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CASE REPORT Table of Contents  
Ahead of print publication
Sulfasalazine-induced reaction cascade


 Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India

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Date of Submission29-May-2022
Date of Decision25-Jun-2022
Date of Acceptance28-Jun-2022
Date of Web Publication21-Sep-2022
 

  Abstract 

Sulfasalazine, a relatively well-tolerated, disease-modifying anti-rheumatoid drug has been reported to be associated with hepatic and cutaneous adverse events, in addition to its common adverse effect profile. The present case reports a reaction cascade involving hepatic, ocular, and cutaneous reaction in a female patient secondary to her sulfasalazine use. The report highlights the importance of multidisciplinary teamwork in the treatment and adverse event management in these cases, to help patients with better and safer treatment outcomes.

Keywords: Disease-modifying antirheumatic drugs, drug-induced liver injury, reaction cascade, sulfasalazine


How to cite this URL:
Saha K, Mukherjee S. Sulfasalazine-induced reaction cascade. APIK J Int Med [Epub ahead of print] [cited 2022 Sep 25]. Available from: https://www.ajim.in/preprintarticle.asp?id=356509



  Introduction Top


Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of rheumatoid arthritis and many other autoimmune conditions. Commonly used DMARDs include methotrexate, sulfasalazine, and antimalarials. Adverse drug reactions commonly reported include liver or bone toxicity and allergic skin reactions. These reactions have been a major concern with DMARDs monotherapy as well as combination therapy.[1] Sulfasalazine has been widely used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, the drug is known to have diverse adverse reaction profile based on its severity and rarity. While acute liver injury with sulfasalazine use has been reported to occur in 1/1,000 users, sulfasalazine has been held as a culprit drug for a wide range of dermatological reactions.[2] Majority of the reactions are noted in the initial months of therapy. The present case describes a reaction cascade secondary to sulfasalazine use in a female patient.


  Case Report Top


A 44-year-old normotensive euglycemic female, known case of polyarthritis and hypothyroidism presented with generalized skin rash [Figure 1] extending over upper arms and torso. On history elicitation, patient-reported to be initially on methylprednisolone 4 mg and well-tolerated. However, 7 days before presentation, she was put on sulfasalazine 500 mg twice daily substituting methylprednisolone, though no need for substitution was noted. Five days following intake of sulfasalazine, the patient developed this generalized skin rash. With sulfasalazine being the strongest suspicion, the drug was withdrawn and the patient was initiated on methylprednisolone 4 mg along with montelukast-levocetirizine combination and pantoprazole-domperidone combination. The rash however progressed to maculopapular form extending to the face and lower extremities, necessitating escalation of methylprednisolone dosing to 12 mg/day. The liver profile revealed increased bilirubin and liver enzyme levels along with three episodes of vomiting, progressing anasarca, fever, anorexia, and necrotizing dermatitis, the patient was advised admission under gastroenterology consultation. On admission, the patient was conscious but slightly confused. Her vitals were stable with pulse 86/min, BP – 130/80, SpO2 – 92%, respiratory rate – 20/min, and temperature – 99.6°F. On the general survey, the patient was moderately anemic and jaundiced with no edema or palpable lymph node. Abdominal examination stated the abdomen to be soft and nontender, spleen palpable, and a normal intestinal peristaltic sound heard. All other systemic examinations were within normal limits. Blood investigation revealed bilirubin – 4.8 mg/dl, SGOT – 6400 U/L, SGPT – 2610 U/L, ALP – 1980U/L, and INR 2. WBC count, erythrocyte sedimentation rate, and procalcitonin were high 17,300/cmm, 78 mm/h, and 0.83 ng/mL, respectively. Whole abdomen ultrasound revealed Grade II fatty liver, contracted thick-walled gallbladder, and mild splenomegaly. High-resolution computed tomography thorax revealed multiple bilateral axillary lymph nodes and right-sided thin pleural effusion. INR increased to 3.2, with Immunoglobulin E level at 3149 IU/mL. Urine culture revealed urinary tract infection with Escherichia coli. Accordingly, she was treated with rifaximin, Vitamin K, fosfomycin, moxifloxacin, and hydrocortisone. Upper glycemic index endoscopy was normal. Viral hepatitis and HIV profile were negative. Gradually, the patient worsened with bilirubin increased to 6.74 mg/dL. At this point, the patient was transferred to a higher center for better management. The patient improved under similar conservative management and was discharged in a hemodynamically stable state [Figure 2], [Figure 3], [Figure 4]. Although the patient's blood investigation errors were corrected, she was complaining of blurring of vision and redness of the eyes. She was referred to an ophthalmology hospital as symptoms started progressing to vision loss and floaters. Investigations revealed tractional retinal damage including macula in the left eye. The treatment was started with oral steroid prednisolone once daily and azathioprine 50 mg thrice daily. Serial reports of liver and renal function tests were done and found normal over the next 5 months. She underwent a vitrectomy operation for retinal detachment under steroid and azathioprine coverage. After multiple surgeries, her vision improved to near normal. However, while weaning prednisolone, she started having tinea corporis infection which was treated with antifungals (oral and locally applied). Careful restart and extremely slow tapering of steroids along with antifungal treatment finally cured fungal infections. The liver function continued to be within normal limits posttreatment. At present, she is on her regular hypothyroid treatment and calcium only. On pharmacovigilance workup, the WHO-UMC causality assessment scale[3] conferred the case to be under “probable” category. As per Hartwig-Siegel Scale,[4] the case was “severe” (level-5). The case was reported to the National Pharmacovigilance Programme.
Figure 1: Generalized Maculopapular Rash (Day 6 of drug intake)

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Figure 2: Patient on remission – Day 17 of admission

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Figure 3: Patient on remission – Day 17 of admission

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Figure 4: Patient on remission – Day 17 of admission

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  Discussion Top


Sulfasalazine is a modified sulfonamide composed of sulfapyridine that is covalently linked to 5-aminosalicylic acid. Most ingested sulfasalazine reaches the large bowel unchanged where it is split by colonic bacteria into sulfapyridine and 5-aminosalicylic acid (mesalazine). The latter remains in the large bowel but sulfapyridine is largely absorbed and eliminated in the urine, primarily after acetylation, which is primarily determined by polymorphisms of the N-acetyltransferase Type II (NAT2) gene. Almost 60% of Indians are slow acetylators as compared to a much smaller proportion of Caucasians, Chinese, and Japanese. Toxicity due to sulfasalazine including hepatitis appears, in general, to be more common in slow acetylators. Hepatotoxicity with sulfasalazine may occur as a direct result of the drug or its metabolites on hepatocytes or through immune activation.[5] Reactions to sulfasalazine are believed to arise because of an idiosyncratic delayed-type hypersensitivity reaction that may affect internal organs variably.

Treatment of drug-induced hepatotoxicity is mostly supportive, with prime focus on the immediate cessation of culprit drugs and institution of steroids based on reaction severity. Toxicity without typical features of hypersensitivity, such as a skin rash, is also well recognized. Ocular side effects with sulfasalazine have been earlier reported in some studies.[6],[7] The present case reports retinal detachment secondary to sulfasalazine use. The global database (VigiAccessTM) confers reporting of six cases of retinal disorders with sulfasalazine.[8] Ocular side effects have been reported to occur in 1% of total reported cases.[8] Cutaneous reactions have been reported in <5% of patients, usually maculopapular, pruritic, and generalized in nature.[9] Hypersensitivity has been principally linked to its sulfapyridine moiety. Severe cutaneous manifestations of erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, lichenoid, and lupus-like reactions have been also reported with sulfasalazine.[10]

Reaction cascade in a single patient often begets prolonged suffering in terms of psychological stress and economic aspect. It has a significant negative impact on patients' and caregivers' quality of life, and thus warrants caution. Such reaction cascade with a single moiety can also hinder future treatment adherence in such patients, which is very important in treating chronic ailments. Thus, patient education regarding the safety concerns as well as the efficacy of the treatment modalities is necessary.

Therapy initiation with sulfasalazine requires prudent risk-benefit assessment while prescribing, which can help mitigate these harmful incidents to the extent best possible. With the safety profile having multifactorial involvement, treatment and concerns with sulfasalazine can be best managed with interpersonal decision-making and coordination to achieve safer patient outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that their name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to acknowledge and support the untiring efforts and contribution of the Pharmacovigilance Programme of India toward ensuring better patient safety nationwide.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Wilsdon TD, Hill CL. Managing the drug treatment of rheumatoid arthritis. Aust Prescr 2017;40:51-8.  Back to cited text no. 1
    
2.
de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: A population based case-control study. Br J Clin Pharmacol 2004;58:71-80.  Back to cited text no. 2
    
3.
The Use of the WHO-UMC System for Standardised Case Causality Assessment. Available from: http://www.who-umc.org/Graphics/24734.pdf. [Last accessed on 2022 May 09].  Back to cited text no. 3
    
4.
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 4
    
5.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Sulfasalazine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548792/. [Last updated on 2017 Sep 25].  Back to cited text no. 5
    
6.
Jobanputra P, Amarasena R, Maggs F, Homer D, Bowman S, Rankin E, et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008;9:48.  Back to cited text no. 6
    
7.
Santodomingo-Rubido J, Gilmartin B, Wolffsohn JS. Drug-induced bilateral transient myopia with the sulphonamide sulphasalazine. Ophthalmic Physiol Opt 2003;23:567-70.  Back to cited text no. 7
    
8.
Sulphasalazine. Available from: https://www.vigiaccess.org/. [Last accessed on 2022 May 20].  Back to cited text no. 8
    
9.
Cannella AC, O'Dell JR. Traditional DMARDs: Methotrexate, sulfasalazine, leflunomide, hydroxychloroquine and combination therapies. In: Firestein GS, Budd R, Gabriel SE, McInnes IB, editors. Kelley's Textbook of Rheumatology. 10th ed. Philadelphia: Elsevier; 2017. p. 971-4.  Back to cited text no. 9
    
10.
Mushtaq S, Sarkar R. Sulfasalazine in dermatology: A lesser explored drug with broad therapeutic potential. Int J Womens Dermatol 2020;6:191-8.  Back to cited text no. 10
    

Top
Correspondence Address:
Shatavisa Mukherjee,
Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata - 700 073, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_71_22



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