Sulfasalazine

What is sulfasalazine?

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 Food and Drug Administration (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 spontaneous urticaria
• Plaque psoriasis
• Cutaneous lupus erythematosus
• Urticaria
• Generalised morphoea
• Atrophie blanche.

With the exception of psoriasis, alopecia areata and lichen planus, all off-label dermatology indications are based on isolated case reports and/or small, uncontrolled series.

Pemphigus vulgaris

• 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 spontaneous 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.

Lichen planus

• 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.

Plaque psoriasis

• The efficacy of sulfasalazine 3-4 g/day in plaque psoriasis has been explored in at least 2 studies from the 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.

Atrophie blanche

• 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.

Alopecia areata

• Sulfasalazine has been used to treat alopecia areata. The literature is anecdotal.
• A retrospective chart review of a series of patients from the 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% 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.

Pyoderma gangrenosum

• 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.

Dermatitis herpetiformis

• 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.

How does sulfasalazine work in inflammatory diseases?

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 a tumour necrosis factor inhibitor.
• The immunomodulatory effects of sulfasalazine seem to be particularly important when used for dermatological purposes.
• It is also a folate antagonist, so it is antiproliferative.
• It has antimicrobial properties. 

What are the drug interactions with sulfasalazine?

• Concomitant intake of sulfasalazine and digoxin may reduce serum digoxin levels by 50% resulting in a lack of efficacy of digoxin.
• Concomitant treatment with azathioprine may increase azathioprine toxicity.
• Rarely, sulfasalazine increases the effect of oral diabetic treatments and of warfarin.

What are the adverse effects of sulfasalazine?

Side effects are more likely in slow acetylators, who have higher plasma concentrations of sulfapyridine.

Common but harmless and transient adverse effects include:

• Nausea, vomiting and diarrhoea
• Headache
• Dizziness.

Other rare but potentially serious adverse effects include:

• Neutropenia (reduced neutrophil white cells)
• A moderate increase in liver transaminases (abnormal liver function tests)
• Rare pulmonary toxicity, most often eosinophilic pneumonia
• Potentially fatal mucocutaneous reactions.

Potential cutaneous adverse events due to sulfasalazine include:

• Morbilliform rash
• Drug-induced urticaria
• Drug hypersensitivity syndrome
• Lichenoid drug eruption
• Drug-induced lupus erythematosus
• Drug-induced photosensitivity
• Drug-induced hyperpigmentation
• Drug-induced alopecia
• Raynaud phenomenon
• 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 to a sulfonamide or salicylate
• Glucose-6-phosphate-dehydrogenase (G6PD) deficiency
• Severe liver or kidney disease
• Acute intermittent porphyria and variegate porphyria.

A pretreatment workup should include:

• 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.

Dosing

• The starting dose is 500 mg/day.
• The dose is titrated up to a maximum of 3000 mg/day in divided doses.
• Additional folic acid supplementation is advised.
• The dose should be reduced in patients with renal disease.

Pregnancy

The US FDA has classified sulfasalazine as Category B.

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. However:

• The effect that sulfasalazine has on an unborn child has not been studied extensively
• Sulfasalazine should only be used during pregnancy if clearly needed
• Folic acid is recommended during pregnancy to reduce the risk of neural tube defects in patients taking folate antagonists
• Sulfapyridine does pass into breast milk and could affect a nursing infant
• Male fertility may be reduced on sulfasalazine.

Treatment monitoring

• Complete blood and platelet count, and renal and liver function tests should be carried out prior to treatment, every two weeks for two months and then every three months thereafter.
• Pretest for G6PD deficiency.
• Tests for antinuclear and native anti-DNA antibodies should be carried out at baseline and once a year, where necessary.