Continuing Education Activity

Sulfasalazine is a disease-modifying antirheumatic drug (DMARD) used in the treatment and management of autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease. This activity reviews the indications, contraindications, mode of action, adverse events, and other key elements of sulfasalazine therapy in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients with inflammatory bowel disease and rheumatoid arthritis and its related conditions and sequelae.

Objectives:

• Explain the mechanism of action of sulfasalazine.
• Describe the adverse effects and contraindications of sulfasalazine.
• Identify appropriate monitoring steps and toxicity of sulfasalazine.
• Outline interprofessional team strategies for improving care coordination and communication to advance sulfasalazine and improve outcomes.

Indications

Sulfasalazine is indicated for the treatment of chronic inflammatory diseases such as rheumatoid arthritis in children and adults and ulcerative colitis. It also has off-label uses in treating patients with ankylosing spondylitis, mild to moderately active Crohn's disease, psoriasis, and psoriatic arthritis.

FDA-approved Indications

Rheumatoid Arthritis

The FDA approved sulfasalazine for the treatment of patients with rheumatoid arthritis. It is cheap, easy to administer, and lacks teratogenicity compared to other disease-modifying antirheumatic drugs. There is currently no cure for rheumatoid arthritis. Non-steroidal anti-inflammatory medications and corticosteroids are most frequently used to relieve pain and stiffness. However, they do not moderate disease progression. Disease-modifying antirheumatic drugs can decrease or delay disease progression. Sulfasalazine has been in use for decades as a disease-modifying antirheumatic drug.[1][2] Newly developed biological disease-modifying antirheumatic drugs include tumor necrosis factor (TNF)-alpha inhibitors (infliximab, adalimumab, etanercept, golimumab, certolizumab), anti-CD 20 antibodies (rituximab), T-cell targeted therapies (abatacept), interleukin-6 receptor antibody (tocilizumab), interleukin-1 inhibitor (anakinra), and Janus kinase inhibitor (tofacitinib).[3]

Sulfasalazine is indicated for patients with rheumatoid arthritis who have not responded adequately with salicylates or other non-steroidal anti-inflammatory drugs. Clinical trials have proven that sulfasalazine was associated with a significant reduction in disease activities, whether used alone or in combination. In the American College of Rheumatology 2015, sulfasalazine is part of the non-biologic disease-modifying antirheumatic drugs for use in the management of rheumatoid arthritis patients with low to moderate or even high disease activity.[4] A few studies have suggested that genetic polymorphisms, especially genes involved in the folate pathway, affect the efficacy of sulfasalazine in rheumatoid arthritis; this is still an ongoing area of research, hence routine genetic testing is not recommended before treatment initiation.[5]

Polyarticular Juvenile Idiopathic Arthritis 

Although sulfasalazine has been used for more than four decades to treat patients with rheumatoid arthritis, the first multicenter, double-blind, and randomized controlled trial of patients with active juvenile idiopathic arthritis conducted in 1998. This study has shown that sulfasalazine is effective in the treatment of this condition. Although treatment withdrawal due to adverse events was more frequent in the sulfasalazine treated group, sulfasalazine still rated as safe as those events were transients or reversible upon treatment cessation.[6] A follow-up study 10 years later did show significantly better outcome scores, including several active joints, patients' well-being, duration of the clinical remission off medication in the sulfasalazine group.[7]

Ulcerative Colitis

Sulfasalazine was initially used for patients with rheumatoid arthritis, but further study discovered that it has some role in treating patients with inflammatory bowel disease. Sulfasalazine is FDA-approved for ulcerative colitis but not FDA-approved for Crohn disease. Two randomized controlled trials have shown that sulfasalazine was more effective than a placebo for the induction and maintenance of remission in ulcerative colitis. The current ulcerative colitis guideline suggests using sulfasalazine in patients who are in remission and already on sulfasalazine or patients that have dominant arthritic symptoms.[8]

Non-FDA Approved (off-label) Indications

Ankylosing Spondylitis

Tumor necrosis factor inhibitors are the favored therapeutic agents for the treatment of ankylosing spondylitis. Sulfasalazine is used off-label for a patient who has persistent peripheral arthritis, but a tumor necrosis factor inhibitors are contraindicated.[9] Its usage in ankylosing spondylitis is limited to certain situations such as no other treatment options left duet to toxicity, contraindication, cost, and patient with peripheral arthritis involvement.[10][11]

Crohn's Disease

Sulfasalazine may serve as an alternative option for patients with mild Crohn disease based on a meta-analysis of 19 randomized controlled trials where sulfasalazine was superior to placebo in inducing remission.[12][13] However, the evidence for its effectiveness in the mucosal healing is not available and therefore is not strongly recommend in Crohn's disease.[14] In contrast, sulfasalazine is the first-line therapy for mild to moderate ulcerative colitis because the disease is limited to the mucosal surface layer. 

Psoriatic Arthritis

Psoriasis is a chronic inflammatory disease with signs and symptoms in the skin and joints. Although the first-line of treatments for mild disease is a topical agent, systemic therapy is indicated for some patients with more severe disease. Monoclonal antibody biologics such as TNF-alpha blockers are useful agents for treatment. However, they should be administered by injection, and have serious adverse effects. Newly developed drugs such as tofacitinib (Janus kinase inhibitor) and apremilast (inhibitor of phosphodiesterase-4) are small molecules that can be given orally. Also, disease-modifying antirheumatic drugs such as methotrexate and sulfasalazine may be administered orally. The role of sulfasalazine in psoriatic arthritis is limited based on current evidence that it only gives benefit for the joint and skin disease and is less effective and tolerated than other commonly used agents such as methotrexate and leflunomide.[15][16][17][18]

Mechanism of Action

The exact mechanism of sulfasalazine is not fully understood. Furthermore, it is not known whether sulfasalazine or its metabolites such as sulfapyridine and 5-aminosalicylic acid are responsible for its anti-inflammatory effects. The detailed description for the mode of action of sulfasalazine is still under investigation as does the immunological and pathological mechanisms involved in rheumatoid arthritis and inflammatory bowel disease. 

Sulfasalazine is a prodrug that consists of the 5-aminosalicylic acid (mesalamine or mesalazine) and sulfapyridine linked by an azo bond. Sulfasalazine is too big to be absorbed in the small intestine. Bacteria in the colon cleaves the azo bond and liberates active compound 5-aminosalicylic acid, which is believed to work locally in ulcerative colitis rather than systemically after being absorbed into the circulation.[19]

The following immunomodulatory effects of sulfasalazine and its metabolites have been suggested as the underlying mechanisms of their action; (1) Sulfasalazine inhibits transcription factor nuclear factor kappa-B (NF-kB), thereby suppressing the transcription of NF-kB responsive pro-inflammatory genes including TNF-alpha.[20]; (2) Sulfasalazine inhibits TNF-alpha expression by inducing caspase 8-induced apoptosis in macrophage.[21]; (3) Sulfasalazine inhibits osteoclast formation by suppression of receptor activator of NF-kB ligand (RANKL) expression and stimulation of osteoprotegerin, which is a natural inhibitor of RANKL.[22]; (4) Sulfasalazine induces conversion of adenine nucleotides to adenosine by ecto-5’-nucleotidase and its anti-inflammatory activities mediated by adenosine.[23]; (5) Salicylates and sulfasalazine inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of the NF-kB pathway or prostaglandin synthesis.[24]; (6) Sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid inhibit B cell function but not T cell function and suppress the production of IgM and IgG.[25]; (7) Sulfapyridine inhibits the secretion of inflammatory chemokines interleukin-8, growth-related gene product-alpha, and monocyte chemotactic protein-1.[26]; (8) Phosphorylation and activation of adenosine monophosphate-activated protein kinase by 5-aminosalicylic acid inhibit the pro-inflammatory NF-kB signaling pathway.[27]

Administration

Sulfasalazine is available in 500 mg oral tablets, immediate and delayed-release form. Delayed-release tablets should not be chewed and swallowed whole. The administration is preferable after meals. 

Clinical indication directs dosing guidelines in adults.

• Rheumatoid arthritis: 500 mg once daily or 1 g per day in 2 divided doses up to a maximum of 3 g per day in divided doses.
• Ulcerative colitis: initial dose:3 to 4 g per day in divided dose at less than equal 8-hour intervals. Maintenance: 2 g per day in divided dose at less than equal 8-hour intervals. 
• Ankylosing spondylitis (off-label): 500 mg or daily up to 2 to 3 g per day in divided doses.
• Crohn disease: 3 to 6 g per day in divided doses up to 16 weeks.
• Psoriatic arthritis: initial 500 mg once daily up to 2 to 3 g per day.
• In children and adolescents (6 to 16 years) for juvenile idiopathic arthritis: 30 to 50 mg per kg per day in 2 divided doses up to a maximum of 2 g per day.

There is a desensitization regimen for patients who may be hypersensitive to treatment. The recommendation is to start with a daily dose of 50 to 250 mg and double it every 4 to 7 days until achieving the therapeutic level. Discontinue the drug if symptoms of hypersensitivity occur. 

Adverse Effects

The most common side effects include nausea, vomiting, anorexia, dyspepsia, male infertility (reversible), headache, and skin rash. The types of skin rashes related to its use include urticaria, maculopapular lesions, and blue discoloration.[28] The most serious skin hypersensitivity reaction is toxic epidermal necrosis.[29] In a study of more than 250 men exposed with sulfasalazine, researchers found the subjects to have low sperm counts, abnormal sperm motility, and morphology, which were reversible within mostly three months of stopping sulfasalazine treatment.[30]

The less common reactions include leukopenia, thrombocytopenia, hemolytic anemia, abnormal liver function tests, fever, and dizziness. Reports exist of the most serious side effects affecting almost every organ, but they are rare. A few case reports showed some relationships between sulfasalazine use and Epstein-Barr virus-associated hypersensitivity syndrome, granulomatosis with polyangiitis, and hemophagocytic syndrome.[31][32]

Contraindications

Contraindications to sulfasalazine include patients with hypersensitivity to sulfasalazine, its metabolite, sulfonamides, salicylates, or any component of the formulation, intestinal or urinary obstruction, and porphyria. 

Monitoring

There are reports of blood dyscrasias, pancreatitis, interstitial nephritis, hepatitis, and hepatic failure in patients treated with 5-aminosalicylic acid or sulfasalazine.[33] The baseline level of complete blood count, serum creatinine, and liver function test should be obtained before initiating pharmacotherapy with sulfasalazine. The test should be repeated every 2 to 4 weeks for the first three months after the start of treatment or following an increase in dose, then every 8 to 12 weeks during the subsequent three months and every 12 weeks afterward. Serious skin reactions require monitoring.

Toxicity

Dose-related toxicity of sulfasalazine includes gastrointestinal upset such as nausea, vomiting, diarrhea, and anorexia, central nervous system symptoms like headache, and hematologic manifestations including leukopenia, hemolytic anemia, macrocytosis, and megaloblastic anemia. There is no specific antidote for sulfasalazine overdose toxicity. Symptomatic and the healthcare team should provide supportive care. Patients require monitoring for signs of respiratory distress and other vital signs. 

Enhancing Healthcare Team Outcomes

Sulfasalazine has been widely used for the treatment of inflammatory bowel disease and rheumatoid arthritis.[28] Rheumatology and gastroenterology are the two fields that utilize this drug extensively in managing these diseases. It is not unusual in daily practice to see patients with those diseases maintained with sulfasalazine; hence comanagement with the primary care team and other specialists is fundamental. The physician must able to recognize the adverse reactions and contraindications, as are mentioned above. Patients with decreased blood cell count while using this drug should prompt the health care provider to adjust or even stop this drug with notification to the prescriber (usually a specialist). Physicians, nurses, and pharmacists all must verify the allergic history before prescribing and dispensing sulfasalazine. The pharmacists should also assist the team by verifying appropriate dosing and monitoring interactions with other drugs. Sulfasalazine therapy requires the involvement of interpersonal team and coordination to ensure optimal patient outcomes. [Level 5]