Introduction

Ocrelizumab, a humanized monoclonal that targets the CD20 antigen on B cells, has marked effects in reducing disease activity [1, 2]. Infusion-related reaction and infections have been reported by premarketing data. Increased receptiveness to infections and/or to their increased severity might be due to the long-term depletion of B cells.

Here, we present a case of viral pericarditis that occurred in a woman with relapsing multiple sclerosis, 15 months after ocrelizumab initiation, specifically 3 months after the third infusion of ocrelizumab.

Case report

A 29-year-old woman was diagnosed with RRMS at the age of 21 years old. She started fingolimod in May 2014, suspended in August 2017 for pregnancy. After delivery, she resumed fingolimod from August 2018 until October 2019. In this 5-year period, she experienced 4 clinical relapses (March 2015, July 2016, January 2018, and October 2019), although no new or enlarging T2 lesion or gadolinium (Gd) enhancing lesion were reported in brain and spinal cord MRI (April 2014, July 2016, February 2019). Since the diagnosis, her disability gradually worsened, with EDSS progressing from 1.5 to 4.5. In January 2020, she was switched to ocrelizumab. She underwent 3 cycles of i.v. ocrelizumab (January 2020, July 2020, and February 2021) and experienced 1 relapse (October 2020) characterized by Lhermitte’s sign and girdle-like constriction in the abdomen. Brain and spinal cord MRI performed 6 months after ocrelizumab initiation (July 2020) did not show Gd-enhancing lesion nor new or enlarging T2 lesions compared to the previous MRI scan (February 2019).

At the beginning of May 2021, 3 months after the third ocrelizumab infusion, she started complaining of abdominal and leg pain with a girdle-like constriction in the abdomen. Accordingly, she underwent steroid pulse therapy for 5 days. Ten days after the start of steroid therapy, she reported an acute chest pain with neck irradiation lasting about half an hour with hyperpyrexia (39.9 °C). The patient had neither received a vaccination for SARS-CoV-2 nor experienced COVID-19. She performed routine blood test showing aspartate aminotransferase (AST) 133 U/L (n.v 10–35); alanin aminotransferase (ALT) 250 U/L (n.v. 10–35); gamma-glutamyl transferase (GGT) 73 U/L (5–36); lactate dehydrogenase (LDH) 343 U/L (n.v 135–214); erythrosedimentation rate (ESR) 44 mm/h (n.v. < 18); and C-reactive protein (CRP) 86.7 mg/L (n.v. < 5). Physical and chemical examinations of urine and stools were negative as well as parasite detection. A molecular swab for SARS-COV2 was negative. Moreover, abdomen ultrasound and chest X-ray were reported as negative. On May 19th, she performed cardiologic evaluation that showed normal EKG with a rate of 77 bpm, normal atrioventricular conduction, and no change in ST tract and T-wave (QTc = 407 ms); an echocardiogram presenting pericardial hyperechogenicity with posterior pericardial detachment (Fig. 1A and B) and was consequentially started on ibuprofen 600 mg twice a day. On May 22nd, she was admitted to the infectious disease unit of our University Hospital. Multiplex PCR performed to amplify Human herpesviruses (HHVs) DNA (human herpesviruses 1 and 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human beta herpesvirus 6 and 7) and enterovirus DNA, were negative. Conversely, real-time PCR for adenovirus (ADV) DNA was positive with 327,078 copies/mL. HIV 1 and 2 antigens were negative. Moreover, IgM anti Coxsackievirus were present with negative IgG. Therapy with ibuprofen 600 mg was confirmed and she was discharged on the 28th of May with the diagnosis of viral pericarditis. CRP on dismission was 0.2 mg/L (n.v. < 5).

Fig. 1
figure 1

A and B are recorded during the first echocardiogram showing pericardial hyperechogenicity with posterior pericardial detachment respectively in parasternal short axis and parasternal long axis. C The second echocardiogram, performed 21 days later, showed pericardial hyperechogenicity without effusion in parasternal long axis. D The third echocardiogram, performed 6 months later, showed thickening of the posterior pericardium with no effusion in parasternal long axis

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A new echocardiogram performed on the 9th of June showed pericardial hyperechogenicity without effusion (Fig. 1C). After 6 months, further re-evaluation showed normal EKG and echocardiogram showed thickening of the posterior pericardium with no effusion and normal ventricular filling patterns (Fig. 1D).

At flow cytometry analysis data, performed before ocrelizumab initiation and after 1 year of therapy (immediately before the occurrence of the viral pericarditis), results were comparable to other MS patients treated with ocrelizumab; indeed, we observed the depletion of B cells and reduction of CD8 T lymphocytes (Table 1).

Table 1 Flow cytometry analysis data, before ocrelizumab initiation and after 1 year of therapy
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Discussion

Here, we reported the first case of infective pericarditis following ocrelizumab therapy.

In 2017, ocrelizumab was approved for the treatment of both relapsing and primary progressive multiple sclerosis [3].

A systematic review including 78 records (4 randomized controlled trials (RCTs), 4 open-label trials, 29 observational studies, 27 case reports, and 14 complementary studies) reported a higher risk of infections in ocrelizumab-exposed patients compared to those treated with beta interferon, including urinary-related, respiratory-related, herpes-related infections, nasopharyngitis, and rhinitis [4]. Recently, a case of bacterial endocarditis was described in a RRMS patient after three cycles of ocrelizumab; moreover, a case of fatal enterovirus-related myocarditis has been reported after eleven cycles of rituximab [5]. However, to our knowledge, no cases of pericarditis have been documented after infusion with anti-CD20 therapies in MS subjects.

Nabati and colleagues reported a rare case of pericarditis in a non-Hodgkin’s lymphoma patient who received R-CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin®, and prednisone or prednisolone, combined with the monoclonal antibody rituximab) chemotherapy. Therefore, it is reasonable to hypothesize that the increased risk of pericarditis may be due to either the treatment with anti-CD20 monoclonal antibodies or to the combination of anti-CD20 monoclonal antibodies with steroids [6].

Cases of infectious pericarditis have also been described in rheumatologic diseases, occurring after exposure to rituximab [7].

The diagnosis of pericarditis is clinical and instrumental [8]. Two of the following criteria are required: (i) sharp pain in the chest that improves when leaning forward and in the sitting position; (ii) pericardial friction rub on auscultation; (iii) typical changes on the electrocardiogram (EKG); and (iv) pericardial effusion. Our patient presented with sharp chest pain, pericardial effusion at echocardiogram, and detection of high title of DNA copies of Adenovirus, confirming the diagnosis of viral pericarditis. Moreover, she had no history or familiarity of heart disease or previous trauma that might have predisposed to the development of pericarditis.

In conclusion, we report the first case of infective (viral) pericarditis in a patient under ocrelizumab treatment. Although viral pericarditis is an unusual complication associated with anti CD20 therapy, clinicians should be aware of these rare but potentially severe conditions and consider rapid cardiologic evaluation in patients with chest pain, t fever, and laboratory findings of systemic inflammation.