Sulfasalazine-Induced Delayed Hypersensitivity Reaction Presenting as Fever, Aseptic Meningitis, and Mesenteric Panniculitis in a Patient with Seronegative Arthritis

Background

Aseptic meningitis is the inflammation of the meninges from a non-infective etiology. The 3 etiologies of aseptic meningitis include rheumatological diseases (eg, neurologic manifestations of sarcoidosis, Behçet disease, lupus, and granulomatosis with polyangiitis), malignancy (eg, solid organ and hematologic cancers with metastasis), and drug-induced aseptic meningitis (DIAM) [1,2]. Commonly implicated drugs in aseptic meningitis include non-steroidal anti-inflammatories, beta-lactam and sulfa antibiotics, and other immune-modulating agents, such as sulfasalazine[3]. The time from drug ingestion to manifestation of meningitis symptoms is highly variable, ranging from mere minutes to several months [2]. Common signs and symptoms of drug-induced aseptic meningitis include fever, headache, nuchal rigidity, photophobia, and altered consciousness [2].

Sulfasalazine is an anti-inflammatory, immunosuppressive drug, structurally related to salicylates. It is indicated for managing rheumatic diseases such as inflammatory bowel disease, rheumatoid arthritis, and polyarticular-course juvenile rheumatoid arthritis [3]. Sulfasalazine-induced aseptic meningitis (SIAM) is a rare cause of DIAM.

Case Report

An 82-year-old woman presented to the Emergency Department with a 3-day history of subjective fevers and chills, band-like headaches, increased lethargy, and dyspnea on exertion. She denied coryzal, urinary, or bowel symptoms, or recent sick contacts. Further systemic inquiry did not reveal any other symptoms. She was previously well at baseline, living alone in the community, and was independent with all activities of daily living.

Her past medical history was significant for recurrent urinary tract infections (UTI), and she had recently completed a course of amoxicillin for Enterococcus faecalis UTI 3 weeks before her hospital presentation. Her other medical history included ischemic heart disease with previous percutaneous coronary intervention 1 year before the admission, Crohn colitis in remission (with a normal colonoscopy 2 years ago), hypertension, polymyalgia rheumatica, steroid-responsive seronegative arthritis secondary to inflammatory bowel disease, asthma, and fibromyalgia. She had no history of smoking or alcohol excess.

Her medications included irbesartan 300 mg daily, isosorbide mononitrate 30 mg daily, aspirin 100 mg daily, clopidogrel 75 mg daily, diltiazem slow release 240 mg daily, esomeprazole 20 mg twice daily, sulfasalazine 1 g twice daily, fluticasone/ umeclidinium bromide/vilanterol inhaler, and methenamine hippurate 1 g twice daily. Of note, the sulfasalazine was newly commenced at 1 g twice daily 3 weeks before admission by her rheumatologist for seronegative arthritis, and her last dose was the day before the hospital presentation. Her drug allergies and intolerances included morphine, which caused vomiting and confusion, and statins and lamotrigine, which caused a mild skin rash.

At presentation, she had tachycardia, at 118 beats per min, and was febrile, at 38.5°C. Other vital parameters were within normal limits, with no supplemental oxygen requirement. She was alert and oriented, with no focal neurological signs. Physical examination revealed mild general abdominal tenderness, with no guarding or peritonism. On examination, she had no skin rashes, oral ulcers, alopecia, or active synovitis. Her hands revealed minor arthropathy, in keeping with osteoarthritis. She also had no palpable nodules on the physical examination. Electrocardiogram revealed new atrial fibrillation with no ischemic changes. Her chest radiograph was normal.

Initial biochemical results showed microcytic anemia with a hemoglobin of 89 mg/L, mean cell volume of 70 mg/L, and C-reactive protein of 96 mg/L. Her total white cells, including neutrophils and eosinophils, were within the normal reference range. A urine dipstick was positive for leukocytes only. The subsequent urine culture and microscopy were negative.

Based on the patient’s examination and biochemical results, her pyrexia was thought to be caused by an infection with an unclear source. Her new onset of atrial fibrillation on electrocardiogram was also thought to be driven by infection. A reaction to sulfasalazine was considered in the differential diagnosis, and the drug was discontinued also as a precautionary measure in the context of her presumed infection.

She was subsequently admitted to the General Medicine ward and underwent further investigation with blood cultures and autoimmune screening. She was also started on intravenous (i.v.) amoxicillin/clavulanate 875 mg/125 mg every 8 h while we were awaiting culture results. Her diltiazem was ceased on admission. Bisoprolol was started for rate control of her atrial fibrillation.

A contrast-enhanced portal venous phased computer tomography (CT) scan of her abdomen and pelvis showed a trace volume of free fluid in the right hemipelvis, with no distinct source of intra-abdominal sepsis identified. There was reported central mesenteric fat stranding and scattered lymph nodes interspersed, which was in keeping with mesenteric panniculitis (Figure 1). No hydronephrosis, hydroureter, or abnormal perinephric fat stranding was seen. No intrahepatic biliary dilatation or pancreatic, splenic, adrenal, or bladder anomalies were found.

A transthoracic echocardiogram did not show infective endocarditis. She had ongoing fever spikes despite i.v. antibiotics and acetaminophen. However, her other vital parameters remained within normal limits. After 4 days of i.v. amoxicillin/clavulanate, she remained febrile, with fluctuating temperatures from 37 to 40°C. She was given supplemental i.v. gentamicin, then switched to i.v. meropenem after consultation with the Infectious Diseases team over concerns of possible encephalitis. On day 5, she displayed a normal white blood cell count of 7.6 mg/L, an elevated erythrocyte sedimentation rate of 16 mmol/h, and a decreased C-reactive protein level of 48 mg/L. A third set of urine, blood, and stool cultures remained negative. Her serological screen was also negative for rheumatoid factor, anti-citrullinated protein antibody, anti-nuclear antibody, extractable nuclear antigen, and anti-neutrophil cytoplasmic antibodies.

Further serological testing for HIV, hepatitis, legionella, Q fever, and syphilis returned negative. Further workup for her pyrexial illness included a chest CT scan and respiratory swabs for viruses and atypical respiratory pathogens. Both were subsequently normal.

On day 7 of admission, the patient remained febrile, with a new onset of fluctuating attention and psychomotor retardation in keeping with hypoactive delirium. She did not develop any focal neurological signs and had no clinical signs of meningism. Aciclovir i.v. was added, and a contrast CT scan of the brain was obtained, which did not show any acute intracranial abnormality or contrast enhancement. A repeat abdominal CT scan showed a trace volume of free fluid in her right hemi-pelvis with no distinct source of intra-abdominal sepsis identified. There were also multiple discrete sub-centimeter mesenteric lymph nodes with a relative improvement of the central mesenteric haziness from the previous CT scan.

On cerebrospinal fluid (CSF) testing, a lumbar puncture showed pleocytosis (leukocytes 266 μL, polymorphonuclear neutrophils 34%), normal glucose level, and increased protein level (0.86 g/L). Magnetic resonance imaging of the brain was performed at this stage, which did not reveal any cerebral anomaly or features of encephalitis.

As the patient remained febrile and delirious, we decided to increase the patient’s meropenem to 2 g every 8 h while awaiting further CSF testing. In summary, CSF analyses for anti-neuronal antibodies, cryptococcal antigen, Epstein-Barr virus, cytomegalovirus, N-methyl-d-aspartate receptor antibodies, Rickettsia, Enterovirus, Neisseria meningitidis, Streptococcus pneumoniae, Listeria monocytogenes, and Herpes simplex virus were all negative. CSF cytology also revealed an increased proportion of T cells in the CSF, which was thought to be reactive.

Both meropenem and aciclovir were ceased after CSF cytology and polymerase chain reaction results were returned. The patient was on meropenem for a total of 9 days.

To rule out paraneoplastic syndromes, a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan was performed, which did not identify any FDG-avid occult malignancy or FDG-avid infection. There was also no metabolic evidence of large vessel vasculitis. Faint increased activity involving multiple small mesenteric lymph nodes favored a resolving inflammatory or reactive process, in keeping with the mesenteric panniculitis reported in a prior CT scan of the abdomen.

We were confident that her clinical course did not fit with any infective etiology. Her autoimmune screen was negative, and she did not have other features pointing toward a flare of her underlying rheumatological disease.

We, therefore, postulated that this was an unusual inflammatory syndrome manifesting as SIAM. We suspected a delayed hypersensitivity reaction based on the increased T-cell population in the patient’s CSF, which was thought to be reactive. A once-only i.v. dose of 8 mg dexamethasone was given, followed by 5 days of oral dexamethasone, with dramatic clinical response. Her pyrexia and delirium resolved within 48 h of administration of steroids (Figure 2). She received a short course of oral prednisolone on discharge and was weaned off her steroid medication. She has not relapsed since discharge and remained clinically well at a 2-month follow-up outpatient clinic review.

Discussion

We present the first Oceanian case of SIAM with atypical symptoms of pyrexial illness without meningism and incidental findings of mesenteric panniculitis of the abdominal CT scan. This case posed a diagnostic challenge due to the extended workup needed to exclude infective, autoimmune, and paraneoplastic causes of pyrexial illness.

A rheumatological patient on disease-modifying therapies presenting with headache and pyrexial illness of uncertain etiology should prompt consideration of DIAM, mainly when sero-logical and CSF testing is negative for pathogens. High-dose i.v. steroids, such as dexamethasone, effectively induce the resolution of aseptic meningitis, as indicated by the dramatic termination of pyrexia and symptoms of fatigue and hypoactive delirium in our patient.

SIAM is a rare disorder with competing hypotheses of its patho-physiology. The exact mechanism by which sulfasalazine causes hypersensitivity reactions is not fully understood. Some postulate type III or IV hypersensitivity reactions, while others theorize direct meningeal irritation, which would be more common in intrathecal drug administration [1]. Other pathways have also been proposed, such as immune complex deposition or induction of autoantibodies [4]. A summary of the proposed mechanisms of sulfasalazine-induced hypersensitivity reactions in the current literature is as follows:

Drug metabolism: Sulfasalazine is metabolized in the liver to form sulfapyridine and 5-ASA. The literature on SIAM data is rare; sulfamethoxazole/trimethoprim (SMX/TMP)-related DIAM has been better described. The exact pathophysiology of SMX/TMP-related DIAM has yet to be fully understood. Sulfapyridine, the active metabolite of sulfasalazine, is also a sulfonamide drug, like sulfamethoxazole. Both drugs contain an aromatic amine group at their N4 position. The cross-reactivity between sulfasalazine and SMX/TMP is supported by positive lymphocyte transformation tests for both medications in patients previously known to have either sulfasalazine or SMX/TMP allergy [4]. Given her medical history of uri-nary tract infections and previous tolerance of trimethoprim, this is not a sufficient explanation of our patient’s hypersensitivity reaction.

Immune system activation (type I and III hypersensitivity reactions): Sulfasalazine can trigger an immune response, which can lead to the release of inflammatory mediators, such as histamine, prostaglandins, and leukotrienes. This release of inflammatory molecules can cause rash, pyrexia, and joint pain. In type III hypersensitivity reactions, antibodies form complexes with the drug, activating complement [1]. In rare instances, sulfasalazine can cause a type I immediate hypersensitivity reaction. Type I reactions usually present as urticaria, angioedema, dyspnea, and hypotension within minutes to hours of drug ingestion. In severe cases, it can lead to anaphylaxis. In our patient’s case, type I and type III reactions are unlikely explanations for her symptoms due to her delayed presentation and lack of active synovitis, arthritis, vasculitis, or glomerulonephritis.

Genetic predisposition: Some patients can have genetic variants that make them more susceptible to hypersensitivity reactions to sulfasalazine. For example, specific HLA alleles, such as HLA-B*08: 01 or HLA-A*31: 01, have been associated with agranulocytosis in patients taking sulfasalazine [5]. Our patient was not tested for HLA alleles during this admission.

Type IV T-cell activation (type IV hypersensitivity reactions): Sulfasalazine has been shown to activate T cells in vitro, which could lead to a hypersensitivity reaction in some patients. This mechanism could be involved in type IV delayed hypersensitivity reactions, which typically occur several days after exposure to the drug [1]. Hydroxylamine metabolites in the sulfapyri-dine group of sulfasalazine can form a haptenized structure. The immune system can perceive the haptenized structure as foreign, initiating antibody production and immune cell activation, which can cause a hypersensitivity reaction involving cytotoxic CD4+ and CD8+ T cells [6]. Delayed-type hypersensitivity reactions are commonly characterized by a rash, which can be pruritic or painful. The rash can also appear on any part of the body. Other symptoms include pyrexia, arthralgia, and edema [7]. Interestingly, while our patient’s timeline was most in keeping with a delayed-type hypersensitivity reaction, she did not exhibit any dermatologic signs, unlike the other case reports of sulfasalazine-related hypersensitivity reactions [7,8].

The most likely explanation for our patient’s hypersensitivity reaction to sulfasalazine is a type IV delayed hypersensitivity reaction. Type IV hypersensitivity reactions often manifest 1 to 8 weeks after initiating drug therapy, which is in keeping with our patient’s symptom onset [9]. We do not believe that the patient’s aseptic meningitis can be attributed to her underlying inflammatory bowel disease, as Crohn disease had been in remission at the time of her presentation. She did not experience any symptoms associated with a Crohn flare, such as abdominal cramping, diarrhea, or hematochezia [10]. There was also no colitis on the CT scan of the abdomen.

Case reports on SIAM in published literature are rare, with only 7 cases published outside Australia in the last 3 decades [3,11,12]. This may be the first case report of SIAM in Oceania.

Our patient also had unique symptomatology, as she did not have overt features of meningism (such as photophobia and nuchal rigidity), which are commonly described in the other case reports of SIAM [3,11,12]. The patient’s abdominal CT finding of mesenteric panniculitis is also a novel manifestation of SIAM not reported anywhere else in the literature. Mesenteric panniculitis is defined as the inflammation of the mesenteric fat of uncertain etiology and pathophysiology. It has been detected in patients with various pathologies, such as surgery, trauma, biliary tree disorders, vasculopathy, neoplasms, infections, and autoimmune diseases [13]. The diagnosis of mesenteric panniculitis is usually one of exclusion after ruling out other causes of abdominal pain, such as acute cholecystitis, acute pancreatitis, and appendicitis [14]. We believe that this patient’s mesenteric panniculitis was acutely caused by SIAM, given that she presented with vague abdominal pain on her initial examination. Her subsequent FDG-PET scan excluded any FDG-avid malignancies and showed radiological improvement before steroid therapy commenced.

The treatment of SIAM needs to be well-delineated. Ceasing the drug is an obvious first step; however, as in our case, the patient remained symptomatic for almost 2 weeks before steroid therapy. Corticosteroids, such as dexamethasone and prednisolone, help to reduce meningeal inflammation and irritation by inhibiting pro-inflammatory signals and promoting anti-inflammatory signals. Healthcare providers should be cognizant of this rare adverse reaction and monitor patients on sulfasalazine for signs and symptoms of aseptic meningitis. Speedy diagnosis and discontinuation of the medication are paramount. In our case, initialization of corticosteroids led to rapid resolution of symptoms, in contrast to the results of a literature review on managing aseptic meningitis [1].

Conclusions

In conclusion, SIAM is a rare but potentially severe adverse reaction that should be considered in patients on sulfasalazine who develop fever, headache, and neck stiffness. Prompt diagnosis and discontinuation of the offending medication, supportive care, and corticosteroids remain the mainstay of therapeutic management.