Herpes zoster meningitis in a rheumatoid arthritis patient treated with tofacitinib

Abstract

A man in his 70s with rheumatoid arthritis presented with seizures and coma and was transferred to our emergency department. Two months prior to admission, he started to take tofacitinib 10 mg/day. On admission, we noted a rash with a blister on the forehead, and herpes zoster was diagnosed. Cerebrospinal fluid examination suggested meningitis. An MRI of the brain showed no abnormality. Based on these findings, he was suspected with herpes zoster meningitis. We discontinued tofacitinib and treated the patient with intravenous acyclovir for 2 weeks. He regained complete consciousness, but right forehead skin lesion, severe vision loss in the right eye and right facial nerve paralysis remained as sequelae. Six weeks after admission, we restarted tofacitinib with oral valaciclovir as antiviral prophylaxis. Two years after admission, we administered Shingrix, an adjuvant recombinant vaccine for herpes zoster, and discontinued oral valaciclovir.

Background

Janus kinase inhibitors (JAKi) are new synthetic disease modifying antirheumatic drugs that interfere with signal transduction pathways of several cytokines.¹ In 2012, tofacitinib, the first JAKi, was approved for treating rheumatoid arthritis in the USA. In recent years, JAKi has played a key role in the treatment of rheumatoid arthritis. Recent guidelines recommend considering JAKi for rheumatoid arthritis patients who are not a treatment target for conventional synthetic disease modifying antirheumatic drugs or biological disease modifying antirheumatic drugs.^{2 3} Currently, five of the available JAKis are approved for use in patients with rheumatoid arthritis.¹ Furthermore, JAKi appears to be effective for other diseases, such as psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease and COVID-19.^{1 4} Thus, it is expected that the use of JAKi will increase.

Type 2 cytokines play a major role in innate antiviral defence. Inhibition of interferon signalling using JAKi increases the risk of herpes zoster infection, particularly among Asians.^5–7 Moreover, the efficacy of a live-attenuated varicella zoster virus vaccine for patients with rheumatoid arthritis treated with JAKi remains questionable.¹ Live-attenuated varicella zoster virus vaccine should be avoided for patients using JAKi, since there is a risk for disseminated varicella-zoster virus infection.⁸

Furthermore, after administration of the live vaccine, one should wait for 3–4 weeks to start JAKi.¹ Shingrix, an adjuvant recombinant vaccine for herpes zoster, was approved by the Food and Drug Administration in 2018.

The central nervous system (CNS) is one of the sites of herpes zoster infection, and its involvement can be fatal.^{9 10} In the literature, there have only been a few reports of CNS infections related to the use of JAKi.^11–13 Here, we present a case of herpes zoster meningitis in a patient with rheumatoid arthritis, who was treated with tofacitinib.

Case presentation

A man in his 70s had rheumatoid arthritis for the last 30 years. He had been previously treated with etanercept, abatacept, tocilizumab and golimumab, all of which had failed. Methotrexate was discontinued due to pancytopenia. Two months prior to admission, he started to take tofacitinib 10 mg/day in addition to salazosulfapyridine 1000 mg/day. He was admitted to our hospital for seizures and coma. He had not been vaccinated against herpes zoster. He had no history of herpes zoster infection (chicken pox and shingles). On admission, seizure was noted to have been stopped and the patient had a Glasgow coma scale (GCS) score of 3/15. Vital signs were normal except for a fever of 37.8℃. We observed a rash with a blister on the forehead, around the eye and the nose; accordingly, herpes zoster was diagnosed. The following blood parameters were observed: serum creatinine, 0.93 mg/dL; blood urea nitrogen, 18.0 mg/dL; sodium, 133 mmol/L; potassium, 4.3 mmol/L; chloride, 101 mmol/L; C reactive protein, 2.56 mg/dL; white blood cells, 13.2×10⁹/L; haemoglobin, 157 g/L; platelets, 235 × 10⁹/L. Cerebrospinal fluid examination revealed the following: 25/µL polymorphonuclear cells, 180/µL monocytes, 134 mg/dL protein level and 81 mg/dL glucose concentration. An MRI of the brain showed no abnormality. Based on the characteristic skin lesions, we suspected herpes zoster meningitis. We terminated tofacitinib and started to treat him with intravenous acyclovir 10 mg/kg every 8 hours. In the emergency room, seizure relapsed, prompting immediate administration of 5 mg diazepam. Seizure soon stopped, but the patient remained comatose.

Outcome and follow-up

On the following day, the patient recovered with a GCS score of 14/15. The following results were obtained. Blood culture and cerebrospinal fluid culture were negative. The corrected visual acuity and intraocular pressure in the right eye were 0.01 and 38 mm Hg, respectively. We also conducted an anterior eye examination and funduscopy. Based on the findings of these examinations, we diagnosed that the patient’s vision loss was attributed to iridocyclitis and the resulting secondary glaucoma.

Although we did not obtain information regarding serum and cerebrospinal fluid varicella zoster virus, herpes zoster meningitis was diagnosed based on the presence of typical skin lesions and good response to acyclovir. We continued acyclovir for 2 weeks. He eventually regained complete consciousness (GCS score of 15/15); however, his right forehead skin lesion (figure 1), severe vision loss in the right eye and right facial nerve paralysis remained as sequelae. Six weeks after admission, his rheumatoid arthritis disease activity was extremely high. We restarted tofacitinib with oral valaciclovir as antiviral prophylaxis to control the disease activity of rheumatoid arthritis. Three months later, visual acuity was not recovered, and we evaluated that it was irreversible. Two years after admission, Shingrix had become commercially available in Japan. Therefore, we administered Shingrix and discontinued oral valaciclovir. At 3 years and 7 months postadmission, there is no recurrence of herpes zoster infection.

Figure 1.

A rash was noted on the right aspect of the forehead.

Discussion

We report a serious case of herpes zoster meningitis in a patient with rheumatoid arthritis, who was treated with tofacitinib. Although we saved the patient’s life, his right forehead skin lesion, severe vision loss in the right eye and right facial nerve paralysis remained as sequelae.

A few cases of CNS infection as a result of adverse event of JAKi had been reported.^11–13

In particular, one patient had polycythaemia vera and was treated with ruxolitinib.¹¹ The case was a 39-year-old woman who was diagnosed with meningoencephalitis. She was treated with a 14-day course of intravenous acyclovir. She recovered without sequalae and restarted JAKi with long-term oral acyclovir. Similar to our patient, disease activity for some patients cannot be controlled without using JAKi, in which some patients can develop recurrent zoster. Following recovery from herpes zoster infection, restarting JAKi with oral valaciclovir as antiviral prophylaxis can be an option in such cases.¹

In 2018, incidence rates of herpes zoster infection in patients with ulcerative colitis receiving tofacitinib was reported.¹² Among 1157 patients treated with tofacitinib, 65 patients developed herpes zoster, reporting an incidence rate of 4.07 per 100 patient-years in their cohort. Of the 65 patients, one patient developed encephalitis.

In 2021, the first case of herpes zoster myelitis in a patient with rheumatoid arthritis, who was treated with tofacitinib, was reported.¹³ They concluded that clinicians should be aware of the severe neurological complications in immunocompromised patients, especially those receiving JAKi.

Unfortunately, since the reports on CNS infection associated with JAKi are limited, we could not assess its clinical features; therefore, further studies are warranted.

Shingrix has been shown to be safe in patients with rheumatoid arthritis treated with JAKi. However, its efficacy in preventing herpes zoster infection in patients treated with JAKi has not been established.^{14 15} Furthermore, it has been established that using JAKi is a risk factor for herpes zoster infection.^{6 7} Administering Shingrix before initiating JAKi may be beneficial, especially for those older than 50 years, since Shingrix is recommended for people older than 50 years old in the general population.¹⁶

To summarise, we encountered a serious case of herpes zoster meningitis in a patient with rheumatoid arthritis, who was treated with tofacitinib. If herpes zoster infection occurs in patient on JAKi therapy, restarting JAKi with oral valaciclovir as antiviral prophylaxis can be an option. As reports on CNS infection associated with JAKi are limited, further studies are warranted.

Learning points.

• We report a rare case of herpes zoster meningitis in patient with rheumatoid arthritis, who was treated with tofacitinib.

• Herpes zoster infection in a patient using JAKi can be serious.

• Following recovery from herpes zoster infection, restarting JAKi with oral valaciclovir can be an option.

• Administering Shingrix before initiating JAKi may be beneficial, especially for patients older than 50 years.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).