Identification, Significance, and Management of Complement Inhibitor–Induced Headaches in Patients With Paroxysmal Nocturnal Hemoglobinuria

Lindsey Fold, PharmD, The University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, NC; Nina Inayan, PharmD, PGY-1 Pharmacy Resident, NYU Langone Health, New York, NY; Justin Arnall, PharmD, BCOP, FCCP, Clinical Pharmacist, Hematology, Atrium Health Specialty Pharmacy Services, Charlotte, NC

After receiving the complement inhibitors that were recently approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), headaches are a common and often undercharacterized side effect. The headaches described in clinical trials may be benign, but they can also be a symptom of bacterial meningitis, a condition for which patients receiving complement inhibitors have an increased risk. In patients with PNH, headaches related to treatment with complement inhibition result from elevated nitric oxide levels, whereas headaches in patients with meningitis are a result of inflammation of the meninges. It is essential for pharmacists and other practitioners to educate patients and appropriately distinguish between these types of headaches in patients with PNH who receive complement inhibitors because treatment approaches differ significantly. The prompt recognition of headache that results from meningitis is crucial for timely antimicrobial intervention and the prevention of potentially serious complications.

Symptom Overview

The mainstay of treatment for the ultra-rare hematologic disorder PNH is complement inhibition, which can be achieved through several agents that act on various points in the complement cascade.¹ Among the FDA-approved therapies for PNH, the most frequently reported adverse event is headache, which occurs in more than 10% of patients.^2-7 Patients who receive complement inhibitors also have an increased risk for bacterial meningitis, which is often characterized by severe headache as well.⁸ It is essential for patients and prescribers to differentiate between a headache that is related to complement inhibition and a headache that results from meningococcal disease, because each type of headache requires a different treatment approach.

The incidence of headaches that result from receiving complement inhibitors ranges from 7% with pegcetacoplan to 44% with eculizumab (Table 1).^2-7 These headaches predominantly occur during the initial 6 months of treatment, after which they significantly decrease. Typically, these headaches are brief, mild to moderate in intensity, and can be effectively managed with nonopioid analgesics, which allows patients to continue therapy with complement inhibitors.

Bacterial meningitis classically presents as a triad of symptoms, including headache, fever, and nuchal rigidity.⁹ Headaches associated with meningitis tend to be diffuse, have a sudden onset, and affect the entire head rather than a specific area.⁹ Early recognition and initiation of antimicrobials are essential to minimize the risk for death and other serious complications that result from bacterial meningitis (Table 2).

Etiology

One of the defining features of PNH’s pathophysiology is the presence of blood cells that are deficient in surface proteins linked to the cell membrane by glycosylphosphatidylinositol molecules.¹⁰ Glycosylphosphatidylinositol-linked proteins serve many functions, one of which is complement mediation. Consequently, red blood cells in patients with PNH are more vulnerable to complement-mediated destruction, which results in a significantly shortened half-life in circulation. Complement inhibitors have the ability to obstruct this process, thus preventing intravascular hemolysis and the subsequent complications of PNH.¹⁰

If PNH is not appropriately treated, the lysis of red blood cells causes hemoglobin to be released into the patient’s circulatory system.¹⁰ Initially, this free hemoglobin binds to haptoglobin; however, once the haptoglobin becomes saturated, the remaining free hemoglobin rapidly and irreversibly binds nitric oxide, leading to a rapid drop in nitric oxide levels in the peripheral blood. Nitric oxide is recognized for its vasodilatory properties and plays a pivotal role in the regulation of vascular tone, blood flow, and systemic oxygenation.^10,11 Nitric oxide depletion has been linked to primary headaches, including migraine, tension-type, and cluster headaches, as a result of its vasodilation and ability to enhance central sensitization at the spinal or trigeminal levels.¹¹ Because complement inhibition in patients with PNH leads to less hemolysis, hemoglobin release into the bloodstream is minimized, thus preserving the patient’s nitric oxide levels.¹⁰ This preservation may contribute to the headaches that patients who are receiving these agents have, which are typically transient, because symptoms decrease as the body undergoes a physiologic restoration back to steady-state nitric oxide levels. This is also why these headaches tend to diminish with subsequent treatment or when the medications are used for the treatment of non-PNH indications.¹²

Complement inhibitors increase the risk for meningococcal disease by up to 2000-fold as a result of the inhibition of terminal complement, which is vital in the defense against encapsulated bacteria.⁸ Bacterial meningitis occurs when bacteria travel to the brain, where they infect the meninges; this can lead to inflammation and the destruction of nerve cells, causing dull-to-severe pain, brain damage, or even stroke.⁹ A headache resulting from bacterial meningitis might feel similar to a migraine headache, with a key differentiator being that the pain is typically diffuse, whereas pain resulting from migraines tends to be unilateral.¹³

Treatment Options

Because headaches associated with complement inhibition are primarily mediated by nitric oxide, therapies that reduce nitric oxide levels are the treatment of choice. Nonopioid analgesics have inhibited nitric oxide in a variety of clinical and experimental studies.^14-17 For example, ibuprofen decreases the levels of inducible nitric oxide synthase mRNA and protein, thereby modulating nitric oxide production in vitro.¹⁸ Acetaminophen inhibits the same inducible nitric oxide synthase, but at a different level; it acts transcriptionally, whereas nonsteroidal anti-inflammatory drugs act translationally or posttranslationally.¹⁹ Although evidence largely suggests that aspirin also inhibits the synthesis of nitric oxide, some studies hint at a potential stimulatory role, so this agent should be used with caution for this indication.^20-22 Because PNH may be associated with thrombocytopenia in cases where platelet activation leads to cell lysis, the use of acetaminophen would be preferred over nonsteroidal anti-inflammatory drugs to reduce the risk for bleeding.²³ Acetaminophen should be dosed at 325 to 650 mg orally every 4 to 6 hours or at 1 g every 6 hours as needed, with a maximum dose of 4 g daily.²⁴

With bacterial meningitis–related headaches, prevention is key. The Centers for Disease Control and Prevention recommends ensuring that patients who are receiving complement inhibitors are up-to-date on the meningococcal ACWY and meningococcal group B vaccines to cover the most common serogroups.⁸ All FDA-approved complement inhibitors for PNH have associated Risk Evaluation and Mitigation Strategy (REMS) programs in place that require certain vaccinations and education for patients and prescribers on the early signs and symptoms of meningococcal infection to facilitate timely intervention if necessary.^25,26 The REMS programs for the distal complement inhibitors (eculizumab, ravulizumab, and crovalimab) only require vaccination against meningitis,^25,26 whereas the proximal inhibitors (danicopan, iptacopan, pegcetacoplan) also carry an indication for protection against Streptococcus pneumoniae via the pneumonia vaccine and H. influenzae type B via the Haemophilus influenzae type B vaccine,^2-7 although it is best practice to ensure that patients are protected against all of these organisms, regardless of the agent used (Table 3).^27,28

According to the Centers for Disease Control and Prevention, if treatment with a complement inhibitor must be started within 2 weeks of vaccination, patients should receive antimicrobial prophylaxis to encapsulated organisms for at least the 2-week duration from the vaccines to allow time to develop an adequate immune response.^2-7 If a patient has meningococcal infection, they should start treatment with dexamethasone and empiric antibiotic therapy until a causative pathogen can be identified per the Infectious Diseases Society of America.²⁹ For individuals aged 2 to 50 years, empiric therapy typically targets Neisseria meningitidis and S. pneumoniae. The agents preferred by the Infectious Diseases Society of America are vancomycin combined with a third-generation cephalosporin, such as ceftriaxone. For patients aged >50 years, empiric coverage is broadened to include Listeria monocytogenes and aerobic gram-negative bacilli. In these cases, vancomycin and a third-generation cephalosporin such as ceftriaxone should be used, with the addition of ampicillin to specifically cover L. monocytogenes. Once the culture data have been finalized, empiric antibiotics can then be switched to targeted therapy based on the patient’s susceptibilities.²⁹

Course of Therapy

In patients who received eculizumab, the complement inhibitor most likely to cause a headache, 94% of those who had headaches reported symptoms within the first 48 hours of administration.³⁰ These headaches were primarily confined to the first 2 weeks of therapy during the induction phase.³⁰ They are transient and will likely resolve once the patient’s nitric oxide levels normalize, but nonopioid analgesics such as acetaminophen may be used to control symptoms in the interim. It is important to monitor the patient’s total daily intake of acetaminophen to avoid hepatotoxicity, with a maximum daily dose of 4 g daily for most people. Patients with liver disease should restrict the daily dose of acetaminophen to 2 g daily or even less if severe liver disease is present.³¹ Nonsteroidal anti-inflammatory drugs may also be used, albeit sparingly, to avoid antiplatelet effects in patients with PNH, who may have thrombocytopenia at baseline.²³

For bacterial meningitis, prompt recognition and treatment are essential. With early intervention, the symptoms, including headache, should gradually improve within the first 2 to 3 days.³² Infections that have not been treated for longer and have thus become more serious are more likely to cause longer-term problems.

Conclusion

Headaches that result from treatment with complement inhibition in patients with PNH arise from a transient increase in nitric oxide levels, which is why they typically occur after initial doses, and the headaches that occur after receiving complement inhibitors also present different from headaches that result from meningitis, which allows for straightforward differentiation as long as providers are informed about these distinctions. With the recent approval of novel complement inhibitors for the treatment of PNH, their use for this indication is expected to grow, underscoring the importance of accurately identifying headache etiology to provide proper care.

Author Disclosure Statement
Dr Fold, Dr Inayan, and Dr Arnall have no conflicts of interest to report.

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