Infliximab-induced headache and infliximab-induced meningitis: two ends of the same spectrum?

Abstract: This report describes a case of aseptic meningitis induced by the tumor necrosis factor-[alpha] inhibitor infliximab. The patient, a 51-year-old female, was being treated for Crohn's disease. After an infliximab infusion, she had headache, fever, arthralgia, myalgia, and meningismus. Cerebrospinal fluid analysis was remarkable for a neutrophilic pleocytosis and elevated protein. Other potential causes of meningitis were excluded. Her symptoms completely resolved within 24 hours of presentation. Because infliximab commonly causes headache and is very immunogenic, we infer that infliximab-induced meningitis is immune-mediated and underrecognized. Potential risk factors and means for minimizing its occurrence are offered.

Key Words: aseptic meningitis, Crohn's disease, headache, infliximab, serum sickness

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Infliximab (Remicade, Centocor, Inc; Malvern, PA) is a chimeric monoclonal antibody that binds to tumor necrosis factor-[alpha] (TNF-[alpha]), preventing it from binding to TNF-[alpha] receptor. Common side effects of infliximab include headache, fever; chills, nausea, myalgia, arthralgia, rash, and infection. We describe the second reported case of aseptic meningitis induced by infliximab.

Case Report

A 51-year-old female presented to our emergency department in June 2004 with headache, fever, arthralgia, myalgia, and neck stiffness. Her medical history was remarkable for Crohn's disease. On the day before her admission, she had received intravenous infliximab infused over a period of 2 hours. The infusion was uneventful, but 3 hours later, she had severe arthralgia and myalgia that began in her lower extremities and then ascended to involve her entire body. Severe cephalgia, neck stiffness, and fever soon followed. The patient reported no localizing neurologic symptoms, photophobia, cough, dyspnea, nausea, diarrhea, or rash. In 1999, she had received two doses of infliximab and recalled having diaphoresis, chills, and jitteriness after the second infusion. She then received two more doses early in 2004 after being premedicated with prednisone, with no significant reaction. She had not received any steroids before this infusion. She denied recent ingestion of any other prescription medications, over-the-counter agents, or herbal remedies.

Upon presentation, she was febrile (temperature, 101.1[degrees]F), in obvious distress from pain, and exhibited meningismus. The remainder of her physical examination was normal. Blood chemistry panel, blood count, and chest roentgenogram were all normal. A lumbar puncture yielded a grossly turbid cerebrospinal fluid (CSF) and microscopic analysis revealed 2,075 white blood cells, of which 60% were segmented cells, 39% monocytes, and 1% lymphocytes. CSF total protein was elevated at 212 mg/dL (normal, 15 to 45) and CSF glucose was normal at 41 mg/dL (normal, 40 to 70). No organisms were seen with the Gram stain.

Empiric administration of intravenous cefotaxime, ampicillin/sulbactam, vancomycin, fluconazole, and methylprednisolone was initiated. The patient's symptoms dramatically improved during the initial 6 hours after admission and had resolved by 24 hours. The following CSF studies were also negative: cultures; antigens for Haemophilus influenzae, Neisseria meningitides, Streptococcus pneumoniae; and polymerase chain reaction for herpes simplex virus and enterovirus. Blood culture and serum Cryptococcal antigen were also negative. Antigens for Legionella, S pneumoniae, and Histoplasma were absent from the urine. The PPD skin test was nonresponsive. The patient was discharged to home 2 days after admission without any antibiotics or corticosteroids. Her discharge diagnosis was infliximab-induced aseptic meningitis.

Discussion

Infliximab was approved by the US Food and Drug Administration in August 1998 for the treatment of Crohn's disease and in October 1999 for the treatment of rheumatoid arthritis. Some common side effects of infliximab are headache (29%), fever (13%), infection (35%), arthralgia (13%), and rash (18%). (1) Our search of the medical literature uncovered only one previous report of infliximab-induced meningitis. (2) A database search of our hospital system's medical records found no additional cases of aseptic meningitis associated with infliximab therapy. The manufacturer and the Food and Drug Administration have received no additional such reports.

The diagnosis of drug-induced aseptic meningitis requires exclusion of other causes of meningitis, a temporal association of the clinical onset of meningitis with the administration of the suspected agent, and resolution of the meningitis after withdrawal of the agent. Analysis of the CSF in drug-induced meningitis typically demonstrates neutrophil-predominant pleocytosis with cell counts in the 100 to 1,000 cells per cubic millimeter range, normal to low glucose, and increased protein. The most common offending drugs are nonsteroidal antiinflammatory drugs and antibiotics. Patients with underlying autoimmune disorders appear to be predisposed to drug-induced meningitis. The interval between drug intake and the development of meningitis varies from several minutes to several hours. Prior exposure to the medication has been documented in one third to one half of the patients. After drug withdrawal, clinical recovery occurs in 1 to 5 days. (3)

Antibodies to infliximab are much more likely to develop in response to episodic treatment and in patients who have had a prolonged drug holiday between courses. (4) One study reported serum sickness reactions in one fourth of patients who received infliximab after at least a 2-year treatment interval and affected patients had high titers of anti-infliximab antibodies. (5) Antibodies are less likely to develop when the patient is simultaneously receiving other immunosuppressants (eg, methotrexate). (6) Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease. (7) The presence of antibodies to infliximab is associated with an increased risk of infusion reactions and serum sickness as well as an attenuated response to treatment. (6) We did not obtain antibody titers to infliximab. Our patient appeared to be at high risk for an adverse reaction, as she had a prior reaction, did not receive pretreatment corticosteroids with this dose, had a 5-year drug holiday, and was receiving no additional immunosuppressants.

A comparison of our case with that reported previously is warranted. Both patients had development of meningitis after several doses, had accompanying severe myalgia, and had a milder serum sickness response to an earlier dose. The attribution of meningitis as due to infliximab was clear in our case, as infectious causes and other pharmacologic causes of meningitis were excluded. Application of the Naranjo ADR probability scale to our case assigns the likelihood that meningitis was caused by infliximab as "probable."

Our patient's clinical presentation with fever, myalgia, and arthralgia was consistent with a serum sickness reaction. Serum sickness reactions are not uncommon with infliximab administration, having been reported to occur in 2.8% of patients in one large clinical trial. (8) The induction of meningitis may be mediated through infliximab's effects on TNF. More likely, however, meningitis is the result of a hypersensitivity reaction, as supported by its occurrence only after several doses and its accompaniment with a serum sickness-like reaction.

Clinicians need to be aware that infliximab predisposes patients to infections, including infectious meningitis. There is evidence that these patients appear to be at particular risk for acquiring Listeria, coccidioidomycosis, and Tuberculous meningitis. (9-11)

Infliximab-induced meningitis probably is underrecognized with milder cases or those not dominated by meningeal symptoms, not investigated further. As noted, headaches are very common reactions to infliximab and may be part of a clinical spectrum that includes serum sickness and meningitis.

Conclusion

Several lessons emerge from our observations. First, our case provides the most compelling evidence thus far that infliximab can induce aseptic meningitis, a diagnosis that is made after excluding other causes of meningitis including Listeria, coccidioidomycosis, and Mycobacterium tuberculosis. This acute reaction appears to be an immune-mediated, perhaps hypersensitivity phenomenon and may represent part of a serum sickness reaction to the murine component. Infliximab-induced meningitis may not be rare but simply underrecognized, based on the fact that headache and serum sickness commonly occur in response to infliximab therapy. Patients at particular risk for infliximab-induced meningitis may be those who had serum sickness symptoms in response to prior infusions. Effective measures can be taken to minimize the incidence of infliximab-induced serum sickness in general and meningitis specifically. These measures include administration through a maintenance regimen rather than through episodic treatments, avoidance of prolonged drug holidays, and avoidance of infliximab as monotherapy. (4,6) Pretreatment with intravenous hydrocortisone appears to be helpful in patients with prior infliximab-induced, acute immune-mediated reactions or in those at high risk for such reactions. (7)

Enjoy when you can, and endure when you must.
--Johann Wolfgang von Goethe

Accepted October 19, 2004.

References

1. Remicade. Physician's Desk Reference. Montvale, NJ: Thomson PDR, 2004, pp 1145-1148.

2. Marotte H, Charrin JE, Miossec P. Infliximab-induced aseptic meningitis. Lancet 2001;358:1784.

3. Moris G, Garcia-Monco JC. The challenge of drug-induced aseptic meningitis. Arch Intern Med 1999;159:1185-1194.

4. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: The ACCENT 1 randomized trial. Lancet 2002;359:1541-1549.

5. Hanauer SB, Rutgerts PJ, d'Haens G, et al. Delayed hypersensitivity to infliximab reinfusion after 2-4 year interval without treatment. Gastroenterology 1999;116:G3174.

6. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601-608.

7. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. Gastroenterology 2003;124:917-924.

8. Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: The Mayo Clinic experience in 500 patients. Gastroenterology 2004;126:19-31.

9. Bowie VL, Snella KA, Gopalachar AS, et al. Listeria meningitis associated with infliximab. Ann Pharmacother 2004;38:58-61.

10. Bergstrom L, Yocum DE, Ampel NM, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum 2004;50:1959-1966.

11. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-1104.

RELATED ARTICLE: Key Points

* Infliximab can induce aseptic meningitis.

* This reaction appears to be an immune-mediated, perhaps delayed, hypersensitivity phenomenon.

* Patients at particular risk for infliximab-induced meningitis may be those who had serum sickness symptoms in response to prior infusions.

* Effective measures can be taken to reduce the incidence of infliximab-induced serum sickness in general and meningitis specifically.

Nikita Hegde, MD, Charina Gayomali, MD, and Michael W. Rich, MD

From the Department of Medicine, Summa Health System and Northeastern Ohio Universities College of Medicine (NEOUCOM), Akron, OH.

None of the authors of this manuscript have any commercial, proprietary, or financial interest in any drug, device, equipment, or company mentioned in the manuscript.

Reprint requests to Dr. Michael W. Rich, Department of Medicine, 75 Arch Street, Suite 303, Akron, OH 44304. Email: [e-mail]