Year in Review:

Clinical Science

Carol A. Langford, MD MHS

Harold C. Schott Chair

Director, Center for Vasculitis Care and Research
Department of Rheumatic and Immunologic Diseases
Cleveland Clinic
 Disclosure Statements - Carol A. Langford, MD, MHS

I have the following relevant financial relationship(s) to disclose:

Research grants: Bristol-Myers

Squibb
Genentech
GlaxoSmithKlin
e
ChemoCentryx
AstraZeneca
Non-paid consultant: Bristol-Myers Squibb
AbbVie
AstraZeneca

This presentation includes discussion of unlabeled commercial products

 Year in Review: Clinical Science
An Outstanding Year for Clinical Rheumatology

Approach to choosing topics:

• November 2021 - November 2022
• Reviewed high-impact journals in rheumatology, internal medicine
Direct Impact on
• Sought out diverse opinions from across rheumatology Clinical Practice

Approach to todays discussion:

• Focused discussion around 7 concepts Innovative Risks vs
• Briefer comment on other equally important publications Approach Benefits

• Not all-inclusive:
 Many important studies that could not be covered due to time
 Ann Rheum Dis 2022;81:925

Randomized, double-blind, placebo-controlled trial that examined the benefit and harm of prednisolone 5 mg/day
given for 2 years added to standard of care in patients age 65 years or older with active RA (DAS28 > 2.6)

Pragmatic trial:
Prednisolone 5 mg/day A clinical trial design that focuses on examining
treatments and outcomes in a real-world practice setting
Oral Placebo every day
Allowed:
0 Month 24 • Co-treatments and changes for RA
Randomized 1:1 ratio Primary endpoint
Biologic and non-biologic DMARDs
Assessments every 3 months NSAIDS
In-person: Baseline, Month 3, 6, 12, 18, 24 Short-term glucocorticoids for flares (not chronic)
Imaging: Baseline and Month 24
Boers M, et al. ARD 2022;81:925

Study population:
451 patients (224 Prednisolone, 225 placebo, 2 no intervention)
Mean age 72, female 70%, disease duration 11 years, DAS28 4.5
79% received DMARDs including 14% on biologics

Co-Primary outcome for benefit and harm:

Benefit: DAS28 over 2 years
• 0.37 points lower on prednisolone than placebo (95% CL 0.23,
p<0.0001)

Harm: Total number of patients with an adverse event of special

interest (AESI)
• AESI: Prednisolone 60% vs placebo 49% (adjusted relative risk
1.24, 95% CL 1.04, p=0.02)
• Majority due to infections (prednisolone 150 vs placebo 107 –
mostly non-severe)
• Number needed to harm (NNH) 9.5

Secondary outcomes:
Boers M, et al. ARD 2022;81:925
Conclusions:
Use of prednisolone 5 mg/day for 2 years compared to placebo in patients > 65 years was associated with:
• Lower disease activity (DAS28 -0.37 difference)
• Reduction in joint damage (Sharp/van der Heijde -1.7)
• Trade-off: 24% increase in adverse events

Points to consider:
Study population (patient age and disease duration), 2-year study

How to weigh benefits and harms ? -- Protocol defined interpretation rules (From the supplementary appendix)

1. Success: success in benefit and success in harm

2. Failure: failure benefit and failure in harm
3. Partial success/tradeoff: all other scenarios

Provides insights that the practitioner can use in weighing the relative benefits vs risks
of low dose prednisolone individualized to each RA patient age 65 years or older
 NEJM 2022;386:316

FDA mandated post-authorization Phase 3b/4 randomized, open-label, non-inferiority safety endpoint trial
Active, moderate to severe RA, despite methotrexate (MTX), age > 50 years, with > 1 cardiovascular risk factor

Tofacitinib 5 mg twice daily Study population:

Tofacitinib 10 mg twice daily * 4362 patients
• 1455 - tofacitinib 5 mg, 1456 - 10 mg, 1451 - TNFi
TNFi: Adalimumab 40 mg every 2 weeks (North America)
• Mean age 61 years (31% > 65 years)
Etanercept 50 mg every week (Rest of world)
• Female 78%
Randomized 1:1:1
Background methotrexate continued
* Reduced to 5 mg BID during the study due to
a higher rate of pulmonary embolism
Ytterberg SR, et al. NEJM; 2022;386:316
Co-Primary endpoints:
1) Major adverse cardiovascular events (MACE): cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
2) Cancers, excluding non-melanoma skin cancer *Number needed to harm
MACE % HR vs TNFi (95% CI) NNH* (5-year) Cancer % HR vs TNFi (95% CI) NNH*(5-year)
Tofacitinib 5 mg 3.2 1.24 (0.81-1.91) 113 Tofacitinib 5 mg 4.3 1.47 (1.00-2.18) 55
Tofacitinib 10 mg 3.5 1.43 (0.94-2.18) 64 Tofacitinib 10 mg 4.1 1.48 (1.00-2.19) 55
Combined 3.4 1.33 (0.91-1.94) Combined 4.2 1.48 (1.04-2.09)
TNFi 2.5 TNFi 2.9

Risks of MACE and cancers were higher with tofacitinib, did not meet non-inferiority criteria (upper limit of 95% CI < 1.8)
Subgroup analysis: in those 65 years or older – higher incidence rate of both MACE and cancers
Secondary endpoints: Found to be higher with tofacitinib compared to TNFi:
• Serious infections (10 mg) • Hepatic events (10 mg)
• Opportunistic infection (5 mg and 10 mg) • Venous thromboembolism (10 mg)
• Herpes zoster (5 mg and 10 mg) • Death (10 mg)

FDA revised indication in RA and added a boxed warning for tofacitinib, baricitinib, and upadacitinib
 ARD 2022; Sep 22. Online ahead of print

Follow-up analysis that looked specifically at those with atherosclerotic cardiovascular disease (ASCVD)
ORAL Surveillance
Cardiovascular Risk Factors ASCVD (15% of the study population)
• Coronary artery disease • Coronary artery disease
• Current cigarette smoker
• Hypertension • Cerebrovascular disease
• HDL < 40 mg/dL
• Diabetes • Peripheral artery disease
• Extra-articular RA
• Family history premature Defined based on:
coronary heart disease Events, diagnoses, procedures
associated with atherosclerosis in
arteries of the heart, head/neck,
periphery
 Charles-Schoeman C, et al. ARD 2022; Sep 22. Online ahead of print
ASCVD (n= 640) % HR vs TNFi (95% CI) NNH (5-yr)
Occurrence of MACE Tofacitinib 5 mg 8.3 1.96 (0.87-4.40) 16
Total population HR vs TNFi 5-year Tofacitinib 10 mg 7.7 2.01 (0.89-4.50) 15
(n=4362) % (95% CI) Combined 8.0 1.98 (0.95-4.14) 16
NNH*
TNFi 4.2
Tofacitinib 5 mg 3.2 1.24 (0.81-1.91) 113
Tofacitinib 10 mg 3.5 1.43 (0.94-2.18) 64 No ASCVD (n=3722) % HR vs TNFi (95% CI) NNH (5-yr)
Combined 3.4 1.33 (0.91-1.94) 82 Tofacitinib 5 mg 2.4 1.03 (0.62-1.73) 869
TNFi 2.5 Tofacitinib 10 mg 2.8 1.25 (0.76-2.07) 124
*Number needed to harm
Combined 2.6 1.14 (0.73-1.78) 223
These results inform shared decision-making TNFi 2.3
Caution with tofacitinib use in RA is warranted in:
• History of ASCVD • CV risk factors
• Age > 65 years • Prior VTE

How should these findings be viewed in relationship to other JAK inhibitors and other disease settings ?
New indications and new mechanisms of JAK inhibition approved in the past year
 Lui C, et al. A&R 2021;12:2166
Cytokine
Receptor
Janus kinase (JAK) proteins
Intracellular tyrosine kinases that
play a direct role in mediating
JAK JAK cytokine-directed immune responses

IL-2 IL-9 EPO IL-3

IL-12 IFNα
IL-4 IL-15 TPO IL-5 IL-6
IL-7 IL-21 GH GM-CSF IL-23 IFNβ

JAK1 JAK3 JAK2 JAK2 JAK1 JAK2 JAK2 TYK2 JAK1 TYK2

JAK1 JAK2
JAK3 TYK2
Tofacitinib +++ ++
+++ + Baracitinib
+++ +++
Upadacitinib +++
 History of FDA Approved Janus Kinase (JAK) Inhibitors for Rheumatology Indications
Including Approvals within 2021-2022

Tofacitini Tofacitini Tofacitinib Tofacitinib

b RA b PsA Polyarticular JIA AS (12/2021)
Baracitinib
RA
Upadacitinib Upadacitinib Upadacitinib Upadacitinib
RA PsA (12/2021) AS nr-axSpA
Deucravacitini Deucravacitinib
b Psoriasis PsA, SLE *

2012 2017 2018 2019 2020 2021 2022

* Publications/abstracts in 2021-2022
but not FDA approved for this indication
 Spondyloarthritis IL-17A and IL-17F
bDMARD, tsDMARD JAKi
JAK TNF CTLA4-Ig PDE4 IL-23 IL-17A (not FDA approved)
i
Non-radiographic
Non-radiographic Secukinumab
Axial Upadacitinib
Upadacitinib Certolizumab Bimekizumab
Axial Spondyloarthritis
Ixekizimab
Spondyloarthritis
Etanercept
Ankylosing Tofacitinib Infliximab Secukinumab
Ankylosing Tofacitinib Adalimumab Bimekizumab
Spondylitis (AS) Upadacitinib Ixekizimab
Spondylitis (AS) Upadacitinib Golimumab
Certolizumab
Etanercept
Psoriatic Tofacitinib Infliximab Guselkumab Secukinumab
Psoriatic Tofacitinib Adalimumab Abatacept Apremilast Bimekizumab
Arthritis (PsA) Upadacitinib Risankizumab Ixekizimab
Arthritis (PsA) Upadacitinib Golimumab
Certolizumab
Etanercept Guselkumab Secukinumab
Psoriasis Infliximab Risankizumab Ixekizimab
Psoriasis (PsO)
(PsO) Deucravacitinib
Deucravacitini Adalimumab
Apremilast
Broadalumab
Bimekizumab
b
Certolizumab Tildrakizuma
b
Received FDA approval 2021-2022 Upadacitinib: Risenkizumab:
Tofacitinib: McInnes IB, et al. NEJM 2021;384:1227 (PsA) Kristensen LE, et al. ARD 2022;81:225
Deodhar A, et al. ARD 2021;80:1004 Mease PJ, et al. ARD 2021;80:312 (PsA) Östör A, et al. ARD 2022;81:351
van der Heijde D, et al. ARD 2022;81:1515
Deucravacitinib: (AS)
van der Heijde D, et al. RMD Op 2022;Jul 8 (AS) Bimekizumab:
Strober B, et al. JAAD 2022;Sep 14 (PsO) Deodhar A, et al. Lancet 2022;400:369 Coates LC, et al. A&R 2022;Jul 13 OAP (PsA)
Mease PJ, et al. ARD 2022;81:815 (PsA) Baraliakos X, et al. A&R 2022;Jul 13 OAP (AS)
 A&R 2022 Sep 13. Online ahead of print

Randomized, double-blind, placebo-controlled trial examining the co-administration of methotrexate (MTX)

to increase pegloticase response rate through reduction of anti-drug antibodies

Oral MTX Pegloticase 8 mg IV every 2 weeks

15 mg/week Oral MTX 15 mg/week
Oral MTX
15 mg/week
Oral Placebo Pegloticase 8 mg IV every 2 weeks
Once a Oral Placebo once a week
week
Week -6 Week -4 (Run-in) Day 1 Month 6 Week 52
(Tolerability Randomized 2:1 (Primary endpoint) (End of study)
)
Study population:
152 patients (100 pegloticase + MTX, 52 pegloticase + placebo)
89% male, mean age 55 years
76% tophi, 100% > 1 flare in the past year, 86% failure to
Botson JK, et al. A&R 2022 Sep 13. Online ahead of print

Primary endpoint:
Proportion of Month-6 responders (serum urate < 6 mg/dL during > 80% of Weeks 20-24)
• MTX 71% vs placebo 39% (95% CI 16.3-48.3%, p<0.0001)

Other exploratory endpoints:

Mean change serum urate through week 24
• MTX -7.6 vs placebo -5.2 (-2.43 95% CI -3.58-1.27, p<0.0001)

Safety:
Infusion reaction: MTX 4% vs placebo 31% (P<0.001)
Anti-drug antibody: MTX 23% vs placebo 50%
Serious adverse events similar: MTX 8% vs placebo
10%

Points to consider:
• In taking this approach, recognizing benefits and
risks remain important
 Benefits: Improved control of gout, safer use
of pegloticase by reducing infusion reactions
 Risks: MTX specific side effects, general
 NEJM 2022;387:1264

Randomized, double-blind, placebo-controlled trial examined the efficacy and safety of IVIG in dermatomyositis

Total Improvement Score (TIS)

IVIG 2 g/kg every 4 weeks Weighted composite score of changes in
IVIG 2 g/kg
every 4 weeks 6 measures of myositis activity (0-100)
Physician global activity 0-20
IV Placebo every 4 weeks
Patient global activity 0-20
0 Week 16 40 Manual muscle testing 0-20
Primary endpoint
Health Assessment Questionnaire 0-20
Randomized Phase Open-Label Extension
Muscle enzymes 0-20
Extramuscular activity 0-20
Study population: Aggarwal et al. A&R 2017;69:898
95 patients (47 IVIG, 48 placebo), DM by criteria of Bohan and Peter ACR/EULAR Response Criteria for
Median age 52 years (22-79), 75% female Adult Dermatomyositis, Polymyositis
 Aggarwal R, et al. NEJM 2022;387:1264
Primary endpoint:
TIS > 20 (at least minimal improvement) at week 16 with no deterioration up to week 16
• IVIG 79% vs placebo 44% (95% CI 17-53, P<0.001)

Secondary endpoints (study had 13):

Mean TIS at week 16
• IVIG 48.4 vs placebo 21.6

Safety:
Adverse events: most within 72 hours and mild
• Headache 42%, Pyrexia 19%, Nausea 16%
• 9 serious treatment-related adverse events
• 6 thromboembolic events

Clinical considerations:
• Cost • Caution in those at risk for thromboembolic events
• Blood product • When to consider use: first-line treatment vs refractory disease

July 2021 - IVIG received FDA approval for adult DM - First approved agent for any inflammatory myopathy
 Nat Med 2022;28:2124

What are chimeric antigen receptor (CAR) T cells ?

CAR T cells are a gene-modified cell therapy in which a viral vector is used to insert a receptor gene into
an autologous T cell which allows the T cell to recognize a cellular antigen and eliminate the target cell.

What has CAR T cell therapy been used for ?

August 2017: CAR T cell therapy FDA approved for refractory B-cell acute lymphoblastic leukemia in children
and adults
Currently 6 approved CAR T cell agents for the treatment of a range of refractory hematologic
malignancies

What are the risks of CAR T cell therapy ?

• Cytokine release syndrome (CRS) occurs in 50-90% of treated patients
 Tocilizumab carries an FDA labelling indication for the treatment of CAR T cell-induced CRS
• Immune effector cell-associated neurotoxicity syndrome (ICANS) (20-60%)
• Use of a lymphodepleting conditioning chemotherapy prior to CAR T cell infusion
 Mackensen A, et al. Nat Med 2022;28:2124

B cell Lentivirus vector

Containing
lysis/depletion Gene sequence
Antihuman CD19

En
zy Patient
m T
e Cell
rel
ea
se

CD19
CAR T
Cell
 CAR
Mackensen A, et al. Nat Med 2022;28:2124 T cell
Rationale:
Deep depletion of CD19+ B cells and tissue plasmablasts could result in immune reset in SLE
Preclinical studies in lupus-prone mice supported efficacy

Study Population:
5 patients with SLE, 4 women, median age 22 (18-24)
• Active multiorgan disease, median SLEDAI-2K 16, h/o biopsy proven glomerulonephritis, no CNS disease
• All refractory to many therapies (glucocorticoids, cyclophosphamide, belimumab, hydroxychloroquine)

Results:
Improvement in all 5 patients, with 4 achieving a SLEDAI-2K = 0 by 3 months
• Labs: Complement levels normalized, disappearance of anti-DNA antibodies
All immunomodulatory drugs could be discontinued in all patients
• Drug-free remission maintained at 8 months even after reappearance of B cells (100 days after)
Safety: Mild CRS in 3 patients with 1 patient receiving tocilizumab for persistent fever, no ICANS

Conclusions:
• Concerns remain for costs and risks
• Innovative approach - longer follow-up in larger numbers will be needed to determine if remission persists
 Phase 2 Randomized Trials in Lupus – Novel Mechanistic Approaches
Liftifilimab
Innate immune system
Monoclonal AB that binds blood dendritic cell antigen 2
(BDCA2) suppresses production of type I interferons
Werth VP, et al. NEJM 2022;387:321
Cutaneous LE (n=132)
Met primary endpoint - skin CLASI-2 week 16
Furie RA, et al. NEJM 2022;387:894
SLE: Joint, skin (n=102)
Met primary endpoint – number active joints week 24
Obinutuzumab
B cell
Humanized type II anti-CD20 monoclonal AB - provides
greater B cell cytotoxicity and depletion
Furie RA, et al. ARD 2022;387:321
Lupus nephritis Class III-IV on background MMF (n=125)
Met primary endpoint - complete renal response week
52 (prespecified alpha 0.2). There was further
improvement seen by week 104 (p=0.026)

Safety - 1 episode herpes zoster meningitis Safety - No increase in infections (final data 12/2019)

Iberomide Merrill JT, et al. NEJM 2022;386:1034

Immunomodulatory imide drug (ImiD) that promotes SLE SLEDAI-2K > 6 (mean 9.6), active neuropsychiatric or
degradation of transcriptional factors Ikaros and Aiolos nephritis excluded (n=288)
reducing activity of B cells and type I interferon pathways Met primary endpoint – response by SRI-4 week 24
Safety – increase in adverse events with iberomide - upper respiratory and urinary infections and neutropenia
Class concerns – increased thromboembolic risk and teratogenicity (same family as thalidomide)

Further studies are needed to better understand the potential roles of these agents
 JAMA 2022;328:1053
Randomized trial of IV tocilizumab 8 mg/kg every 4 weeks or placebo with standardized prednisone taper
101 patients with PMR, mean age 67 years, 67% female
All glucocorticoid-dependent (unable to decrease below 10 mg/day after 8 weeks)

Primary endpoint: CRP PMR-AS < 10 and prednisone < 5 mg/day or decrease 10 mg from baseline at
week 24
• Tocilizumab 67% vs placebo 31%, adjusted relative risk 2.3 (95% CI 1.5-3.6, p< 0.001)

Secondary endpoints: Tocilizumab: lower mean prednisone dose, greater ability to discontinue
prednisone

Points to
Safety: consider:
Infection: tocilizumab
• Enrolled47% vs placebowith
a population 39%, no GI perforations
demonstrated with
inability to tocilizumab
reduce prednisone
• Main consideration -risk of prednisone compared to risk of the adjunctive agent

2/28/2022 FDA approval of intravenous tocilizumab for giant cell arteritis (GCA)
• Based on pharmacokinetic data from Schmitt C, et al. Art Res Ther 2022;24:133
• 2017 First FDA approval of tocilizumab in GCA which was for subcutaneous administration
 Arthritis Rheumatol 2022;74:766

Systematic literature review

14 databases 1/1/2019-2/13/2021
5799 abstracts screened, 100 studies met criteria for review
• Relative risk of developing infection 52% higher in patients with RMD compared to general population
• Higher risk of poor outcome with a 74% increased risk of death

RMD Open 2022;8:e002187

197 COVID infections in partially/fully vaccinated patients occurred 1/5-9/30/2021 in the GRA database
• 34% conventional DMARD, 28% biologic/synthetic DMARD (11% B cell-depleting), 31% both, 7% no DMARD
• Over half requiring hospitalization were receiving B cell-depleting therapy or mycophenolate mofetil
 NEJM 2022;86:2188

Tixagevimab and cilgavimab (Tix-Cil) are fully human monoclonal antibodies that bind to the SARS-CoV-2
spike protein to neutralize the virus to provide non-vaccine based pre-exposure prophylaxis
Study Population:
5197 patients age > 18 years, increased risk of an inadequate response to vaccination or increased risk of
exposure to the infection were randomized 2:1 to receive Tix-Cil (n=3460) or placebo (n=1737)

Efficacy:
COVID-19: Tix-Cil 0.2% vs Placebo 1.0% (Risk reduction 77%, p<0.001)

Safety:
Most common side effects: Headache, fatigue, cough
Serious adverse events (SAE) 1.4% for both Tix-Cil and placebo
Cardiac SAE Tix-Cil 0.6% vs Placebo 0.2%
Limitations:
Pre-omicron
Few enrolled patients received immunosuppression (3.3%)
 Clin Infect Dis 2022 Jul 29; Online ahead of print

• Retrospective study utilizing centralized database of the Maccabi

HealthCare Services (2nd largest HMO in Israel)

• 2/23/2022 all patients who met definition of severe

immunosuppression invited via email/SMS to receive Tix-Cil
 825 received, 4299 did not receive

• COVID-19: 3.5% who received Tix-Cil vs 7.2% did not receive

(p<0.001)

• Tix-Cil treated group:

 Half as likely to become infected
 92% less likely to be hospitalized/die

While Tix-Cil does not prevent all COVID infections, it

appears to lessen the frequency and severity
12/8/2021 FDA EUA – Current: Tixagevimab 300 mg -
 Calabrese L, et al. A&R 2022;
COVID – Strategies in Optimizing Care Aug 26. Online ahead of print

Prevention Risk Assessment

Non-pharmacologic Underlying disease

Vaccination Immunosuppression
Pre-exposure Comorbidities
prophylaxis Age

Treatment Education
Patient
Early identification Symptom awareness
Early treatment Home testing
Rheumatology
practitioner
Information
The rheumatology practitioner hasdistribution
played a central role
in advocating for immunocompromised rheumatic disease patients in the COVID-19 era
 THANK YOU
To So Many Without Whose Help
This Would not Have Been Possible