Continuing Education Activity

Sulfasalazine, a potent disease-modifying antirheumatic drug (DMARD), helps manage autoimmune conditions like rheumatoid arthritis and inflammatory bowel disease. This activity discusses sulfasalazine's therapeutic indications, contraindications, and mechanism of action, crucial elements indispensable for the interdisciplinary team involved in patient care. Moreover, the activity focuses on adverse events and other essential facets of sulfasalazine therapy, ensuring healthcare professionals can navigate its complexities to optimize patient outcomes. By exploring off-label applications, pharmacokinetics, monitoring protocols, and clinical toxicology, participants gain an excellent grasp of sulfasalazine's utility, enabling them to tailor treatment strategies for individuals with inflammatory bowel disease, rheumatoid arthritis, and polyarticular juvenile idiopathic arthritis. With this understanding, healthcare practitioners can fine-tune therapeutic regimens to meet diverse patient needs, enhancing sulfasalazine therapy's efficacy and precision across various clinical contexts.

Objectives:

• Describe the mechanism of action of sulfasalazine.

• Identify the adverse effects and contraindications of sulfasalazine.

• Determine appropriate monitoring steps and toxicity of sulfasalazine.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from sulfasalazine therapy.

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 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 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-CD20 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 to salicylates or other non-steroidal anti-inflammatory drugs. Clinical trials have proven that sulfasalazine significantly reduced disease activities, alone or in combination. According to the American College of Rheumatology 2015, sulfasalazine is part of the non-biologic disease-modifying antirheumatic drugs for managing 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 4 decades to treat patients with rheumatoid arthritis, the first multicenter, double-blind, and randomized controlled trial of patients with active juvenile idiopathic arthritis was conducted in 1998. This study has shown that sulfasalazine is effective in treating this condition. Although treatment withdrawal due to adverse events was more frequent in the sulfasalazine-treated group, sulfasalazine was still rated as safe as those events were transient 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, and duration of the clinical remission of 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 in remission who are already on sulfasalazine or patients with dominant arthritic symptoms.[8]

Off-Label Indications

Ankylosing Spondylitis

Tumor necrosis factor inhibitors are the favored therapeutic agents for treating ankylosing spondylitis. Sulfasalazine is used off-label for a patient who has persistent peripheral arthritis, but tumor necrosis factor inhibitors are contraindicated.[9] Its usage in ankylosing spondylitis is limited to certain situations, such as no other treatment options left due to toxicity, contraindication, cost, and patient with peripheral arthritis involvement.[10][11] In adults experiencing active ankylosing spondylitis despite undergoing treatment with NSAIDs, the guidelines from the American College of Rheumatology recommend considering sulfasalazine, methotrexate, or tofacitinib. Sulfasalazine is suggested specifically for patients exhibiting prominent peripheral arthritis and when TNF-α treatment is either unavailable or not feasible.[12]

Crohn 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.[13][14] However, the evidence for its effectiveness in mucosal healing is not available and, therefore, is not strongly recommended for Crohn disease.[15] 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 treatment for mild disease is a topical agent, systemic therapy is indicated for some patients with more severe disease. Monoclonal antibody biologics such as TNF-α 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 benefits joint and skin disease. It is less effective and tolerated than other commonly used agents such as methotrexate and leflunomide.[16][17][18][19]

Mechanism of Action

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

Sulfasalazine is a prodrug comprising 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 cleave the azo bond and liberate the active compound 5-aminosalicylic acid, which is believed to work locally in ulcerative colitis rather than systemically after being absorbed into the circulation.[20]

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-α.[21]
2.  Sulfasalazine inhibits TNF-α expression by inducing caspase 8-induced apoptosis in macrophages.[22]
3.  Sulfasalazine inhibits osteoclast formation by suppressing receptor activators of NF-kB ligand (RANKL) expression and stimulating osteoprotegerin, a natural RANKL inhibitor.[23]
4.  Sulfasalazine induces the conversion of adenine nucleotides to adenosine by ecto-5’-nucleotidase and its anti-inflammatory activities mediated by adenosine.[24]
5.  Salicylates and sulfasalazine inhibit leukocyte accumulation by an adenosine-dependent mechanism independent of inhibiting the NF-kB pathway or prostaglandin synthesis.[25]
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.[26]
7.  Sulfapyridine inhibits the secretion of inflammatory chemokines interleukin-8, growth-related gene product-α, and monocyte chemotactic protein-1.[27]
8.  The pro-inflammatory NF-kB signaling pathway inhibits the phosphorylation and activation of adenosine monophosphate-activated protein kinase by 5-aminosalicylic acid.[28]

Pharmacokinetics

Absorption: Following oral administration, less than 15% of a dose of sulfasalazine is absorbed as the parent drug. Serum concentrations of sulfasalazine can be detected within 90 minutes of ingestion. The highest levels of sulfasalazine in the body are typically attained between 3 and 12 hours after ingestion, with the average highest concentrations occurring at around 6 hours. In comparison, peak plasma levels of sulfapyridine and 5-ASA occur for approximately 10 hours. The longer time it takes to reach peak plasma concentration suggests that the drug undergoes metabolism in the intestine by bacteria.[29] Sulfapyridine is well absorbed from the colon, with an estimated bioavailability of 60%. 5-aminosalicylic acid has an estimated bioavailability of from 10% to 30%. 

Distribution: The volume of distribution for sulfasalazine is 7.5 ± 1.6 L. Sulfasalazine is primarily bound to albumin (>99%), while sulfapyridine is only about 70% bound to albumin. Acetylsulfapyridine, the principal metabolite of sulfapyridine, is approximately 90% bound to plasma proteins.

Metabolism: Sulfasalazine is metabolized by intestinal bacteria to sulfapyridine and 5 ASA. Approximately 15% of a dose of sulfasalazine is absorbed as a parent and is metabolized in the liver. 5-aminosalicylic acid is primarily metabolized in the liver and intestine to N-acetyl-5-aminosalicylic acid via a non-acetylation phenotype-dependent route.[30]

Elimination: Sulfapyridine and 5-ASA metabolites are primarily eliminated as free metabolites or glucuronide conjugates in the urine. 5-aminosalicylic acid remains within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA in the feces. The clearance of sulfasalazine is 1 L/hr. Renal clearance is estimated to account for 37% of total body clearance. The plasma half-life for sulfasalazine is 7.6 ± 3.4 hrs. The rate of metabolism of sulfapyridine to acetyl-sulfapyridine is dependent upon acetylator phenotype. In fast acetylators, the mean half-life of sulfapyridine is 10.4 hrs, while in slow acetylators it is 14.8 hrs.

Administration

Available Dosage Forms and Strengths

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

Adult dosage: 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: The initial dose is 3 to 4 g per day divided into doses at less than equal 8-hour intervals. The maintenance dose is 2 g per day divided into doses at less than equal 8-hour intervals.
• 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 daily.
• Ankylosing spondylitis (off-label): 500 mg or daily up to 2 to 3 g per day in divided doses.[31]

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.

Specific Patient Populations

Hepatic impairment: The product labeling does not include dosage adjustments for sulfasalazine; use with caution.

Renal impairment: Sulfasalazine is associated with nephrolithiasis, especially in patients with inflammatory bowel disease undergoing sulfasalazine therapy. Ensuring hydration is essential to mitigate this complication.[32] Acute interstitial nephritis is a severe adverse event, and early recognition, along with the prompt discontinuation of sulfasalazine, is required.[33]

Pregnancy considerations: Sulfasalazine and its metabolite sulfapyridine can cross the placental barrier. Instances of neural tube defects (NTDs) in infants born to mothers exposed to sulfasalazine during pregnancy have been documented. According to the American Gastroenterological Association, sulfasalazine can be considered during pregnancy with folate supplementation.[34]

Breastfeeding considerations: Sulfasalazine and its active metabolite mesalamine exhibit limited excretion into breast milk. Sulfasalazine metabolite, sulfapyridine, is detected in both milk and infant serum, posing a potential risk of hemolysis, particularly in newborns and those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The highest risk of hemolysis in full-term newborns without G6PD deficiency is 8 days post-birth. Most experts generally regard mesalamine derivatives as safe for breastfeeding. In situations where maternal sulfasalazine use is necessary, discontinuing breastfeeding is not typically warranted. However, close monitoring of breastfed infants for diarrhea is advised. Preferential consideration is given to mesalamine derivatives that lack a sulfonamide component.[35]

Pediatric patients: The safety and efficacy of sulfasalazine in patients younger than 2 years old have not been documented. For juvenile idiopathic arthritis patients aged 6 to 16, the recommended dosage is 30 to 50 mg/kg/d, administered in 2 divided doses, with a maximum daily limit of 2 g.

Older adults: Older adults with rheumatoid arthritis demonstrated an extended plasma half-life for sulfasalazine, sulfapyridine, and their respective metabolites.

Adverse Effects

The most common adverse effects include nausea, vomiting, anorexia, dyspepsia, male infertility (reversible), headache, and skin rash. The skin rashes related to its use include urticaria, maculopapular lesions, and blue discoloration.[36] The most severe skin hypersensitivity reaction is toxic epidermal necrosis.[37] In a study of more than 250 men exposed to sulfasalazine, researchers found the subjects to have oligospermia, abnormal sperm motility, and morphology, all of which were reversible within 3 months of stopping sulfasalazine treatment.[38]

The less common reactions include leukopenia, thrombocytopenia, hemolytic anemia, abnormal liver function tests, fever, and dizziness. Reports exist of the most serious adverse 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.[39][40]

Drug-Drug Interactions

• The inhibition of thiopurine methyl transferase enzyme activity by SZ can potentially enhance the toxicity of azathioprine.[41]
• Sulfasalazine exerts inhibits the gastrointestinal absorption of digoxin, resulting in diminished bioavailability. Use with caution.
• Sulfasalazine infrequently may potentiate the effects of oral hypoglycemic medications and augment the anticoagulant impact of warfarin.[30]

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.[30]

Warning and Precautions

Acetylator status: The metabolism of sulfapyridine (SP) into acetylated sulfapyridine (AcSP) is influenced by polymorphic enzymes, leading to 2 distinct groups of individuals categorized as slow and fast acetylators. Roughly 60% of the Caucasian population falls into the category of slow acetylators. These individuals exhibit an extended plasma half-life for sulfapyridine (14.8 hours compared to 10.4 hours) and accumulate higher sulfapyridine levels in their plasma compared to fast acetylators. There is a potential association between being a slow acetylator of sulfapyridine and a higher likelihood of experiencing adverse events.[42]

Allergic reactions: The administration of sulfasalazine tablets warrants caution in individuals with pronounced allergic reactions. Sulfasalazine-induced hypersensitivity syndrome has been reported.[43]

Crystalluria: Ensuring sufficient fluid intake is imperative to mitigate the risk of crystalluria and the formation of stones.[44]

G6PD deficiency: Close monitoring for signs of hemolytic anemia is essential in patients with glucose-6-phosphate dehydrogenase deficiency.[45]

Monitoring

There are reports of blood dyscrasias, pancreatitis, interstitial nephritis, hepatitis, and hepatic failure in patients treated with 5-aminosalicylic acid or sulfasalazine.[46] 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 3 months after the start of treatment or following an increase in dose, then every 8 to 12 weeks during the subsequent 3 months and every 12 weeks afterward. Serious cutaneous adverse reactions such as toxic epidermal necrolysis require prompt discontinuation and intensive treatment.[47][48]

Toxicity

Signs and Symptoms of Overdose

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. Patients require monitoring for signs of respiratory distress and other vital signs.

Management of Overdose

There is no specific antidote for sulfasalazine overdose toxicity. The healthcare team should provide supportive and symptomatic care. Patients receiving sulfasalazine are at an increased risk of urolithiasis and may benefit from adequate hydration and urinary alkalization.[49][44]

Enhancing Healthcare Team Outcomes

Sulfasalazine has been widely used to treat inflammatory bowel disease and rheumatoid arthritis.[36] Rheumatology and gastroenterology are the 2 fields that utilize this drug extensively in managing these diseases. Seeing patients in daily practice with these diseases maintained with sulfasalazine is not unusual; collaborating with the primary care team and other specialists is essential for effective management. As mentioned above, the physician must recognize the adverse reactions and contraindications.

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 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 and coordination of an interprofessional team, including clinicians (MDs, DOs, NPs, PAs), specialists, nurses, and pharmacists to ensure optimal patient outcomes.