Azathioprine/rituximab

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

An approximately 70-year-old woman [exact age at the time of reaction onset not stated] developed liver toxicity following treatment with azathioprine for myasthenia gravis (MG). Subsequently, she developed myasthenia crisis secondary to COVID-19 following treatment with rituximab for MG [routes and time to reaction onsets not stated; not all dosages and outcome stated].

The woman, who had hypothyreosis and arterial hypertension, was diagnosed with AChR antibody positive MG in November 2018. In January 2019, she developed global respiratory insufficiency secondary to MG and required mechanical ventilation. She was treated with neostigmine, immune globulin [immunoglobulin], pyridostigmine and unspecified steroids. She started receiving azathioprine. However, she developed liver toxicity.

Azathioprine was discontinued following administration for only short-term. Despite immune globulin therapy, disease control was inappropriate. In July 2019, the woman started receiving rituximab 1000mg. Significant clinical improvement was noted with reduction in steroid requirement. The last dose of rituximab was administered on January 2020. In the beginning of March 2020, she developed mild symptoms of an upper respiratory tract infection with cough, fever and arthralgia. A nasopharyngeal test was positive for SARS-CoV-2 RNA. She was placed in home quarantine for 2 weeks. Thereafter, flu-like symptoms regressed. Four weeks after onset of COVID-19, at the age of 71 years, she experienced deterioration of her myasthenia with head drop, dyspnoea, bulbar symptoms, and mild proximal weakness of lower extremities. Myasthenia crisis was suspected. She was hospitalised. Upon admission, she did not have fever. However, a nitrite positive urinary tract infection was diagnosed [aetiology not stated]. She was initiated on immune globulin and piperacillin/tazobactam. On the second day, she developed respiratory insufficiency. A chest CT scan revealed signs compatible with COVID-19 pneumonia. Repeat nasopharyngeal test for SARS-CoV-2 RNA was found to be positive. She exhibited fluctuating subfebrile temperature. She required non-invasive positive pressure ventilation. She was treated with neostigmine and unspecified steroids. She received off-label treatment with two doses of convalescent-anti-SARS-CoV-2-plasma [convalescent plasma] 200mL transfusion from recovered donors within the first week after admission. Laboratory investigation revealed pre-existent lymphopenia along with elevated levels of CRP, interleukin-6 and ferritin. Serological analysis showed no specific IgG antibodies against SARSCoV-2 prior and after convalescent-anti-SARS-CoV-2-plasma therapy. Total Ig to SARS-CoV-2 was noted to be slightly increased 2 weeks after convalescent-anti-SARS-CoV-2-plasma transfusions. Her clinical course gradually improved. Five weeks after onset of myasthenia crisis, she was discharged in a good condition with only mild exertional dyspnoea. However, weekly SARS-CoV-2 PCR tests remained positive until May 2020. She continued to receive immune globulin therapy. In July 2020, a negative SARS-CoV-2 test was documented. At re-evaluation in August 2020, she had persistent mild dyspnoea, mildly reduced diffusion capacity, normal total lung capacity, elevated alveolar-arterial gradient and mildly reduced partial oxygen pressure in arterial blood. Chest CT scan demonstrated considerable improvement of the pneumonia pattern with mild residual parenchymal bands without evidence for pulmonary fibrosis. Evidence of chronic heart failure was also observed with elevated N-terminal-pro-B-type natriuretic peptide but preserved ejection fraction.