|CASE BASED REVIEW
|Ahead of print publication
Monoclonal antibodies to treat COVID-19 in rheumatoid arthritis: A case report and a clinical appraisal of selected drug trials
Centre for Rheumatic Diseases, Pune, Maharashtra, India
|Date of Submission||06-Jan-2022|
|Date of Acceptance||18-Feb-2022|
|Date of Web Publication||20-Jun-2022|
Centre for Rheumatic Diseases, Hermes Elegance, 1988 Convent Street, Camp, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
The current report describes successful treatment of a rapidly progressive severe breakthrough COVID-19 in a female physician, a known case of rheumatoid arthritis (RA). She received monoclonal antibody (Mab) combination cocktail (Casirivimab™ plus Imdevimab™) infusion on day 4 after the onset of symptoms. RA was in prolonged remission with tofacitinib. She had completed vaccination 6 weeks earlier and worked in a COVID hospital. Post infusion, there was substantial improvement, and she was discharged after 3 days. However, she required intermittent domiciliary oxygen for a fortnight. Fatigue and ageusia persisted for 5 weeks. Several Mabs were recently approved for emergency use in mild-to-moderate ambulant COVID-19 patients. Controlled drug trials confirmed excellent efficacy and safety. Selected data on clinical relevance and limitations are currently described. RA is susceptible to COVID-19, and some vaccines may be less effective. Intervention with Mabs ought to be judicious and timely.
Keywords: Breakthrough infections, COVID-19, monoclonal antibodies, rheumatoid arthritis, vaccination
| Introduction|| |
Monoclonal antibodies (MAbs) were recently approved for treatment of mild-to-moderate COVID-19 patients in an outpatient setting and who are likely to progress to severe disease and require hospitalization. Emergency authorization was provided to three Mab regimens (bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab) by the US FDA. These neutralizing Mabs bind to the receptor-binding domain of the virus spike protein.
A case report of a young female physician with rheumatoid arthritis (RA) who was treated with Mab for severe COVID-19 following vaccination (COVID-19) is presented and discussed. The emphasis is on MAb use in rheumatology practise. And, supporting data from drug trials are presented.,, The outcome of the latter drug trials contributed to early emergency authorization use of Mab.
| Method|| |
Mabs approved by the US FDA till December 10, 2021, and described in the treatment guidelines of the National Institute of Health, USA, were selected along with their references in the report.,,, Further manual search was carried out using internet-based search engines (Google and Pubmed) using primary keywords and phrases with Boolean expression pertaining to “Monoclonal Antibody,” “COVID-19,” “Drug Trial,” and “Rheumatoid Arthritis” to download full-length text of the identified drug trials and some other relevant references as per the choice of the author. No search of any clinical drug trial database was carried out. This was essentially a clinical appraisal by the author and not a systematic review.
| Case Report|| |
On July 8, 2021, 49 days after COVID vaccination (whole virion inactivated BBV152, Covaxin™), a 36-year-old female physician suddenly developed moderately severe maiden COVID-19 (direct antigen and reverse transcriptase-polymerase chain reaction [RT-PCR] assay [cycle threshold value 15]) and was immediately hospitalized. She was obese (body mass index: 33.7). She was a known case of RA (4 years' duration) in remission and on long-term oral therapy with tofacitinib (Xeljanz™ 5 mg bid) and deflazacort (6 mg od). At onset, she had high fever and chills and developed mild-to-moderate symptoms of cough, breathlessness, ageusia, and anosmia. Skiagram and a high-resolution computed tomography (CT) scan of chest was reported normal. She was administered oxygen (facial mask and rate 4–8 l/min) to stabilize arterial hemoglobin oxygen saturation (digital oximetry). Other medications included remdesivir, oral anticoagulants, and prednisolone (10 mg daily). The high fever persisted and symptoms seem to worsen despite standard care. She developed mild persistent hypertension and hyperglycemia (required insulin).
Meanwhile, routine investigation results including total and differential cell counts remained repeatedly normal. Serum C-reactive protein (59 mg/l) and D-Dimer (754 ng/ml) increased several folds; the corresponding normal values were 10 mg/l and less 250 ng/ml. Serum interleukin-6 and liver enzymes were marginally elevated. Serum procalcitonin was repeatedly negative. Color Doppler cardiac evaluation was normal. On day 4, chest skiagram showed features of pneumonitis, suggestive of COVID-19. She was administered a single infusion of MAb cocktail (Casirivimab™ 600 mg plus Imdevimab™ 600 mg). Within few hours, she became afebrile, and other symptoms improved substantially. She became normotensive and normoglycemic and was discharged on day 7. Anti-platelet agent and low-dose steroids (deflazacort 6 mg od) were continued. However, she continued to require intermittent oxygen (2–5 l/min) at home for 12 days. Fatigue and ageusia lasted for over a month. She resumed medical duties 5 weeks after discharge.
RA medication was stopped on hospitalization, and her arthritis remained in remission for about 8 weeks. On September 21, she had a moderately severe relapse. Tofacitinib (5 g bid) was restarted, and steroid dose increased (deflazacort 6 mg bid). On October 21, her RA was assessed as mild (DAS 28 ESR 4.7) during rheumatology evaluation. Her fatigue seemed to influence her general health more (and increase DAS score). Tofacitinib and deflazacort were continued unchanged. On December 2021 (16 weeks after discharge), she noticed progressive pedal edema, facial fullness, and easy fatigability. She was mildly hypertensive and diagnosed with Cushingoid features. Cardiac Doppler showed early left ventricular hypertrophy. High-resolution CT scan of the chest was reported normal. A comprehensive laboratory evaluation (including thyroid) was normal. She improved substantially with diuretics, antihypertensive medication, and reduced steroid (deflazacort 3 mg od) use. RA was in remission and tofacitinib was continued.
A week after the onset of COVID-19 illness, the patient's husband (physician) also suffered from mild confirmed COVID-19 and recovered within 5 days. He had been earlier vaccinated, same time as his wife, and did not suffer from any comorbidity.
[Table 1] shows the comparison of selected features of Mab drug trials (Phase 2/3) published in interim analysis reports.,, [Figure 1] was drawn based on drug trial data and shows viral load and symptom recovery. All trials were randomized, double blind, placebo controlled, multicentric, and with multiple MAb interventional arms (varying doses and in combination) [Table 1]. Excellent safety and efficacy were demonstrated. Participants with mild-to-moderate COVID-19 (confirmed) were treated in an outpatient facility. A substantial proportion of participants had risk factors (mostly age and obesity). Severe cases were excluded. Combination Mab (cocktail) was shown superior to a monotherapy [Table 1]. The incidence of mutant strains was low with the cocktail use [Table 1]., Mabs were fully humanized and administered within 7 days of the onset of symptoms (self-reported).
|Table 1: Comparison of selected drug trials for the use of monoclonal antibodies in the treatment of COVID-19 (see text for details)|
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|Figure 1: (a) Viral clearance (mean), (b) symptom score (mean)and (c) symptom improvement (percent), and resolution scores at different time-points in the randomized, double-blind, placebo-controlled Drug Trial (BLAZE-1) of monoclonal antibody use in COVID-19:Proportion (percent) of patient shown. This is based on selected data shown in Table 2 for Mab monotherapy (700 mg and 7 gm), Combo Mab (combination Mab) and Placebo arms, and published by Gottlieb et al. (See text for details and full citation)|
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The primary efficacy was reduction in the viral load [Table 1]. Viral clearance (two successive negative RT-PCR assays) was demonstrated in 50%–60% of patients by day 29.
Weinrich et al. focused on participants who were seronegative for specific antibodies to SARS-CoV-2 at baseline (45% of sample size) and demonstrated a higher viral load reduction [Table 1]. The seronegative group was considered to have an inadequate immune response.
Interestingly, higher doses [Figure 1] of Mab did not necessarily lead to better viral or clinical outcome and by day 22, responses across the study seemed almost similar [Figure 1].
Clinical efficacy, safety, and pharmacokinetics
Significant symptomatic recovery (score reduction) was conspicuous by day 2 in the Mab group; −0.79 (95% confidence interval −1.35 to −0.24) (2). By day 4 randomization, the symptom score reduced substantially, and only minimal-to-mild changes were observed subsequently (2). Forty to fifty participants showed symptom resolution by day 11 [Figure 1]. There were lesser hospitalizations and medical attendance visits with Mab intervention [Table 1]. Only one patient (placebo) progressed to severe stage. The half-life of Mab (mono or combination) was from 25 to 37 days and the serum drug concentration at day 29 was considered sufficient to neutralize the virus according to data from preclinical studies. The safety profile in each of the drug trials was impressive [Table 1].,, The incidence of serious adverse events and local hypersensitivity skin reactions was strikingly low. None of the adverse events pertained to musculoskeletal system. Importantly, there were no deaths.
| Discussion|| |
The patient in the current case report was successfully treated with a Mab cocktail (Casirivimab™ plus Imdevimab™) infusion administered within 4 days of the onset of rapidly progressive severe COVID-19. The patient was a fully vaccinated young doctor working in a COVID hospital. She was a known patient of RA in remission and on treatment with tofacitinib for over a year. She showed dramatic relief but after discharge continued to require intermittent domiciliary oxygen (low flow). Fatigue and ageusia persisted for over a month.
Asymptomatic to mild cases of breakthrough SARS-CoV-2 infections were described in a large sample size study from Israel conducted on health workers following vaccination, with an incidence of 0.4%. RA is an immunosuppressed state and prone to COVID-19. The breakthrough infection was severe in the current case report. An inadequate humoral response to an inactivated COVID vaccine was recently reported in Indian patients of RA. To the best of our knowledge, treatment of severe breakthrough COVID-19 in RA with Mab is not reported. Thirty-eight patients (<1%) in two large European cohorts of patients suffering from autoimmune inflammatory rheumatic disease (AIRD) and vaccinated against COVID-19 developed SARS-CoV-2 infections (January–July 2021); 40% of infections were reported in RA. The severity or treatment was not described in the latter report. The reported outcome was recovery in 32, ongoing COVID sequel in 3, and death in 3 patients.
Rheumatologists were advised to exercise caution when treating RA during the COVID-19 pandemic. Treatment of COVID-19 in Auto immune rheumatic diseases (AIRD) requires due diligence, but the role of Mab is not yet described. EULAR provided guidelines for immunomodulatory therapies to treat COVID-19. Interestingly, the risk of COVID-19 in RA was reported either nil or modest., AIRD is often treated with immunosuppressives and biologic response modifiers, which increase susceptibility to infection and may delay early recognition by suppressing cardinal symptoms (such as fever). However, several anti-rheumatic drugs including Janus Kinase inhibitors (JAKi) were also used empirically to treat COVID-19.,, JAK-STAT pathway inhibition leads to potent suppression of several cytokines including interferon which is a pivotal anti-viral cytokine. The latter may be relevant to the severity of COVID-19 in the current case report. JAKi may benefit COVID-19 in a later phase characterized by immune-mediated hyperinflammatory response. Tofacitinib (a JAK inhibitor) was stopped in the current case and restarted several weeks later for a relapse (RA).
Some analogies may be drawn with the plasma exchange therapy., Plasma exchange has shown poor efficacy. The Mab infusion was reported to be about 1000 times more potent than the plasma therapy. The influence of SARS-CoV-2 infection or Mab infusion (COVID-19) on RA is not yet known.,
The drug trials described in the current report [Table 1] and [Figure 1] showed unprecedented therapeutic benefit of Mab [Table 1] and [Figure 1].,, It should be noted that currently, Mabs are not recommended for severe COVID-19 requiring hospitalization. The participants in the drug trials were predominantly Caucasian and from the USA and any extrapolation of results to the rest of the World needs caution. Viral load [Table 1] and [Figure 1] was based on nasopharyngeal swab which may not truly reflect the viral burden in the lungs. Participants' self-reported symptoms and ageusia and anosmia were not included (score). Reduction and resolution of symptoms in the trials seemed insufficient to judge the efficacy (Mab) [Table 1] and [Figure 1]. The data on peripheral blood oxygen saturation (pulse oximetry) were not published. Viral RNA persisted for a prolonged period in the drug trials, but the clinical implication is not known [Figure 1]. The latter was shown to be nonreplicating in some studies. However, in view of the long-term complications and sequel of COVID-19, patients receiving Mab need long-term follow-up. The current case report also supports this contention.
In the recently published drug trial report following an interim analysis, Mab cocktail infusion (REGEN-COV) showed significant efficacy irrespective of the baseline serological status (antibodies) and further endorsed excellent safety. The median time for symptomatic resolution was 4 days shorter as compared to that of placebo.
Sotrovimab is an engineered MAb that neutralizes SARS-CoV-2 and showed significant reduction (85%) in hospitalization in high-risk ambulatory patients and with excellent safety in an interim analysis (at day 29 randomization) report of a controlled drug trial. Patients requiring intensive care belonged to the placebo group.
Most (>80%) patients of COVID-19 recovered within a short period (<10 days)., Several patients who were hospitalized for complicated severe disease also recovered. Mortality varied, but about 2% of all cases died during the 1st year of pandemic.,, An early robust virucidal immune response determines recovery and a late exuberant immune-mediated inflammatory often leads to life-threatening complications and death. Though several risk factors are known, it is difficult to predict the course of illness in early disease., However, specific Mabs are likely to benefit most when administered early in patients with severe COVID-19 onset and/or patients with rapid disease progression and risk factors.
There are several more Mabs in the pipeline for the management of COVID-19. Cocktail (combination) use of Mab seems to address the problem of virus variants and mutations.,, Rheumatologists need to be aware of their therapeutic potential., However, physicians would be expected to exercise due diligence when prescribing MAb and avoid injudicious use. Access and affordability will be an important concern. The clinical decision (Mab) should not be based on “fear” and “apprehension.”
There has been a fresh COVID-19 pandemic insurgent wave largely due to the Omicron variant since November 2021. The previously approved Mab by the US FDA (under discussion in this paper) may have limited or nil efficacy against this variant. In the latter laboratory study published in January 2022, among the approved Mab for the treatment of COVID-19, only sotrovimab and casivirimab (monotherapy) showed efficacy and cocktail use (described above) did not show efficacy in the focus reduction neutralization assay. However, clinical data are keenly awaited.
Dr. Kiran Adams coordinated in obtaining medical records used in the case report. I thank the concerned doctor for providing a written consent for her case report in this manuscript.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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