Latest COVID and Rheumatic

Disease Therapies: What You

Need to Know
Rachael Perritt, PharmD, BCPS
Clinical Pharmacy Specialist, Ambulatory – Rheumatology
Hospital of the University of Pennsylvania

Stephen Saw, PharmD, BCIDP

Clinical Pharmacy Specialist, Infectious Diseases
Hospital of the University of Pennsylvania
Disclosure Template

Stephen Saw, PharmD, BCIDP: I have no relevant financial relationships

with ineligible companies to disclose.

Rachael Perritt, PharmD, BCPS: I have no relevant financial relationships

with ineligible companies to disclose.
Key References

• American College of Rheumatology Guidance for the Management of

Rheumatic Disease in Adult Patients During the COVID-19 Pandemic
• Version 3; Arthritis & Rheumatology Vol. 73, No. 2, February 2021, pp e1–e12
• American College of Rheumatology Guidance for COVID-19
Vaccination in Patients with Rheumatic and Musculoskeletal
Diseases – Version 5
• Arthritis Rheumatology 2022.
• COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019
(COVID-19) Treatment Guidelines. National Institutes of Health.
• Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed 11/11/22
Objectives

• Review current literature and guidance on pharmacologic

management of patients with rheumatologic diseases during the
COVID-19 pandemic

• Discuss challenges in treating COVID positive patients with

rheumatologic diseases

• Describe the intersection of rheumatology and infectious

diseases in the utilization of DMARDs for treatment of COVID
 Ambulatory Management of
Rheumatology Patients in the
COVID-19 Era
Rachael Perritt, PharmD, BCPS
Hospital of the University of Pennsylvania
COVID Risk
SARS–CoV‐2 Infection and COVID‐19 Outcomes in Rheumatic Diseases: A Systematic Literature Review and
Meta‐Analysis

Arthritis & Rheumatology, Volume: 74, Issue: 5, Pages: 766-775, First published: 22 Novem ber 2021, DOI: (10.1002/art.42030)
 Comorbid Risk

Ann Rheum Dis 2021;80:930–942.

 Medication-related Risk

Ann Rheum Dis 2021;80:930–942.

ACR Guidance – General
Management
• Social distancing and general preventative measures
• Reducing healthcare encounters based on shared decision
making may be reasonable
• Lowest dose glucocorticoids possible
• Don’t abruptly stop glucocorticoids
• Continue current treatment
• Do not dose-reduce for patients with vital-organ threatening disease
• Access issues – switch to alternative if necessary
• Continue IL-6 inhibitors if well-controlled, switch if access is an issue

Arthritis & Rheumatology Vol. 73, No. 2, February 2021

New Medication and Escalation of
Therapy
• Start HCQ/CQ at full dose for SLE and inflammatory arthritis
conditions if available
• Start biologics for inflammatory arthritis if moderate- high-
disease activity uncontrolled by csDMARD
• Start or switch csDMARDs for new diagnoses
• Use low-dose corticosteroids or NSAIDs if necessary
• Systemic inflammatory or organ-threatening disease
• Initiate high-dose corticosteroids or immunosuppressants if needed

Business as usual?

Arthritis & Rheumatology Vol. 73, No. 2, February 2021

Vaccination

Arthritis Rheumatol 2022

Medication Management –
Peri-vaccine
• No modification
• Hydroxychloroquine, IVIG
• No consensus
• TNFi, IL-6R, IL-1R, IL-17i ,IL-12/23i,
IL-23i, cytokine inhibitors
• Time it
• Abatacept IV
• Cyclophosphamide
• Rituximab and other anti-CD20 B-
cell depleting agents
• Hold
• Abatacept subcutaneous
• Belimumab subcutaneous
• All other conventional/targeted
immunomodulators (JAKi, MMF)
Arthritis Rheumatol 2022
Flare Post-Vaccination

• Studies report association of SARS-CoV-2 infection and flare

• Independent risk factor for flare
• Reported 20-40%
• Observational studies report flare rate after vaccination ranging
from 0.4% to 20%
• Meta-analysis shows rate of 7%
• High level of heterogeneity
• Overall mostly mild flares with vaccination
• Joint pain, stiffness, swelling
• Cutaneous and mucosal symptoms (malar rash, alopecia)
Front. Immunol. 13:919979.
Flare Post-Vaccination

• Potential risk factors

• Type of rheumatic disease (potentially lower in inflammatory arthritis)
• Higher disease activity
• Age
• Female sex
• Effect of medication withdrawal
• ACR/EULAR guidance recommends vaccination while disease
is quiescent if possible

Front. Immunol. 13:919979.

Vaccine Response

• Seroconversion better with two doses vs. one

• Good seroconversion rates (>90%)
5-aminosalicylates Anti-TNF Anti-integrin Anti-IL-6
Anti-IL-12/23 Anti-IL-17

• Lower seroconversion rates (70-90%)

Corticosteroids Hydroxychloroquine Methotrexate JAKi
Belimumab Leflunomide Mycophenolate

• Low seroconversion rates

• Anti-CD20 monoclonal antibodies
Autoimmunity Reviews 21 (2022) 102927
Pre-Exposure Prophylaxis -
Tixagevimab and cilgavimab
• Moderate-severe
immunocompromise AND may not
mount immune response to
COVID-19 vaccination
• Vaccination not recommended due to
severe adverse reaction to COVID-
19 vaccine or component
• At least 2 weeks after vaccine
• Every 6 months

EUA Fact Sheet for Healthcare Providers: Emergency Use Authorization for Evusheld
Tixagevimab-cilgavimab
Susceptibility

• Clinical correlation and outcomes?

• Current recommendation – continue use

EUA Fact Sheet for Healthcare Providers: Emergency Use Authorization for Evusheld
Post-exposure Management

Arthritis & Rheumatology Vol. 73, No. 2, February 2021

Post-exposure Management

Arthritis Rheumatol 2022

 My patient tested positive!

HUP Outpatient COVID-19 Management

 Antiviral Agents
Nirmatrelvir/ritonavir
Authorized use Treatment of mild-moderate
COVID-19 in outpatients with
Risk factors for Progression
to Severe COVID-19
Route oral
Outpatient data Hospitalization/mortality
Efficacy against variants Good in vitro activity
Renal/Hepatic Renal: adjust eGFR < 30
Hepatic: avoid, Child-Pugh
class C
Drug interactions Many – CYP450, P-gp
Molnupiravir Remdesivir
Treatment of mild-moderate Treatment of moderate-
COVID-19 in outpatients severe COVID-19 in
with Risk factors for inpatients or treatment of
Progression to Severe mild-moderate COVID-19 in
COVID-19 outpatients with Risk factors
for Progression to Severe
COVID-19
oral IV
Conflicting Hospitalization/mortality
Good in vitro activity Good in vitro activity
No adjustment necessary Renal: not studied eGFR <
30 (toxicity unlikely)
Hepatic: Noted hepatotoxicity
Cladribine Hydroxychloroquine
chloroquine
Nirmatrelvir/Ritonavir – First Line
• EPIC-HR

• Viral rebound seen in observational studies

• Mechanism unknown
• Adverse effects
• GI – dysguesia, diarrhea
• Myalgia
• Hypertension
Management of Drug Interactions
Molnupiravir

• Variable effectiveness reported

• Lieu, et.al. – reduction in VL and shorter LOS
• Poznanski, et.al. – safe and well-tolerated in ESRD/kidney transplant
• AGILE CST-2 – moderate effect, reduction in VL
• PANORAMIC Preliminary Analysis – no difference in
hospitalization/death, reduction in time to reported recovery
(symptoms)
• Adverse effects – dermatologic, hypersensitivity
• Current place in therapy?
 Bebtelovimab

• Patients not eligible for

antiviral therapy
• Limited clinical data
• Treatment within 7 days of
symptom onset with Mab
with activity against
predominant regional
variants

Statement on Omicron Subvariants | COVID-19 Treatment Guidelines (nih.gov)

CDC COVID Data Tracker: Variant Proportions
Next in line…

• Predominant strains resistant to current therapies

• Phase 1/2/3 trials ongoing for additional monoclonal antibodies
• COVID-19 Biologics Tracker - The Antibody Society
• Antiviral agents
• Phase 1/2 trials ongoing/recruiting
• Increased use of outpatient remdesivir as alternative when
nirmatrelvir/ritonavir contraindicated - PINETREE

N Engl J Med 2022;386:305-15

Re-initiation of Treatment After
Infection
• Uncomplicated COVID-19 infections
• Re-starting rheumatic disease treatments within 7 to 14 days of
symptom resolution
• Asymptomatic positive PCR test for SARS-CoV-2
• consideration may be given to re-starting rheumatic disease treatments
(e.g., DMARDs, immunosuppressants, biologics and JAK inhibitors) 10
to 17 days after the PCR test is reported as positive
• Severe COVID-19-related illness
• Re-initiation should be decided on a case-by-case basis

Arthritis Rheumatol 2020;72:1241–51.

Translation into Practice

• High-risk patient population

• Vaccination is key
• High efficacy – most of our patients
• Low risk of flare
• Current therapy is limited by evolving variants
• Antibody PrEP is still available
• Treatment relies heavily on antiviral agents with good in vitro
susceptibility
• Awareness of drug interactions
The Intersection of Rheumatology
and Infectious Diseases: Use of
DMARDs in COVID-19
Management
Stephen Saw, PharmD, BCIDP
Hospital of the University of Pennsylvania
DMARDs and Use in COVID-19

• Interleukin-6 antagonists
• Tocilizumab
• Sarilumab

• Janus kinase inhibitors

• Baricitinib
• Tofacitinib

• Miscellaneous agents
• Anakinra
• Hydroxychloroquine
• Infliximab
Pathogenesis of COVID-19

• Early COVID-19 driven by viral replication

• Late COVID-19 driven by dysregulated

immune/inflammatory response → leads to
tissue damage

• COVID-19 associated systemic inflammation

and hypoxemic respiratory failure → can be
associated with heightened cytokine release
indicated by elevated biomarkers such as IL-6,
C-reactive protein, D-dimer, and ferritin

Attaway AH, et al. BMJ. 2021 Mar 10;372:n436

COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
Tocilizumab and Sarilumab

• IL-6 receptor antagonists; bind to both soluble and membrane bound IL-6 receptors
• Administration
• Tocilizumab: intravenous
• Sarilumab: intravenous administration requires compounding from pre-filled syringes used for
subcutaneous administration
• Warnings
• Infections
• Gastrointestinal perforation
• Hepatic impairment
• Hematologic effects
• Cost
• Tocilizumab 800 mg: $5893.6
• Sarilumab 400 mg: $4068.78

Actemra® [package insert]. San Francisco, CA: Genentech Inc.; 2022.

Kevzara® [package insert]. Bridgewater, NJ. Sanofi-Aventis U.S. LLC.; 2018.
COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
 The IL-6 Antagonist Timeline

October 2020
3 studies
published: BACC
May 2020 July 2020 BAY, CORIMUNO-
CORIMUNO-TOCI COVACTA press TOCI, and
press release release Salvarani C, et al.

June 2020 September 2020 November 2020

Somers EC, et al. EMPACTA press UPHS “retires”
pre-print and release and tocilizumab
Salvarani C, et al. COVACTA pre-
press release print
 The IL-6 Antagonist Timeline

October 2020
3 studies
published: BACC
May 2020 July 2020 BAY, CORIMUNO-
CORIMUNO-TOCI COVACTA press TOCI, and
press release release Salvarani C, et al.

June 2020 September 2020 November 2020

Somers EC, et al. EMPACTA press UPHS “retires”
pre-print and release and tocilizumab
Salvarani C, et al. COVACTA pre-
press release print
 The IL-6 Antagonist Timeline

January 2021
REMAP-CAP V.1 pre-print,
June 2020 October 2020 EMPACTA published, and
Somers EC, et al. pre-print 3 studies published: BACC TOCIBRAS published
and Salvarani C, et al. BAY, CORIMUNO-TOCI, Incorporated into UPHS
press release and Salvarani C, et al. guideline

September 2020 November 2020

EMPACTA press release UPHS “retires”
and COVACTA pre-print tocilizumab

http://www.quickmeme.com/meme/3p384i
REMAP-CAP – Design

International,
adaptive
826 patients platform trial,
IL-6 portion
open label • Adaptive design did not have significant
impact given rapid rate of enrollment
• 1st patient enrolled in immune modulation
arm 4/19/20
• RECOVERY dexamethasone press release on
113 sites across 6/16/20 and pre-print published 6/22/20
6 countries, • Will not review sarilumab with version 1
3/9/20 to
primarily in the
11/19/20
United
Kingdom

REMAP-CAP Investigators. N Engl J Med. 2021 Apr 22;384(16):1491-1502.

 Methods
Inclusion
• Age >18 years
• Suspected OR confirmed COVID-19
• Admitted to ICU for <24 hours
• Respiratory or cardiovascular support
• MV
• NIV or HFNC with flow rate >30 L/min
and FiO2 >40%
• Vasopressor or inotrope
Interventions
Tocilizumab (n=353)
• 8 mg/kg (max 800 mg) IV x 1
• 2nd dose could be given 12-24h later at
discretion of the treating clinician
ALT: alanine aminotransferase
AST: aspartate aminotransferase
HFNC: high flow nasal cannula
ICU: intensive care unit
MV: mechanical ventilation
NIV: non-invasive ventilation
Exclusion
• Admitted >14 days with symptoms of due
to SARS-CoV-2
• Immune suppression
• Pregnancy
• AST or ALT >5x upper limit of normal
• Platelets <50
Control (n=402)
• Other aspects of patient management per
each site’s standard of care
• Randomization to steroid domain closed
6/17/20 so steroids were allowed per
standard of care after this date
REMAP-CAP Investigators. N Engl J Med. 2021 Apr 22;384(16):1491-1502.
Notable Demographic Variables
Tocilizumab (n=353) Control (n=402)

Mean age (years) 61.5 (12.5) 61.1 (12.8)

Median APACHE II score 13 (8-19) 12 (8-18)

Confirmed SARS-CoV-2 82.3% 84.8%

Median time to enrollment from
1.2 (0.8-2.8) 1.2 (0.8-2.8)
hospital admission (days)
Median time to enrollment from ICU
13.1 (6.6-19) 14 (6.8-19.5)
admission (hours)
High flow nasal cannula 28.6% 27.4%
Non-invasive ventilation 41.6% 42%
Mechanical ventilation 29.5% 30.1%
Median C-reactive protein (mcg/mL) 150 (85-221) 130 (71-208)
• Received at least 1 dose of tocilizumab: 92%
• Received 2nd dose of tocilizumab: 29%
Key notes
• Enrolled after dexamethasone RECOVERY: 85.6%
• Received steroids within 48 hours of enrollment: 610/654 (93%)

REMAP-CAP Investigators. N Engl J Med. 2021 Apr 22;384(16):1491-1502.

 Outcomes
• Primary outcome from -1 to 21 for number of organ support free days
• Death = -1
• Higher number = faster recovery

Primary Outcome Tocilizumab (n=353) Control (n=402) Adjusted ratio and 95% CI NNT
Respiratory and cardiovascular organ
support free days up to day 21, median 10 (-1 to 16) 0 (-1 to 15) OR 1.64 (1.25 to 2.14) --
(IQR)
Key Secondary Outcomes Tocilizumab (n=353) Control (n=402) Adjusted ratio and 95% CI NNT
In-hospital mortality 28% 35.8% OR 1.64 (1.25 to 2.14) 13
90 day survival -- -- HR 1.59 (1.24 to 2.05) --
Progression to MV, ECMO, or death 41.3% 52.7% OR 1.69 (1.17 to 2.42) 9
Serious adverse events 2.5% 2.7% -- --

ECMO: extracorporeal membrane oxygenation

HR: hazard ratio
MV: mechanical ventilation
NNT: number needed to treat
OR: odds ratio REMAP-CAP Investigators. N Engl J Med. 2021 Apr 22;384(16):1491-1502.
 Conclusions and Limitations
Conclusions
• 64% higher odds of respiratory and
cardiovascular organ support free days up
to day 21
• 64% higher odds of in hospital survival
• Numerous favorable and statistically
significant secondary outcomes
TCZ: tocilizumab
Limitations
• Complex design
• Open label
• Included suspected COVID-19 cases
• 2nd dose at discretion of treating physician
• Lacked granular detail about steroid use
• 8% of TCZ group did not receive assigned
treatment but were included in outcome
analyses
• Under reporting or under-recognition of
adverse events
REMAP-CAP Investigators. N Engl J Med. 2021 Apr 22;384(16):1491-1502.
 Immediate Impact
UPHS
• COVID-19 pneumonia
• COVID-19 symptoms <14 days
• Hospital admission <72 hours
• ICU <24 hours
• Oxygen support with any of
the following:
• NIV/HFNC >40% FiO2
• MV
• AST & ALT <3x ULN
• Platelets >50
HFNC: high flow nasal cannula
IDSA: Infectious Diseases Society of America
NIH: National Institutes of Health
NIV: non-invasive ventilation
MV: mechanical ventilation
UPHS: University of Pennsylvania Health System
NIH IDSA
• Insufficient data to • Suggests against routine use
recommend for or against
• Some panel members would
administer with
dexamethasone if:
• ICU <24 hours
• Requiring oxygen support
with any of the following:
• NIV/HFNC >40% FiO2
• MV
• Exhibiting rapid progression
of respiratory failure
Bhimraj A, et al. Clin Infect Dis. 2021 Feb 10.
COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
The IL-6 Antagonist Timeline

February 2021
November 2020 RECOVERY press release and pre-
UPHS “retires” tocilizumab print published

January 2021
REMAP-CAP V.1 pre-print,
EMPACTA published, and
TOCIBRAS published
Incorporated into UPHS guideline
RECOVERY – Design
Investigator
initiated,
individually
Randomized in 1:1
randomized,
ratio, un-stratified
controlled, open
label study in the • RECOVERY dexamethasone press release on
United Kingdom 6/16/20 and pre-print published 6/22/20
• Arms could be added or removed as data
emerges
• Not all treatment available at every hospital

Tocilizumab was
4/23/20 to
part of 2nd
1/24/21
randomization

RECOVERY Collaborative Group. Lancet. 2021 May 1;397(10285):1637-1645.

 Design
Main Randomization
Part 1: placebo vs. either
• Dexamethasone
• Lopinavir/ritonavir
• Hydroxychloroquine
• Azithromycin
• Colchicine
Part 2: placebo vs. either:
• Convalescent plasma
• Casirivimab/imdevimab
Part 3: placebo vs. aspirin
Second Randomization
• Up to 21 days after main
randomization
• Patients with progressive disease could
be considered for randomization to
tocilizumab or placebo:
• Oxygen saturation <92% on
room air OR receiving oxygen
support
• C-reactive protein >75 mg/L
Inclusion
• Suspected or confirmed SARS-CoV-2
infection
• No medical history that might put the
patient at significant risk if they
participate
Exclusion
• Tocilizumab not available at hospital
• Belief by attending that tocilizumab is
contraindicated
• Active tuberculosis
• Clear evidence of active bacterial, fungal,
viral, or other infection

Interventions
Tocilizumab (n=2022) Control (n=2094)
• >90 kg: 800 mg • “Usual care” for the participating
• 66-90 kg: 600 mg hospital
• 41-65 kg: 400 mg
• <40 kg: 8 mg/kg
• 2nd dose could be given 12-24 hours
later if patient’s condition had not
improved per attending clinician

RECOVERY Collaborative Group. Lancet. 2021 May 1;397(10285):1637-1645.

 Notable Demographic Variables
Tocilizumab (n=2022) Control (n=2094)

Mean age, years 63.3 (13.7) 63.9 (13.6)

SARS-CoV-2 positive at 1st
95% 96%
randomization
Median days since 1st randomization 0 (0-1) 0 (0-1)
Median days since hospitalization 2 (1-5) 2 (1-5)
Oxygen support 46% 45%
HFNC, CPAP, or NIV 41% 41%
MV or ECMO 13% 14%
Median C-reactive protein (mg/L) 143 (107-203) 144 (106-205)
Steroids 82% 82%
• Not on any oxygen support: 9 patients total
• Information on steroid use collected from 6/18/20 onward
• All patients prior, if not randomized to dexamethasone, assume to
Key notes
NOT receive steroids
• Randomized to dexamethasone in phase 1: 2% in both arms
• Received more than 1 dose of tocilizumab: 29%

CPAP: continuous positive airway pressure

ECMO: extracorporeal membrane oxygenation
HFNC: high flow nasal cannula
MV: mechanical ventilation
NIV: non-invasive ventilation RECOVERY Collaborative Group. Lancet. 2021 May 1;397(10285):1637-1645.
 Primary Outcome – 28 Day Mortality
NNT = 25

NNT: number needed to treat RECOVERY Collaborative Group. Lancet. 2021 May 1;397(10285):1637-1645.
 Notable Secondary Outcomes
TCZ (n=2022) CON (n=2094) RR (95% CI) NNT
Discharge alive at day 28 54% 47% 1.22 (1.12 to 1.34) 15
Progression to MV 12% 15% 0.81 (0.68 to 0.95) 35
Progression to MV or death 33% 38% 0.85 (0.78 to 0.93) 18
Use of hemodialysis or hemofiltration 5% 7% 0.75 (0.59 to 0.96) 59
Successful cessation of MV 34% 32% 1.07 (0.8 to 1.43) --
Serious adverse event 3 total None -- --

CON: control
MV: mechanical ventilation
NNT: number needed to treat
RR: rate/risk ratio
TCZ: tocilizumab RECOVERY Collaborative Group. Lancet. 2021 May 1;397(10285):1637-1645.
 Conclusions and Limitations
Conclusions
• Significantly reduced rate (14%) of 28-day
mortality
• Significant improvement in secondary
outcomes including:
• Discharge alive within 28 days
• Lack of progression to MV or death
• Use of hemodialysis and hemofiltration
MV: mechanical ventilation
TCZ: tocilizumab
Limitations
• Open label
• Subjective inclusion and exclusion criteria
• Heterogeneous patient population
• Inclusion of suspected COVID-19 cases
• Not all eligible patients included based on
hospital supply
• 2nd dose at discretion of attending clinician
• Information available for 92% of patients at
time of pre-print
• Likely under reporting or lack of recognition
of adverse events
• Lack of per-protocol analysis; 17% in TCZ arm
did NOT receive assigned treatment
RECOVERY Collaborative Group. Lancet. 2021 May 1;397(10285):1637-1645.
 Immediate Impact
UPHS NIH IDSA
• Revised strict intensive care unit (ICU) • Recommends with dexamethasone if: • Suggests tocilizumab with standard of care
criteria to: • Recently hospitalized (i.e. steroids) for progressive severe or
• ICU eligible • AND admitted to ICU <24 hours critical COVID-19 with elevated markers of
• Or not in an ICU but high risk for or active systemic inflammation
• AND requires MV, NIV, or HFNC (>40%
clinical deterioration FiO2) • Severe: oxygen saturation <94% on room
air or supplemental oxygen
• Recently hospitalized + non-ICU
• Give in conjunction with dexamethasone • Critical: MV and ECMO; end organ
• AND rapidly increasing oxygen needs
dysfunction as seen in sepsis/septic shock
who require NIV or HFNC
• AND significantly elevated markers of
inflammation

• Insufficient evidence to recommend in

patients on low flow oxygen
• Some panel members would consider it if
rapidly increasing oxygen needs
• AND already on dexamethasone
• AND C-reactive protein >75 mg/L

• Avoid in significant immunosuppression

and absolute neutrophil count <500
cells/mL among other criteria

ECMO: extrapcorporeal membrane oxygenation MV: mechanical ventilation

FiO2: fraction of inspired oxygen NIH: National Institutes of Health
HFNC: high flow nasal cannula NIV: non-invasive ventilation Bhimraj A, et al. Clin Infect Dis. 2021 Feb 22.
IDSA: Infectious Diseases Society of America UPHS: University of Pennsylvania Health System COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
 The IL-6 Antagonist Timeline

January 2021
REMAP-CAP V.1 pre-
print, EMPACTA
published, and March 2021 June 2021
TOCIBRAS published COVINTOC published EUA issued and October 2021
Incorporated into and REMDACTA press REMAP-CAP V.2 pre- REMDACTA
UPHS guideline release print published

February 2021 May 2021 August 2021

RECOVERY press RECOVERY published Shortage ensues
release and pre-print
published

UPHS: University of Pennsylvania Health System

REMAP-CAP Part 2

International,
adaptive • Placebo arm stopped enrollment 11/19/20
826 2216
platform trial, (end date for REMAP-CAP part 1)
patients
IL-6 portion • Immune modulation arm stopped enrollment
open label 4/10/21
• Will not discuss anakinra (n=373)

113 sites across

6 countries, 3/9/20 to • No change to inclusion/exclusion criteria
primarily in the 11/19/20 • Sarilumab given as 400 mg IV x 1 dose
United 4/10/21
Kingdom

Derde LPG, et al. Pre-print 2021 Jun 25. https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2

 Notable Demographic Variables
Tocilizumab (n=353 952) Sarilumab (n=485) Control (n=402 406)

Mean age (years) 60.8 (12.2) 59 (13.2) 61.1 (12.9)

Median APACHE II score 13 (8-19) 12 (7-20) 12 (8-18)

Confirmed SARS-CoV-2 85.1% 88.6 85.7%

Median time to enrollment from
1.4 (0.9-3.3) 1.6 (0.9-3.5) 1.2 (0.8-2.8)
hospital admission (days)
Median time to enrollment from
13.4 (6.9-19.1) 15.1 (7.8-19.9) 14 (6.8-19.5)
ICU admission (hours)
High flow nasal cannula 23.7% 19.8% 27.1%
Non-invasive ventilation 42.4% 49.7% 42.1%
Mechanical ventilation 33.6% 30.5% 30%
Median C-reactive protein
132 (69-201) 120 (70-199) 129 (71-208)
(mcg/mL)
Received steroids at randomization 82.1% 89.4% 66.9%

Derde LPG, et al. Pre-print 2021 Jun 25. https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2

 Results
• Primary endpoint (respiratory and Secondary
Tocilizumab Control Adjusted ratio (95% CI) NNT
(n=952) (n=406)
cardiovascular organ support free
days up to day 21): In-hospital
28% 33.6% 35.8% 36.9% OR 1.42 (1.05 to 1.93) 13 31
mortality
• Tocilizumab and sarilumab both 90 day survival -- -- HR 1.39 (1.11 to 1.74) --
superior to control
Progression to
MV, ECMO, or 41.3% 43.4% 52.7% 53.3% OR 1.67 (1.2 to 2.36) 9 11
• Main limitation death

• Lack of contemporary controls Sarilumab Control Adjusted ratio (95% CI) NNT
Secondary
(n=485) (n=406)
In-hospital
• Conclusion mortality
32.7% 36.9% OR 1.51 (1.06 to 2.2) 24
• Sarilumab is a reasonable 90 day survival -- -- HR 1.44 (1.11 to 1.89) --
alternative for tocilizumab during
Progression to
times of shortage
MV, ECMO, or 45% 53.3% OR 1.43 (0.98 to 2.1) --
death

ECMO: extracorporeal membrane oxygenation

HR: hazard ratio
MV: mechanical ventilation Bhimraj A, et al. Clin Infect Dis. 2021 Sep 21.
NNT: number needed to treat COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
OR: odds ratio Derde LPG, et al. Pre-print 2021 Jun 25. https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2
Baricitinib
• Janus kinase inhibitor
• Prevents activation of signal transducers and activators of transcription and reduces serum IgG, IgM, IgA,
and C-reactive protein
• Theoretically interferes with viral endocytosis → preventing SARS-CoV-2 from entering and infecting cells
• Notes
• Administered oral or via-feeding tube
• Use not recommended if eGFR <15 or on renal replacement therapy
• VTE prophylaxis recommended
• Warnings
• Infections
• Gastrointestinal perforation
• Hepatic impairment
• Hematologic effects
• Cost
• Per day: $199.78
• Per 14 day course: $2796.92

Olumiant® [package insert]. Lilly USA, LLC.;2022.

COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
 The Baricitinib Timeline

September September
2020 April 2021 July 2021 2021
ACTT-2 press COV-BARRIER EUA COV-BARRIER
release press release expanded published

November May 2021 August 2021 October 2021

2020 COV-BARRIER Tocilizumab COV-BARRIER
EUA issued pre-print shortage and MV/ECMO
based on COV-BARRIER pre-print
ACTT-2 MV/ECMO
press release

EUA: emergency use authorization

MV: mechanical ventilation
COV-BARRIER - Design
10/20/20: enrollment limited to low flow oxygen and Stemmed from FDA request to evaluate MV and ECMO patients
HFNC/NIV after results of ACTT-2 released

Randomized, 101 centers Exploratory, 18 centers across

double blind, across 12 randomized, 4 countries
placebo countries, double blind, (Argentina,
controlled, primarily in place controlled, Brazil, Mexico,
parallel group, North and parallel group, and United
phase 3 trial South America phase 3 trial States)

Stratified
6/11/20 to randomization 12/23/20 to Stratified
1/15/21 by disease 4/10/21 randomization by
severity, age, region
(n=1525) region, and (n=101)
steroid use

Ely EW, et al. Lancet Respir Med. 2022 Apr;10(4):327-336.

Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 Inclusion and Exclusion
Inclusion Exclusion
• Hospitalized adults • Unlikely to survive >48 hours
• Confirmed COVID-19 with pneumonia or active & symptomatic • Anticipated discharge within 72 hours
disease • Immunosuppressed
• At least 1 elevated inflammatory marker > upper limit of normal • Ever received convalescent plasma, intravenous
(ULN) prior to study entry (C-reactive protein, D-dimer, lactate immunoglobulin, or neutralizing antibodies for COVID-19
dehydrogenase, or ferritin) • Active tuberculosis (TB) or latent TB treated for <4 weeks
• ***Only difference between COV-BARRIER part 1 and 2 was: • Suspected serious infection
• Part 1: requiring supplemental oxygen (after 10/20/20 • Active malignancy
amendment to protocol) • VTE within 12 weeks of history of >1 VTE
• Part 2.: use of mechanical ventilation or ECMO • Pregnant
• Live vaccine within 4 weeks
• ANC <1000, ALC <200, AST or ALT >5x ULN, or eGFR <30 mL/min

Interventions
Baricitinib Control
• eGFR >60: 4 mg PO or via NG q24h • Per local clinical practice
• eGFR 30-59: 2 mg PO or via NG q24h • VTE prophylaxis required for all patients unless there was a
• Duration: up to 14 days or until discharge major contraindication

VTE: venous thromboembolism AST: aspartate aminotransferase

ANC: absolute neutrophil count ALT: alanine aminotransferase Ely EW, et al. Lancet Respir Med. 2022 Apr;10(4):327-336.
ALC: absolute lymphocyte count eGFR: estimated glomerular filtration rate Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 Notable Demographic Variables
Baricitinib (n=764) Control (n=761) Baricitinib (n=51) Control (n=50)
Mean age (years) 57.8 (14.3) 57.5 (13.8) 58.4 (12.4) 58.8 (15.2)
Duration of symptoms >7 days
82% 85% 96% 88%
prior to enrollment
Median days of hospitalization
-- -- 4 (2-7) 4 (2-7)
prior to randomization
Ordinal scale 4 (no oxygen) 12% 13% -- --
Ordinal scale 5 (low flow oxygen) 64% 62% -- --
Ordinal scale 6 (HFNC/NIV) 24% 25% -- --
ECMO -- -- 4% 2%
Mean NEWS score -- -- 10.5 (2) 10.6 (2)
Concomitant steroid 80% 78% 84.3% 88%
Dexamethasone 92% 90% -- --
Concomitant remdesivir 18% 19% 0% 4%
Median C-reactive protein (mg/L) 67.5 62 124.9 109.5

ECMO: extrapcorporeal membrane oxygenation NEWS: new early warning score Ely EW, et al. Lancet Respir Med. 2022 Apr;10(4):327-336.
HFNC: high flow nasal cannula NIV: non-invasive ventilation Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 Primary Outcome
• Part 1: composite endpoint of proportion of participants who by day
28 progressed to HFNC/NIV or MV/ECMO or died
• Baricitinib 27.8% vs. control 30.5%
• Odds ratio 0.85 (95% CI 0.67 to 1.08)

• Part 2: all cause mortality at day 28

• Baricitinib 39.2% vs. control 58%
• Hazard ratio 0.54 (95% CI 0.31 to 0.96)
• Number needed to treat = 6

ECMO: extracorporeal membrane oxygenation

HFNC: high flow nasal cannula
MV: mechanical ventilation
NIV: non-invasive ventilation Ely EW, et al. Lancet Respir Med. 2022 Apr;10(4):327-336.
NNT: number needed to treat Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 Part 1 – 28 Day Mortality
4 = no oxygen
5 = low flow
6 = HFNC/NIV NNT = 9

NNT = 20

HFNC: high flow nasal cannula

NIV: non-invasive ventilation
NNT: number needed to treat Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 Notable Secondary Outcomes
Part 1 – 60 day mortality Baricitinib (n=764) Control (n=761) Hazard ratio and 95% CI NNT
Population 1 (all randomized) 10% 15% 0.62 (0.47 to 0.83) 21

Population 2 (no steroids + oxygen) 5/96 (5%) 19/108 (18%) 0.27 (0.1 to 0.75) 9

Ordinal scale 6 42/183 (23%) 63/187 (34%) 0.58 (0.39 to 0.86) 10

Venous thromboembolic event 3% 3% -- --
Treatment emergent infection 16% 16% -- --

Part 2 Baricitinib (n=51) Control (n=50) Hazard ratio and 95% CI NNT
60-day mortality 45.1% 62% 0.56 (0.33 to 0.97) 6
Venous thromboembolic event 6% 6% -- --
Treatment emergent infection 70% 71% -- --

HFNC: high flow nasal cannula

NIV: non-invasive ventilation Ely EW, et al. Lancet Respir Med. 2022 Apr;10(4):327-336.
NNT: number needed to treat Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 COV-BARRIER
Conclusions
• No difference in progression to
HFNC/NIV, MV/ECMO, or death
by day 28
• Significant reduction in both 28
day and 60 day mortality
• Largest mortality benefit seen
in those who started on
HFNC/NIV
• Benefit in regards to 28 day
mortality also seen in several
subgroups
ECMO: extracorporeal membrane oxygenation
HFNC: high flow nasal cannula
MV: mechanical ventilation
NIV: non-invasive ventilation
Limitations
• Excluded patients on
MV/ECMO
• No information regarding time
from admission to enrollment
• Only ~25% of patients
receiving HFNC/NIV at
baseline
• Majority of patients on low
flow oxygen
• Only 18-19% of patients
received remdesivir despite
majority of population being on
low flow oxygen
• No mention of duration of
baricitinib therapy
• Lacking detail regarding
baseline inflammatory markers
aside from C-reactive protein
Conclusions Limitations
• Significant reduction (46%) in • Small sample size
28 day mortality • No formal sample size
calculation
• Significant reduction (44%) in • No requirement for maximum
60 day mortality duration of MV or ECMO
• No information regarding
duration of intensive care unit
stay prior to randomization
• Lacking granular detail
regarding steroid use
• No rationale state as to why
not all patients received
steroids
Ely EW, et al. Lancet Respir Med. 2022 Apr;10(4):327-336.
Marconi VC, et al. Lancet Respir Med. 2021 Dec;9(12):1407-1418.
 Immediate Impact
UPHS NIH IDSA

• None, given more experience • Recommends either baricitinib • Suggests baricitinib in

using tocilizumab and ease of or tocilizumab in recently hospitalized adults with severe
single dose hospitalized patients, with COVID-19 having elevated
rapidly increasing oxygen inflammatory markers
• Incorporated into guideline needs, on HFNC or NIV, who
once tocilizumab was on have increased markers of • Appears to demonstrate most
severe, national shortage inflammation benefit in those with severe
COVID-19 on HFNC/NIV at
• Preferred over tocilizumab in • Insufficient evidence to issue a baseline
December 2021 recommendation in MV/ECMO
patients due to small sample • Limited additional data suggest
size of study a mortality reduction even
among patients requiring MV

ECMO: extrapcorporeal membrane oxygenation NIH: National Institutes of Health

HFNC: high flow nasal cannula NIV: non-invasive ventilation
IDSA: Infectious Diseases Society of America UPHS: University of Pennsylvania Health System Bhimraj A, et al. Clin Infect Dis. 2021 Oct 15.
MV: mechanical ventilation COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
 The Baricitinib Timeline

December 2021
UPHS prefers March 2022 July 2022
baricitinib to RECOVERY pre- RECOVERY
tocilizumab print published

February 2022 May 2022

COV-BARRIER FDA approved
MV cohort indication for
published COVID-19 and
ACTT-4 published

FDA: Food and Drug Administration

MV: mechanical ventilation
UPHS: University of Pennsylvania Health System
 RECOVERY Baricitinib
N=8156
Design Methods
• Baricitinib part of main randomization → not same • Included patients age >2 years
Design population as RECOVERY tocilizumab where patients • Baricitinib given for up to 10 days
had progressive disease • Tocilizumab receipt still permitted
• Short median time from hospital admission to • HFNC/NIV: ~25%
randomization • Steroids: >95%
Patients • COVID-19 vaccine: >40% • Concomitant tocilizumab: >30%
• Low flow oxygen: >65%
28 day mortality – overall 28 day mortality – HFNC/NIV
• TCZ 12% vs. CON 14% • TCZ 20% vs. CON 25%
Results • RR 0.87 (95% CI 0.77 to 0.99) • RR 0.75 (95% CI 0.62 to 0.9)
• NNT = 82 • NNT = 20
• Subjective inclusion/exclusion criteria → heterogeneous patient population
• No mention of number of pediatric cases included
Limitations • Part of main randomization so no criteria for need for progressive disease like RECOVERY tocilizumab
• >30% received concomitant tocilizumab
• No per protocol analysis → 8% did NOT receive baricitinib but included in ITT analysis

HFNC: high flow nasal cannula

NIV: non-invasive ventilation
RR: rate ratio RECOVERY Collaborative Group. Lancet. 2022 Jul 30;400(10349):359-368.
 Current State – Guidelines
UPHS NIH IDSA
• Baricitinib preferred over tocilizumab • Patients on dexamethasone with • Provides separate recommendations
rapidly increasing oxygen needs and
• If all of the following: systemic inflammation • Tocilizumab
• <24 hours of HFNC (>40% FiO2), NIV, • Either baricitinib or tocilizumab • Suggested in combination with
or MV standard of care (i.e. steroids) in
• <14 days of acute symptoms • For most patients on HFNC/NIV who hospitalized patients with progressive
are on dexamethasone: severe or critical COVID-19 who have
• Either baricitinib or tocilizumab elevated markers of systemic
• Can be considered in patients with
inflammation
lower oxygen requirements if
worsening clinical trajectory or concern • MV or ECMO patients on
for high risk of decompensation dexamethasone: • Baricitinib
• Add either baricitinib or tocilizumab if • Suggested in combination with
• Avoid in: not already initiated steroids in hospitalized patients with
severe COVID-19
• RRT or eGFR <15
• ALC <200 • Drug availability:
• ANC <500 • Sarilumab if tocilizumab is not
available
• Tofacitinib if baricitinib is not available

ECMO: extrapcorporeal membrane oxygenation MV: mechanical ventilation

FiO2: fraction of inspired oxygen NIH: National Institutes of Health
HFNC: high flow nasal cannula NIV: non-invasive ventilation Bhimraj A, et al. Clin Infect Dis. 2022 Nov 2.
IDSA: Infectious Diseases Society of America UPHS: University of Pennsylvania Health System COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health.
10,000 Foot Summary

• Shortages have been detrimental

• Baricitinib and tocilizumab are most beneficial if given early in:

• Critical COVID-19
• Patients with progression from severe to critical disease

• Both have been shown to be relatively safe given the shorter durations used for
COVID-19
• Baricitinib up to 14 days
• Tocilizumab x 1 dose

• Baricitinib is up to $3000 cheaper than tocilizumab

 Hot Off the Press!

• Recent study by Karampitsakos T, et al. comparing BAR and TCZ (n=251)

• BAR was non-inferior to TCZ in regards to composite primary end point of progression to MV or
death by day 28
• Non-inferiority margin of 50%
• Significantly higher rate of transaminase elevation with TCZ vs. BAR (7.9% vs. 2.4%; p=0.04)

• Anakinra receives emergency use authorization on 11/9/2022 based on SAVE-MORE

study (n=594)
• Lower odds (67%) of more severe disease at day 28
• Lower risk (52%) of death by day 28
• Lower risk (44%) of severe respiratory failure at day 28
• 100 mg subcutaneously daily x up to 10 days

BAR: baricitinib
MV: mechanical ventilation Karampitsakos T, et al. Clin Microbiol Infect. 2022 Oct 20;S1198-743.
TCZ: tocilizumab Emergency Use Authorization for Anakinra: https://www.fda.gov/media/163075/download
References

• University of Pennsylvania COVID-19 Guideline (publicly available):

http://www.uphs.upenn.edu/antibiotics/COVID19.html

• National Institutes of Health COVID-19 Guideline:

https://www.covid19treatmentguidelines.nih.gov/about-the-
guidelines/whats-new/

• Infectious Diseases Society of America COVID-19 Guideline:

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-
and-management/
Latest COVID and Rheumatic
Disease Therapies: What You
Need to Know
Rachael Perritt, PharmD, BCPS
Clinical Pharmacy Specialist, Ambulatory – Rheumatology
Hospital of the University of Pennsylvania

Stephen Saw, PharmD, BCIDP

Clinical Pharmacy Specialist, Infectious Diseases
Hospital of the University of Pennsylvania