Sulfasalazine is an anti-inflammatory medication consisting of a combination of 5-aminosalicylic acid and the sulphonamide sulfapyridine. Currently this drug is approved by the US FDA for the treatment of ulcerative colitis and rheumatoid arthritis. Sulfasalazine has also been used for some skin conditions.
Off-label indications of sulfasalazine in dermatology
Non-approved reported uses of sulfasalazine in dermatology include:
- pemphigus vulgaris
- pyoderma gangrenosum
- dermatitis herpetiformis
- alopecia areata
- lichen planus
- corticosteroid-dependent chronic idiopathic urticaria
- plaque psoriasis
- cutaneous lupus erythematosus
- atrophie blanche
- Pemphigus vulgaris represents a potentially life-threatening autoimmune blistering disease.
- The use of sulfasalazine and pentoxifylline as adjuvant therapy for the treatment of pemphigus vulgaris has been assessed in at least one double-blind randomised study of 64 patients with pemphigus vulgaris.
- The use of pentoxifylline and sulfasalazine induced a faster and more significant decrease in serum tumour-necrosis-factor-α levels, and this decrease was associated with rapid clinical improvement at 8 weeks in 42 treated patients compared with 22 placebo recipients.
Chronic idiopathic urticaria
- A retrospective medical chart review of 19 patients with antihistamine-unresponsive urticaria treated with sulfasalazine showed that 14 patients (74%) reported significant improvement, 4 patients (21%) reported minimal improvement but were not satisfied with their symptom relief, and 1 patient (5%) reported a worsening of symptoms.
- Of the 13 patients who required systemic steroids to control their urticaria, all were able to reduce or discontinue steroid use during sulfasalazine therapy.
- Results of a double-blind randomised prospective trial of 52 patients with idiopathic lichen planus treated with sulfasalazine for 6 weeks (max dose 2.5 g/day) showed significant improvement in the cutaneous lesions in patients treated with sulfasalazine compared with placebo (82.6% vs 9.6%). The improvement rate of pruritus was 14.3% in the placebo group and 91.3% in the sulfasalazine group.
Cutaneous lupus erythematosus
- The effectiveness of sulfasalazine for the treatment of cutaneous lupus erythematosus was discovered by chance in the early 1990’s when a patient who had been using topical corticosteroids to treat her dermatosis for the past 10 years noticed an improvement in her condition when she was prescribed sulfasalazine for suspected ulcerative colitis, followed by a recurrence when treatment was withdrawn.
- Since this discovery at least 2 open-label studies, one each in Turkey and in France have assessed the efficacy of sulfasalazine in cutaneous lupus.
- A complete or partial response was observed in 9 of the 13 patients enrolled in the Turkish trial and in 13 of the 18 in the French trial. In the latter study sulfasalazine (2 g/d) was given to 18 patients with severe cutaneous lupus, all of whom had contraindications for or treatment failure with antimalarial drugs and thalidomide.
- The French study found a clear correlation between acetylation phenotype and treatment efficacy: nine of the ten patients showing a complete response were fast acetylators, and four of the five patients failing treatment were slow acetylators.
- A response was observed within 4 to 8 weeks of starting treatment, except for scalp lesions which improved at a later date (after 4 to 5 months of treatment).
- Sulfasalazine may be useful as a second-line treatment for fast acetylators with severe SLE as an alternative to thalidomide.
- The efficacy of sulfasalazine 3-4 g/day in plaque psoriasis has been explored in at least 2 studies from USA.
- In an 8-week double-blind trial of sulfasalazine for the treatment of moderate-to-severe psoriasis, 23 and 27 patients received the active and placebo tablets, respectively. At the end of the double-blind phase, in 17 assessable patients receiving sulfasalazine, 7 (41%) had marked improvement, 7 (41%) had moderate improvement, and 3 (18%) demonstrated minimal change.
- Only 1 patient receiving placebo demonstrated moderate improvement
- Sulfasalazine may be an oral treatment option for patients with psoriasis that are unsuitable for methotrexate, acitretin, or phototherapy.
- There is anecdotal evidence that sulfasalazine 1g three times daily may be effective in atrophie blanche. which can be a chronic condition for which there is no satisfactory treatment.
- In two patients, leg ulcers healed within 3 months of commencing treatment with sulfasalazine 1g three times daily.
- Sulfasalazine has been used to treat alopecia areata. The literature is anecdotal.
- A retrospective chart review of a series of patients from USA showed that 7 (23%) of 30 patients with alopecia areata treated with sulfasalazine for 3 months achieved cosmetically acceptable hair regrowth. Doses ranged from 1 to 4 g per day. Eleven patients discontinued medication due to side effects, mainly gastrointestinal.
- In 2 open-label studies involving 64 patients with severe recalcitrant alopecia unresponsive to topical and intralesional corticosteroids, 5% minoxidil, or psoralen plus ultraviolet-A (PUVA) there was complete hair re-growth in approximately 27-30% of patients and partial hair re-growth in 30-40% of patients after sulfasalazine therapy.
- In one study, 26 patients with recalcitrant or severe alopecia areata (>40 percent scalp hair loss) received treatment with sulfasalazine 500 mg bid for the first month, then 1 g bid for the second month, and 1.5 g bid for a further three months.
- In the second study, 39 patients with persistent alopecia areata received 3 g of oral sulfasalazine for 6 months.
- Sulfasalazine has been found useful in the treatment of pyoderma gangrenosum cases that have inflammatory bowel disease.
- Sulfasalazine doses start from 1-4 g daily, with the maintenance dose of 0.5-1 g daily.
- In dermatitis herpetiformis, sulfasalazine 1–2 g/day may provide an effective alternative to dapsone if it fails to control the disease or dapsone causes adverse events.
Mechanism of action of sulfasalazine
- The mechanism of action of sulfasalazine has not yet been fully elucidated but is believed to be multiple.
- It acts both as an anti-inflammatory and an immunomodulant, inhibiting inflammatory cell chemotaxis and cytokine and antibody production.
- It acts in part as an tumour necrosis factor inhibitor.
- When used for dermatological purposes, the immunomodulatory effects seem to play a significant role.
Drug interactions with sulfasalazine
- Concomitant intake of sulfasalazine and digoxin may reduce serum digoxin levels by 50% resulting in lack of efficacy of digoxin.
Adverse effects with sulfasalazine
Common but harmless and transient adverse effects include:
- nausea and vomiting
Other rare but potentially serious adverse effects include:
- neutropenia (reduced neutrophil white cells)
- moderate increase in liver transaminases (abnormal liver function tests)
- potentially fatal mucocutaneous reactions, e.g. morbilliform rash, urticaria and angioedema and Stevens Johnson syndrome / toxic epidermal necrolysis.
Practical tips for using sulfasalazine in dermatology
As the dermatological indications are all off-label, treatment should only be started after receiving patient consent. Contraindications to its use are:
- hypersensitivity (allergy) to sulphonamides
- G6PD (glucose-6-phosphate-dehydrogenase) deficiency
- acute intermittent porphyria and variegate porphyria
A pretreatment work-up should include:
- a complete blood and platelet count
- screening for G6PD deficiency
- liver and renal function tests with urinary protein measurement
- antinuclear and anti-DNA antibody tests if necessary
- N-acetyltransferase (NAT2) genotyping if necessary.
The US FDA has classified sulfasalazine as Category B. The effect that sulfasalazine has on an unborn child has not been studied extensively. Sulfasalazine should only be used during pregnancy if clearly needed. Sulfasalazine does pass into breast milk, and could affect a nursing infant.
The Australian TGA has classified sulfasalazine as Category A. Category A medicines have been taken by a large number of pregnant women and women of childbearing age, without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
- A complete blood and platelet count and liver function tests should be carried out every two weeks for two months and then every three months thereafter
- Tests for antinuclear and native anti-DNA antibodies should be carried out once a year, where necessary.