Sulfasalazine

Saara Rawn MD/PhD, Raj Carmona MBBS FRCPC

INDICATIONS (including off-label uses)
Rheumatoid arthritis, Psoriatic arthritis, Juvenile Idiopathic Arthritis. 

Peripheral arthritis in patients with Spondyloarthritis (eg. ankylosing spondylitis). Inflammatory Bowel Disease (IBD)-related arthritis.

Ulcerative colitis


ADULT DOSING
Starting dose of 500 mg PO BID for 1 week, increasing by 500 mg weekly to maintenance 1000 mg PO BID

In IBD, doses of up to 4-6 g daily are used in 2-3 divided doses.


DOSE ADJUSTMENT
Hepatic Impairment

No dosage adjustments; use with caution.

Renal Impairment  

CrCl >50: No initial dose adjustment.

CrCl 10-50: 50% initial dose reduction (500 mg BID)

CrCl <10: 75% dose reduction (500 mg q daily)


MONITORING
Baseline:  CBC, AST, ALT, ALP, serum creatinine

Monthly for first 3-6 months: CBC, AST, ALT, then every 2-3 months thereafter.


CONTRAINDICATIONS
Hypersensitivity to salicylates, sulphonamides, or sulfasalazine. Urinary tract or intestinal obstruction. Porphyria.


COMMON SIDE EFFECTS AND ADVERSE REACTIONS

Sulfasalazine is considered to be generally safer than other DMARDS such as MTX and Leflunomide.  It is one of the “go to” DMARDs when a patient is considering pregnancy.

GI side-effects are most common: Nausea (RA 19%), dyspepsia (RA 13%), anorexia, gastric distress, vomiting

Central nervous system: Headache (RA 9%), dizziness

Dermatologic: Skin rash (RA 13%), pruritus, urticaria

Genitourinary: Oligospermia (reversible)

Hematologic: can cause agranulocytosis.  Leukopenia (RA 3%), thrombocytopenia (RA 1%), Heinz body anemia, hemolytic anemia

Hepatic: Abnormal hepatic function tests (RA 4%)


PREGNANCY AND LACTATION
Compared to background rates, sulfasalazine does not cause increases in miscarriage or fetal abnormalities.

If sulfasalazine is required by the mother, she may breastfeed, but careful observation of breastfed infants for diarrhea is advised.  In the newborn, it may cause kernicterus. If there is concern, consultation with a specialist is recommended.


MECHANISM OF ACTION
In rheumatoid arthritis, sulfapyridine is traditionally thought to be the active moiety, but some studies show that the parent molecule (salicylic acid and sulfapyridine joined by an azo bond) may also have some independent activity. The mechanism of action in RA has not been identified. Some theories include: B cell activation inhibition, reduces interleukin-6 production, inhibits nuclear factor-kappa B (NFkB), inhibits TNF factor alpha expression of macrophages. 


SUMMARY OF EVIDENCE (in development)
Weinblatt ME, et al. 1999. “Sulfasalazine treatment for rheumatoid arthritis: a meta-analysis of 15 randomized trials.” J Rheumatol 26:2123.

Fleischmann R et al. 2017 “Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor-methotrexate combination therapy versus triple therapy in rheumatoid arthritis” RMD Open Jan 3;3(1):e000371.

Clegg DO et al. 1996. “Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A department of Veterans Affairs Cooperative Study.” Arthritis Rheum 29(12):2013.