Sulfasalazine


Sulfasalazine is used chiefly in the treatment of hemorrhagic ulcerative colitis and Crohn’s disease. It consists of a sulfonamide moiety linked by a nitrogen bond to aminosalicylate.
 
Incidence
5 to 55% of patients present side-effects.
 
Hypersensitivity is involved only in 2% of these manifestations.
 
Clinical manifestations
Manifestations may be divided in two categories:
 
1. Dose-dependent manifestations linked to the rate of acetylation of sulfapyridine are frequent (30%) under the following conditions:
  • doses > 4 g/ day
     
  • serum levels of sulfasalazine > 50µg/ ml
     
  • patients presenting slow acetylation rate.
These manifestations are:
  • General: headache, discomfort
     
  • Digestive: nausea, vomiting, anorexia, epigastralgia
     
  • Hematological: hemolytic anemia, hemolysis without anemia, methemoglobinemia
     
  • Cutaneous: bluish skin.
2. Hypersensitivity manifestations occurring early, independently of the dose or rate of acetylation, are uncommon (2%).
  • General: prolonged fever, arthralgia, vasculitis, lupus
     
  • Cutaneous: rash (1% of treatments), urticaria, erythrodermia, erythema multiforme, Lyell’s syndrome, Stevens-Johnson’s syndrome.
     
  • Hematological: autoimmune anemia, agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia
     
  • Respiratory: bronchospasm, pulmonary infiltrates and eosinophilia, diffuse interstitial fibrosis, obliterans bronchiolitis, subacute hypersensitivity pneumonitis
     
  • Digestive: hepatitis (12 cases, 2 deaths), pancreatitis, bloody diarrhea.
Diagnostic methods
No in vivo or in vitro method is currently available, other than stopping and then restarting sulfasalazine.
 
Mechanisms
Unknown, but the following hypotheses have been proposed:
 
Cytotoxicity in hematological manifestations.
 
Immune complexes in cutaneous vasculitis.
 
Delayed cell-mediated hypersensitivity in some cutaneous manifestations.
 
Management
91% of sulfasalazine intolerant patients are able to tolerate at least one of the three 5 ASA preparations (mesalazine, olsalazine, balsalazide), but adverse effects may occur: colitis, diarrhea and sometimes hypersensitivity reactions.
 
Desensitization is a safe approach in mild hypersensitivity reactions (rash, fever).
 
Absolute contra-indications: toxic epidermal necrolysis, fibrosing pulmonary alveolitis, eosinophilic pneumonia, granulomatous hepatitis, massive hemolytic anemia, agranulocytosis, bone marrow aplasia, neurotoxicity.
 
Many protocols have been published.
 
For example: starting with 1 mg and doubling the dose each week: 1 mg, 2 mg, 4 mg, 8 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1000 mg, 2000 mg. If a reaction occurs, slow the progression.

References

  1. Lachaux A, Legall C, Loras-Duclaux I, Aboufadel A, Hermier M, "Hypersensibilité à l’acide 5-aminosalicylique. Interêt de la désensibilisation par voie orale", Arch. Pediatr., 1997; 4 (2): 144-6
  2. Akahoshi K, Chijiiwa Y, Kabemura T, Okabe H, Akamine Y, Nawata H, "Desensitization for sulfasalazine-induced skin-rash in a patient with ulcerative colitis", J. Gastroenterol., 1994; 29 (6): 772-5
  3. Koski J.M, "Desensitization to sulphasalazine in patients with arthritis", Clin. Exp. Rheumatol., 1993; 11 (2): 169-70
  4. Tolia V, "Sulfasalazine desensitization in children and adolescents with chronic inflammatory bowel disease", Am. J. Gastroenterol., 1992; 87 (8): 1029-32
  5. Giaffer M.H, O’Brien C.J, Holdsworth C.D, "Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients with inflammatory bowel disease intolerant or allergic to sulphasalazine", Aliment. Pharmacol. Ther., 1992; 6 (1): 51-9

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.