate is effective
Radiographic studies indicate that methotrexate
reduces the frequency of erosions and increases the frequency of healing more effectively
than other disease-modifying drugs,3,4 although it does not halt the
progression of rheumatoid arthritis.
In addition, its early use may lead to clinical
remission. A preliminary, observational, retrospective cohort study5
demonstrated a higher frequency of remission in 28 patients initially given methotrexate
than in 55 matched controls treated initially with other disease-modifying drugs.
Methotrexate is safe
Recent meta-analyses and comparative studies have
demonstrated that methotrexate is not only the most effective but also among the safest of
existing disease-modifying drugs for rheumatoid arthritis.6–9 For example,
in one series,9 60% of patients continued to take methotrexate for 5 years vs
fewer than 25% for all other disease-modifying drugs.
The risk of long-term liver toxicity appears to
be low, with cirrhosis occurring in approximately 1 of 1,000 patients treated for 5 years.10
This frequency is so low that routine liver biopsy is no longer recommended.11
Recent reviews have also shown the relative
safety and added benefit of methotrexate when it is combined with other disease-modifying
drugs.12,13 The list of drugs that can be combined with methotrexate continues
to grow and now includes anti-tumor necrosis factor-alpha14 and leflunomide.15
Precautions
The long-term safety of methotrexate depends on
selecting appropriate patients. Do not give methotrexate to patients who:
• Have renal or hepatic impairment
• Use alcoholic beverages regularly
• Have primary hematologic diseases
• Are taking trimethoprim-sulfamethox- azole
long-term
Prescribe folic acid 1 mg/day for all patients
receiving methotrexate.16
Monitor patients for potential adverse effects on
a regular basis. In particular, obtain a:
• Complete blood count
• Serum creatinine level
• Aspartate aminotransferase (AST) level
(formerly known as serum glutamic oxaloacetic transaminase— SGOT)
• Serum albumin level (perhaps).
Conclusion
Methotrexate should be used as a first-line
disease-modifying drug for patients with moderately active rheumatoid arthritis (defined
as elevated acute-phase reactants and five or more swollen joints).12
References
1. Wilke WS, Mackenzie AH.
Methotrexate therapy in rheumatoid arthritis. Current status. Drugs 1986; 32:103–113.
2. Furst DE. Proposition:
methotrexate should not be the first second-line agent to be used in rheumatoid arthritis
if NSAIDs fail. Semin Arthritis Rheum 1990; 20:69–75.
3. Alarcon GS, Lopez-Mendez A, Walter J,
et al. Radiographic evidence for disease progression in methotrexate treated and
non-methotrexate disease modifying antirheumatic drug treated rheumatoid arthritis
patients: a meta-analysis. J Rheumatol 1992; 19:1868–1873.
4. Drosos AA, Tsifetaki N, Tsiakoue K, et
al. Influence of methotrexate on radiographic progression in rheumatoid
arthritis: a 60-month prospective study. Clin Exp Rheumatol 1997; 15:263–267.
5. Bologna C, Jorgensen C, Sany J.
Methotrexate as the initial second-line disease modifying agent in the treatment of
rheumatoid arthritis patients. Clin Exp Rheumatol 1997; 15:597–607.
6. Felson DT, Anderson JJ, Meenam RF.
Use of short-term efficacy/toxicity trade-offs to select second-line drugs in rheumatoid
arthritis: a meta-analysis of published clinical trials. Arthritis Rheum 1992;
35:1117–1125.
7. Fries JF, Williams CA, Ramey D, Bloch
DA. The relative toxicity of disease-modifying antirheumatic drugs. Arthritis
Rheum 1993; 36:297–306.
8. Wolfe F, Hawley DJ, Kathey MA.
Termination of slow-acting anti-rheumatic therapy in rheumatoid arthritis: a 14-year
prospective evaluation of 1017 consecutive starts. J Rheumatol 1990; 17:994–1002.
9. Pincus TE, Marcum SV, Callahan LF. Long-term drug therapy for
rheumatoid arthritis in 7 rheumatology private practices: 2. Second-line drugs and
prednisone. J Rheumatol 1992; 19:1885–1894.
10. Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid
arthritis patients receiving long-term methotrexate therapy: a prospective study of
baseline and sequential biopsy samples. Arthritis Rheum 1989; 332:121–127.
11. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines.
Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996;
39:723–731.
12. Wilke WS, Cash JM. The use of slow-acting (Class III)
symptom-modifying anti-rheumatic drugs in rheumatoid arthritis. Clin Immunother 1996;
5:309–325.
