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Compare Methotrexate vs. Sulfasalazine

Head-to-head comparisons of medication uses, side effects, warnings, and more.

Key takeaways

Methotrexate (Otrexup, Rasuvo) and sulfasalazine (Azulfidine) are both used to treat rheumatoid arthritis (RA), but they have different uses and ways of working. Methotrexate is an antimetabolite that treats various cancers and non-cancer conditions like RA and psoriasis. It is given as an injection or may be taken by mouth as a tablet and works by blocking a protein important for cell growth. Sulfasalazine, on the other hand, is an anti-inflammatory medication available in immediate-release and delayed-release tablets. It treats ulcerative colitis (UC) and RA by breaking down into chemicals that reduce inflammation. Methotrexate can cause serious side effects like low white blood cells and kidney problems, while sulfasalazine commonly causes stomach issues like nausea and indigestion. Methotrexate is not safe during pregnancy, whereas sulfasalazine might not be safe for people with allergies to sulfa drugs. Both medications require regular monitoring by your healthcare provider to ensure safety and effectiveness.

Methotrexate (Trexall)
Sulfasalazine (Azulfidine)
Methotrexate (Trexall)
Sulfasalazine (Azulfidine)

Summary of Methotrexate vs. Sulfasalazine

Summary for Antimetabolite
Prescription only

Methotrexate (Trexall) belongs to a drug class called antimetabolites. It’s used as chemotherapy at high doses to kill cancer cells and treat different cancers, such as acute lymphoblastic leukemia (ALL). At lower doses, methotrexate (Trexall) is considered a disease-modifying antirheumatic drug (DMARD) that treats certain non-cancer conditions, such as rheumatoid arthritis (RA). This medication is a tablet that you take by mouth. For most conditions, it’s taken once a week, but for some, it’s taken more often than that. Methotrexate (Trexall) side effects include mouth sores, nausea, and stomach upset.

Summary for Anti-inflammatory
Prescription only

Sulfasalazine (Azulfidine) is an anti-inflammatory medication that comes in immediate-release and delayed-release tablets. Both formulations are used to treat ulcerative colitis (UC). The delayed-release tablets can also be used for rheumatoid arthritis (RA). Adults and children 6 years and older can take sulfasalazine (Azulfidine). It's best to split your total daily dose into a few smaller doses throughout the day. This medication can commonly cause stomach problems, such as nausea and indigestion, as side effects.

Indications of Methotrexate vs. Sulfasalazine

Indications for

Cancer:

•Acute lymphoblastic leukemia (ALL) in adults and children; given with other chemotherapy
•Cutaneous T-cell lymphoma in adults; given by itself or with other chemotherapy
•Advanced non-Hodgkin lymphoma in adults; given with other chemotherapy

Non-cancer conditions:

•Rheumatoid arthritis (RA) in adults
•Polyarticular juvenile idiopathic arthritis (pJIA) in children
•Severe psoriasis in adults
Indications for
•Ulcerative colitis (UC) - immediate-release and delayed release tablets
•Rheumatoid arthritis (RA) - delayed-release tablets only
•Polyarticular juvenile rheumatoid arthritis - delayed-release tablets only

Pros and Cons of Methotrexate vs. Sulfasalazine

Pros and Const for Antimetabolite
Pros
•Taken by mouth, so a good option for people who don’t like needles
•A non-steroidal option for autoimmune conditions (e.g., rheumatoid arthritis, psoriasis)
•Doesn’t typically cause hair loss or weight gain
Cons
•Might cause nausea and mouth sores
•Can raise your risk for infection
•Requires regular office visits and lab tests to check for serious side effects
Pros and Const for Anti-inflammatory
Pros
•Available as a lower-cost generic medication
•Safe to take for children 6 years and older
•Available as immediate-release and delayed-release tablets
•Delayed-release tablets helpful for people with bothersome stomach upset from the medication
Cons
•Can cause side effects like nausea, vomiting, and stomach upset
•Might cause low sperm count
•Might require regular blood work and lab tests to make sure your liver, kidneys, and blood counts are healthy and normal
•Might not be safe for people with allergies to sulfa drugs, aspirin, or other salicylates

Common Side Effects of Methotrexate vs. Sulfasalazine

Common Side Effects for
•Mouth sores
•Nausea or vomiting
•Diarrhea
•Stomach upset
•Dizziness
•Tiredness
•Chills
•Fever
•Infection
•Higher liver enzyme levels in the blood
•Low white blood cells
•Low platelet levels
Common Side Effects for

For UC:

•Nausea (33%)
•Vomiting (33%)
•Stomach upset (belly pain and cramping; 33%)
•Low appetite (33%)
•Headache (33%)

For RA (delayed-release tablets only):

•Nausea (19%)
•Indigestion (13%)
•Headache (9%)
•Belly pain (8%)
•Vomiting (8%)
•Fever (5%)

Warnings of Methotrexate vs. Sulfasalazine

Common Side Effects for
•Harm to unborn baby
•Allergic reaction
•Low blood cell counts
•Damage to the digestive tract
•Liver damage
•Lung problems
•Serious skin problems (including skin burns)
•Kidney damage
•Risk of serious side effects with dosing errors
•Effect on folic acid levels in the body
•Serious infections
•Serious nervous system problems
•Risk for new cancers
•Tumor lysis syndrome
•Changes to your ability to have children (infertility)
•Higher risk for side effects if you have extra body fluid
Common Side Effects for
•Risk of liver, kidney, and blood problems
•Low sperm count
•Serious infections
•Severe skin and allergic reactions

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