CSF EULAR Symposium Review

Symposium Review

EULAR 2021

Welcome to the CSF EULAR 2021 Symposium Review

The annual EULAR European Congress of Rheumatology is the leading event in the

rheumatology calendar and provides a forum of the highest standard for scientific and

educational exchange between professionals in rheumatology – and the symposiums are

no exception. The quality of the data and discussion this year was exceptional, and we

are delighted to share our pick of the symposiums with you.

The satellite symposiums at EULAR 2021 provided a wide breadth of content on cytokine

signalling and JAK inhibition, including the latest efficacy and safety findings from

clinical trials, practical guidance on the use of JAKinibs in the management of RA, and

how COVID-19 has influenced the management of patients with RMDs. This brochure

summarises the key content from the symposiums on JAK inhibition.

We hope you enjoy this summary from EULAR 2021.

Professor Iain B. McInnes

University of Glasgow,

United Kingdom

HEADLINES

Cytokine signalling

blockade:

Interactions

and outcomes

JAK inhibitors in RA:

What, where, how,

why, who and when?

Striving for remission

with JAK inhibition in

the management of

rheumatoid arthritis

In Darwin’s footsteps:

Exploring the role of

JAK inhibitors within

the diverging RA

treatment landscape

Sponsored by Lilly

Sponsored by Pfizer

Sponsored by Abbvie

Sponsored by Galapagos

Professor John O’Shea

examined cytokine

signalling pathways,

Professor John Isaacs

discussed targeting the

JAK-STAT pathway and

the immune-pathologic

consequences, and

Professor Rieke Alten

described the mechanisms

of JAK inhibition.

Dr Elizabeth Perkins

reviewed the rationale

for selecting JAKinibs

in RA, Professor Hendrik

Schulze-Koops discussed

what have we learned

about JAKinibs in RA,

and Dr Ai Lyn Tan asked

where JAKinibs fit into the

RA treatment paradigm.

Professor Gerd-Rüdiger

Burmester, Professor

Philip G Conaghan,

Professor Hendrik

Schulze-Koops, and

Professor Grace C. Wright

discussed remission in

patients with RA, the role

of JAK inhibitors, and

current evidence on their

safety profile.

Professor Maxime

Dougados discussed

living with RA, Professor

Rieke Alten and Professor

Kevin Winthrop explored

translating clinical

features of treatments to

meet patient needs, and

Professor Ernest Choy

examined the impact of

treatment evolution in RA.

Click here for a summary

of their presentations.







This is supported by an educational grant from Lilly

Symposium Review EULAR 2021

Cytokine signalling blockade: Interactions and outcomes

The CSF symposium, sponsored by Lilly, was chaired by Professor Paul Emery

with presentations from Professors John O’Shea, John Isaacs, and Rieke Alten.

The symposium explored the cytokine signalling pathways and their downstream

effects, as well as the mechanisms of action of cytokine signalling inhibitors.

The clinical outcomes from the blockade and the clinical relevance of different

mechanisms were also discussed.

Cytokine signalling pathways:

What are they and how do

they work?

Professor John O’Shea

There are over 200 cytokines in the human

genome all of which play a critical role

in host defence, immunoregulation and

autoimmunity. Professor O’Shea discussed

the research efforts that have been directed

towards understanding cytokine receptors

and cytokine intracellular signalling

pathways, in particular, the JAKs and

the JAK-STAT signalling pathway.

Early work by Warren Leonard et al 1 elucidated

the role of JAK3 and the potential for

immunosuppressant agents that target it.

This has led to the approval of nine JAKinibs

to date. Ongoing JAK clinical trials continue

to evaluate their use across rheumatologic

indications such as juvenile arthritis and

spondyloarthritis.

JAKs structure and function

There are four JAKs: JAK1, JAK2, JAK3

and TYK2. All except JAK2 work in pairs

and possess kinase (catalytic) and kinaselike

(regulatory) domains. JAK3 knockout in

mice results in combined immunodeficiency,

whereas TYK2 knock-out and mutations,

result in viral susceptibility, human loss-offunction

polymorphism, and a decreased risk

of autoimmune disease. This explains why

JAK-targeted inhibition would potentially be

efficacious for autoimmune diseases. JAK1

knockout is perinatally lethal in mice and JAK2

knock-out was shown to be embryonically lethal

due to defective haematopoiesis.

Next-generation JAKinibs

JAKinibs, such as tofacitinib and baricitinib,

inhibit multiple JAKs and subsequently a wide

spectrum of cytokines. Other JAKinibs have

a narrower spectrum of cytokine inhibition.

To improve specificity, next-generation inhibitors

have been developed that are more selective,

such as deucravacitinib which binds to

the TYK2 pseudokinase domain and is an

allosteric inhibitor.

There are knowledge gaps that necessitate

further research. Questions that remain include:

what is the basis for the efficacy of JAKinibs,

what cytokines and cells are of greatest

importance, in what disease or disease phase,

and dosing. The optimal treatment pathway is

still unclear; there remains a lot to understand

about the cell biology and structure of cytokine

receptors and JAKs.

Targeting the JAK-STAT

pathway: What are the

immune-pathologic

consequences?

Professor John Isaacs

There are several rheumatological smallmolecule

drugs already approved or in

development that target cytokine signalling

pathways. Professor Isaacs explained how

the therapeutic profile of individual JAKinibs

is dependent on multiple factors including

their relative affinity towards different JAKs

(selectivity), PK characteristics and individual

pharmacogenetic differences.

JAKs are typically heterodimers, apart

from JAK2 (the only homodimer), and have

γ-chain cytokines

IL-2, IL-4, IL-7,

IL-9, IL-15, IL-21

JAK1

JAK3

• T cell proliferation

and survival

• T cell memory

• T regulatory cell

function

• B cell function

JAK3 selective

• Peficitinib

JAK1/2 selective

• Baricitinib

Type 1 IFNs

(IFN-α/β)

IL-10 a , IL-22

JAK1

TYK2

• Anti-inflammatory

JAK1

TYK-2 selective

• BMS-986165 (deucravacitinib)*

IL-6, IL-11,

IL-13, IL-27,

IL-31, IL-25

TYK2 b

• Acute phase response

• Lymphocyte growth

and differentiation

• Catabolic metabolism

• Lipid metabolism

• Bone resorption

• T cell differentiation

• Lymphocyte effector

function

JAK1 selective • Filgotinib • Solcitinib*

Inhibits JAK1 and JAK1/3 more potently than JAK • Upadacitinib

Non-selective

• Tofacitinib • Ruxolitinib* • Oclacitinib*

associated cytokines that signal through

the pairings. JAKinibs bind to JAKs and

prevent ATP binding, interrupting the

phosphorylation cascade necessary for

cytokine signalling. The therapeutic profile

of individual targeted JAKinibs depends on

their relative affinity toward different JAKs

(selectivity). No JAKinib is specific for only

one JAK isoform.

The rationale behind engineering JAK

selectivity is to balance the benefits of

inhibiting one JAK against the risk of inhibiting

another. During drug development the aim is

to identify the dosing required to achieve

optimal selectivity. When administered to

patients, optimal therapeutic JAKinib dosing

is dependent upon PK, which influences drug

concentration, and varies from patient-to-patient

due to pharmacogenetic factors.

IFN-γ

IL-12

IL-23

EPO,TPO

GM-CSF

IL-3, IL-5

JAK2 b JAK1 JAK2 JAK2 TYK2 b JAK2 JAK2



function

• Macrophage

activation



function

TYK-2 selective

• BMS-986165*

• Haematopoiesis

• Erythrocytes

• Platelets

• Neutrophils

• Lymphocytes

• Growth

• Anabolic metabolism

The JAK-STAT pathway in cytokine signalling and the selectivity of JAKinibs

EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TPO, thyroid peroxidase. *Drug not approved

for RA at the time of presentation. a IL-10/IL-22 may have pro- or anti-inflammatory activities depending on cellular environment and/or disease state. b Type II

cytokine receptors such as those for gp130 subunit sharing receptors for IL-6 and IL-11 as well as IL-10, IL-19, IL-20, and IL-22, mainly signal through JAK1,

but also associate with JAK2 and TYK2. Figure adapted from: Clark JD, et al. J Med Chem 2014;57:5023–5038; O’Shea JJ, et al. Ann Rev Med 2015;66:311–328;

Schwartz DM, et al. Nat Rev Rheumatol 2016;12:25–36; Ghoreschi K, et al. Immunol Rev 2009;228:273–287; Sanjabi S, et al. Curr Opin Pharmacol 2009;9:

447–453; Guschin D, et al. EMBO J 1995;14:1421–1429; Ivanshkiv LB, Donlin LT. Nat Rev Immunol 2014;14:36–49; Adachi K, Davis M. Proc Natl Acad Sci USA

2011;108:1549–1554; Schwartz DM, et al. Nat Rev Drug Discovery 2017;16:843–862.


Mechanisms of JAK inhibition:

Current results, future

perspectives


Although JAKinibs show similar clinical

efficacy, incidence rates of some AEs

vary, indicating that certain JAKinibs may

be more appropriate for the treatment of

specific patient sub-populations. Professor

Alten reviewed the benefit-risk profiles for

four approved JAKinibs and considered the

recently published consensus statement on

the use of JAKinibs in IMID.

Early this year Nash et al. 2 published a consensus

on points to consider for the treatment of IMIDs

with JAKinibs. The task force agreed on four

principles: (i) initiation of JAKinib treatment should

be based on a shared decision with the patient,

which requires full information on potential

benefits and risks, (ii) therapeutic approaches to

chronic inflammatory conditions should be in line

with international and national recommendations

for the respective disease, (iii) the points to

consider when initiating JAKinib therapy do

ACR20

ACR50

ACR70

CDAI LDA

CDAI CR

DAS28(CRP) ≤ 3.2

DAS28(CRP) < 2.6

HAQ-DI change from BL ≤ -0.22

Filgotinib

-0.50

Favours MTX

-0.30

The FINCH 1 study assessed the efficacy

and safety of filgotinib compared with

adalimumab and placebo, with background

MTX therapy in patients with active RA. This

study demonstrated non-inferiority of filgotinib

not provide information on when JAKinibs

should be used in the treatment algorithm, but

rather attempt to assist the clinician once the

decision to prescribe JAKinib has been made

and (iv) these points address specific aspects

of JAKinibs; therefore, clinicians should also

refer to disease-specific product information.

Upadacitinib

Across the Phase 3 SELECT clinical programme

of five pivotal RA trials (N=4400), upadacitinib

15 mg, as monotherapy or in combination

with csDMARDs or MTX met all primary and

ranked secondary efficacy endpoints. It achieved

significantly higher remission and LDA rates than

placebo, MTX or adalimumab alone. The risks

observed with upadacitinib 15 mg were similar

to those reported for other JAKinibs and the

safety profile was consistent with a previous

integrated safety analysis. Upadacitinib 15 mg

was associated with higher rates of HZ and

creatine phosphokinase elevations but otherwise

had a safety profile similar to that of MTX

and adalimumab. Overall, these data suggest

upadacitinib 15 mg has a favourable benefit–risk

profile for the treatment of RA.

MTX-naïve a MTX-IR b

0.00

0.30 0.50

Difference in proportion through week 12 a or week 14 b (95% CI)

Favours UPA 15 mg c

Methotrexate controlled UPA 15 mg monotherapy analysis set in MTX-IR and MTX-naïve patients: UPA +

MTX (SELECT-EARLY and -MONOTHERAPY)

a

SELECT-EARLY. b SELECT-MONOTHERAPY. c A positive value indicates more favourable efficacy with UPA 15 mg than with methotrexate.

cMTX, continued methotrexate; IR, inadequate responders.

Adapted from Conaghan PG, et al. Drug Saf 2021; DOI: 10.1007/s40264-020-01036-w.

200 mg, but not 100 mg, to adalimumab, based

on DAS28(CRP) LDA. In the FINCH 2 study,

filgotinib significantly improved efficacy versus

placebo in bDMARD-IR patients with active

RA. The FINCH 3 study examined filgotinib use

in patients with MTX-naïve RA. Both doses of

ACR20/50/70 responses among patients remaining in the study at Week 204

Adapted from Kavanaugh A, et al. J Rheumatol 2021; DOI: 10.3899/jrheum.201183.

filgotinib plus MTX significantly improved signs

and symptoms, and physical function. Overall,

both doses of filgotinib showed a favourable

benefit-to-risk profile and were well tolerated.

DARWIN 3 is an ongoing LTE study evaluating

long-term safety and tolerability of filgotinib.

The 4-year data demonstrated that filgotinib

was well tolerated with a safety profile

comparable to that of the parent trials.

Tofacitinib

A study carried out by Finckh et al. 3 compared

the drug maintenance and clinical effectiveness

of three alternative DMARD treatment

options for RA management. Tofacitinib drug

maintenance at 3 years was comparable with

non-TNFi bDMARDs, and somewhat higher than

TNFi. Concomitant csDMARDs appear to be

required for optimal effectiveness of TNFi, but

not for tofacitinib or bDMARDs with OMA.

The Corrona RA registry analysis adds long-term

safety data for tofacitinib in real-world practice.

The 5-year results provide evidence that the

risk of MACE, serious infection, malignancies,

Change from baseline

in mean pain VAS score

Responders (%)

10

0

-10

-20

-30

-40

-50

-60

-70

-80

100

90

80

70

60

50

40

30

20

10

0

Change in pain VAS at Week 24

89.3 91.8

69.6 69.4

49.1

Filgotinib + MTX (n=497)

-27 -27

-37 -38

-46

**

Patients in remission

Patients in remission or LDA

NMSC, and death are comparable in RA patients

receiving tofacitinib versus those receiving

bDMARDs. A post-hoc analysis of tofacitinib

Phase 3 trials indicate that PtGA responses are

closely associated with pain in csDMARD-IR

patients, supporting the role of pain as a key

driver of PtGA in RA. These findings corroborate

the importance of improved PROs and

attainment of low symptom states for optimising

patient care.

Baricitinib

44.4

Filgotinib monotherapy (n=242)

ACR20

ACR50

ACR70

The pain associated with RA is complex and

multifactorial. For patients it is the greatest

contributor to perceptions of RA disease activity.

In contrast, physicians believe SJC is the

greatest contributor to perceptions of disease

activity. In the 52-week RA-BEAM Phase III

study, baracitinib provided improvement in

pain and physical function in patients with

well-controlled RA, and demonstrated significant

improvements in joint stiffness, pain, and

tiredness versus placebo in the Phase 3

RA-BALANCE study of MTX-IR patients.

-21

-28

-46

*

-32

***

*** +

Patients in remission or LDA

PBO + MTX

ADA + MTX

BARI 4 mg + MTX

P-value vs. PBO: ***P<0.001; **P<0.01; *P<0.05. P-value vs. ADA: +P<0.05.

Adapted from Fautrel B et al. J Clin Med 2019;8:1394.


JAK inhibitors in RA: What, where, how, why, who and when?

This symposium, sponsored by Pfizer, was chaired by Professor Gerd-Rüdiger

Burmester and featured presentations from Dr Elizabeth Perkins, Professor

Hendrik Schulze-Koops, and Dr Ai Lyn Tan. The symposium discussed the

rationale for selecting JAKinibs as a treatment option in RA, evaluated the latest

safety and efficacy data for JAKinibs in specific subgroup populations and

examined their place in the RA treatment paradigm.

The rationale for selecting

JAK inhibitors as a treatment

option in RA

Dr Elizabeth Perkins

It is well-understood that JAK inhibition

modulates the signalling of multiple cytokines

involved in RA pathogenesis. This has led

to the development and global approval of

four JAKinibs for adults with moderate-tosevere

RA. Dr Perkins reviewed the wealth

of data gathered from multiple clinical trial

programmes and national registries that

support the efficacy and safety of JAKinibs

for the treatment of RA.

Data gathered across multiple clinical trial

programmes has provided a great deal of

insight on the use and safety of JAKinibs across

different patient types and RA phenotypes.

These studies demonstrated that the earlier

patients are treated with JAKinibs postmethotrexate,

the more likely they are to achieve

a better response to treatment than when their

disease burden has progressed. Real-world

data on JAKinib-treated patients is crucial to

understand how to balance the safety and

efficacy in these patients long-term. Data on

refractory RA patients is also important, as these

patients are often seen in clinic.

Several JAKinib trials in moderate-to-severe RA

have evaluated JAKinib treatment in MTX-IR

versus a TNFi. JAKinibs have shown clinically

meaningful improvement in ACR20, ACR50 and

ACR70 responses, work rapidly and have been

shown reduce pain and fatigue and improve

physical function and mental health.

Real-world evidence for JAKinibs provide

additional information across different patient

types and variables help inform clinical

practice. Global registries play a vital role in

collecting this data, which is more reflective of

the diverse, heterogeneous patient population

seen in practice. For example, the Australian

observational OPAL-QUIM registry study

found similar remission rates with tofacitinib

compared with bDMARDs. The Swiss SCQM

registry showed drug discontinuation rates for

patients on tofacitinib was similar to OMA and

significantly lower than for patients on TNFis.

Probability of staying on treatment

1.0

0.8

0.6

0.4

Number

at risk

Overall drug discontinuation

3978

3398

2735 1940 1445 1101 817 614

0 0.5 1.0 1.5

Drug retention time (years)

Tofacitinib

OMA

TNFi

2.0 2.5 3.0

SCQM Registry: Drug maintenance with

tofacitinib, TNFi and OMA in patients with RA

OMA, other modes of action; TNFi, tumour necrosis factor inhibitor.

Adapted from Finckh A, et al. RMD Open 2020;6:e001174.

What have we learned about

JAK inhibitors in RA?

Professor Hendrik Schulze-Koops

The first JAKinib (tofacitinib) was approved

for RA in 2012. Since then, nearly 10 years

of safety data has been collected on their

use in RA. This pool of data has supported

clinicians in making informed benefit-risk

assessments for their patients. Current safety

data for JAKinibs and the risks that should

be considered when using these treatments

were reviewed.

AEs of special interest reported across

clinical trials with JAKinibs are similar to

those associated with current bDMARDs.

For example, incidence rates of serious

infection, MACE, tuberculosis and opportunistic

infection for tofacitinib and baricitinib are

typically in the same range seen with bDMARDs.

The exception is HZ, which occurs at a

higher rate with all JAKinibs, except filgotinib,

compared with bDMARDs, however, early

vaccination can help reduce the risk of

infection. This provides reassurance that

AEs seen with JAKinibs are similar to those

seen with biological treatments, and informs

patient discussions when considering the

initiation of JAKinib treatment.

In 2021, Pfizer published the results from

the post-marketing ORAL surveillance study.

Where do JAK inhibitors fit into

the RA treatment paradigm?

Dr Ai Lyn Tan

With a variety of treatments available,

deciding which treatment is right for which

patient can be complex and challenging

for rheumatologists. Dr Tan summarised

the latest recommendations by EULAR

for the treatment of RA and explained why

the EULAR-recommended ‘treat-to-target’

strategy provides better long-term

outcomes for patients.

The study was designed to assess the risk of

CV events and malignancies with tofacitinib

(5 mg and 10 mg) versus a TNFi in subjects with

RA who were ≥50 years and had ≥1 additional

CV risk factor. Tofacitinib did not meet the

prespecified noninferiority criteria for both

MACE and malignancies, excluding NMSC.

Overall, 135 patients developed MACE and

164 developed malignancies. The incidence

of adjudicated malignancies was significantly

higher in the tofacitinib group, compared with

the TNFi group (1.13 vs. 0.77 per 100 personyears;

HR, 1.48; 95% CI, 1.04–2.09). The rate

of MACE was also higher in the combined

tofacitinib group (0.98 vs. 0.73 per 100 personyears;

HR, 1.33; 95% CI, 0.91–1.94). The FDA

and the EMA have stated they will evaluate

the final results from the safety trial and will

communicate their recommendations on

completion of their review.

When considering a JAKinib for RA, physicians

should consider several important factors

such as the speed of response, PROs,

patient preference for route of administration,

convenience, and patient adherence, alongside

the characteristics of the patient and the safety

profile of the treatment. Patients should be

educated in patient-appropriate language

about the risks and benefits of treatments

to enable informed, shared decision-making,

which can lead to improved adherence and

optimal treatment outcomes.

The 2019 EULAR recommendations state

that treatment should be aimed at reaching

a target of sustained remission or LDA.

Monitoring should be frequent in active disease

and if there is no improvement by ≤3 months

after the start of treatment or the target has

not been reached by 6 months, therapy

should be adjusted. EULAR recommend that

if the treatment target is not achieved with

the first csDMARD, when poor prognostic

factors are present, a bDMARD or tsDMARD

should be added. The success of this treatto-target

approach is driven by a dedication

to a repeatable, action-orientated process


Mean Difference

in M-HAQ

Mean Difference

in EQ-5D

-0.0823***

0.0478***

Results from the BRASS study

by the patient and physician, initiated by the

identification of a treatment goal in partnership.

Once the target is set, the aim should be to

reach that target through a treatment that

is appropriate for that patient. Regular

assessment that includes disease activity,

PROs, function and QoL, should be carried

out to monitor whether patients are reaching

their target and whether treatment needs to

be adjusted accordingly.

Results from the BRASS study showed

achieving remission using the treat-to-target

strategy improved physical function and

QoL in patients with established RA.

Predictive treatment response

Within the treat-to-target cycle, it is important

to achieve the target as soon as possible

because of the implications on long-term

prognosis. Treatment response at 3 months

has been shown to be predictive of the

likelihood of achieving the target at 6 months.

A post-hoc analysis of the tofacitinib ORAL

standard trial showed patients who failed

to demonstrate a response in CDAI≥6 at

month 1 or 3 were not likely to achieve LDA

at 6 or 12 months. Being able to predict

treatment response early on facilitates quick

clinical decision making and switching to an

alternative effective therapy.

DAS28(CRP) SDAI CDAI

-0.0221

DAS28(CRP) SDAI CDAI

Achieving target vs not achieving

-0.0471 †

-0.0834***

0.0658***

0.0518***

0.02247 §

***P<0.0001, †P=0.0100, ‡P=0.0003, §P=0.0026.

EQ-5D, EuroQol 5 dimensions questionnaire; M-HAQ, modified Health Assessment Questionnaire

Adapted from Alemao E, et al. Arthritis Care Res 2016;68:308–317.

-0.1035***

Achieving target vs achieving LDA

-0.0734 ‡

0.0735***

0.06117***

Where do JAKinibs fit into the RA treatment

paradigm?

When treating with JAKinibs, clinicians should

consider patient history and physical examination,

disease characteristics and preferences for

treatment, such as mode of administration and

frequency. Initiation of a JAKinib should be

fully discussed with the patient, and potential

benefits and risks outlined.

Challenges of treat-to-target

A treat-to-target approach in RA requires frequent

monitoring, particularly in the early phase. Clinical

examinations, blood tests and imaging require

face-to-face visits which can be a challenge in

the current climate. Reduced face-to-face visits

is likely to lead to fewer patients achieving their

treatment goals. Remote consultations may be

suitable for patients with RA on minimal or no

DMARDs and in sustained remission. EULAR

recommends if the disease and its treatment

are stable, and signs and symptoms of drug

toxicity are absent, regular blood monitoring

and face-to-face consultations can be

postponed temporarily or provided remotely.

If the disease is active, drug therapy has recently

been started or needs adjustment, or if signs

and symptoms of drug toxicity emerge, the

patient and rheumatologist should liaise and

evaluate the risks of a face-to-face visit.

A practical guide to use of JAK inhibitors in the management

of RA and SpA

This symposium, sponsored by Abbvie, was chaired by Professor Maya Buch.

The symposium included presentations by Professor Buch, as well as Professor

Andrea Rubbert-Roth, Professor Andrew Östör and Dr Janet Pope, and provided

guidance on management of RA and SpA in patients with JAK inhibitors, including

safety considerations for the clinic.

Understanding and managing

infections

Professor Andrea Rubbert-Roth

Several factors in patients with RA and SpA

contribute to an increased risk of infection.

Controlling factors such as high disease

activity may reduce the risk of infection.

Professor Andrea Rubber-Roth reviewed

guidance on infection risk and the challenges

posed by COVID-19.

The risk of infection in patients with RA increases

with increasing dose of steroids in combination

with the use of DMARDs or TNFi. In clinical

trials, the incidence of infection was similar

for tofacitinib monotherapy and in combination

Overarching principles

• Vaccination status and indications for further vaccination should be

assessed yearly

• The individualized vaccination programme should be implemented by

the primary care physician, the rheumatology team and the patient

• Vaccination should preferably be administered during quiescent disease

• Vaccines should preferably be administered prior to planned

immunosuppression, in particular B cell depleting therapy

• Non-live vaccines can be administered while treated with systemic

glucocorticoids and DMARDs

• Live-attenuated vaccines may be considered with caution

EULAR recommendations for vaccination in adult patients with AIIRD

Adapted from Furer V, et al. Ann Rheum Dis 2020;79:39–52.

with MTX, with a slight increase for HZ with

tofacitinib + MTX. Data from ORAL Surveillance

suggest an increased risk of serious and fatal

infections compared with TNFi. The incidence

of serious and opportunistic infections

was similar for baricitinib and adalimumab,

and overall incidence remained stable up to

8.4 years. For upadacitinib, the incidence

of serious infections was comparable with

adalimumab and MTX monotherapy in RA,

slightly higher in PsA, and had no increase in

AS. The risk of serious infections is higher with

15 mg upadacitinib in patients aged ≥75 years

and smokers, than in younger non-smokers.

A consensus statement relating to infection

risk in patients with immunomodulators, and

guidance on vaccinations for adults with AIIRD

has been published by Nash et al. 2

• Influenza vaccination should

be strongly considered for the

majority of patients with AIIRD

• Pneumococcal vaccination

should be strongly considered

for the majority of patients

with AIIRD

• Hepatitis A and hepatitis

B vaccination should be

administrated to patients

with AIIRD at risk

• Herpes zoster vaccination

may be considered in

high-risk patients with AIIRD


Patients with RA, SLE and PsO have a slightly

increased risk of death from COVID-19. Treatment

with cytokine inhibitors could reduce susceptibility,

but chronic use of moderate- or high-dose

steroids is associated with hospitalisation for

severe COVID-19, particularly in older patients

and those with comorbidities or taking steroid

doses >10 mg/day. bDMARDs and JAKinibs

seem to be associated with a lower risk of

hospitalisation; therefore, patients should continue

these drugs to minimise the risk of disease flare.

ACR, EULAR and GRAPPA all recommend

COVID-19 vaccination for patients with RMDs

Current landscape for herpes

zoster in patients with

rheumatic disease

Dr Andrew Östör

Multiple factors increase the risk of HZ,

including steroid use, and immunotherapies

used to treat rheumatic or immune-mediated

diseases. Reactivation of HZ may be a class

effect of JAKinibs. The benefit–risk profile

of the JAKinib must be considered for

each patient.

and PsA. ACR and EULAR recommend

vaccination for patients receiving

immunomodulators; however, ACR notes

response may be blunted and GRAPPA

reports insufficient evidence to predict efficacy.

Additionally, ACR note a theoretical risk of

disease flare following vaccination, EULAR

recommends vaccination during a quiescent

phase, and GRAPPA reports no evidence that

vaccination affects symptoms. For patients

taking JAKinibs, ACR recommends cessation

of JAKinib for 1 week after the vaccine, without

modifying vaccination timing, while EULAR

and GRAPPA offer no specific guidance.

HZ reactivation has been reported in clinical

trials for all approved JAKinibs. Background

steroids in RA have a dose-dependent risk for

HZ in patients treated with JAKinibs. In pooled

studies with upadacitinib, a history of HZ,

Asian race and older age were associated

with a higher risk of HZ.

A NNT/NNH analysis of SELECT-COMPARE

estimated one additional case of HZ for every

216 patients treated with upadacitinib compared

with adalimumab + MTX, but 20 additional

patients treated could achieve CDAI remission.

Most HZ events with upadacitinib in RA are

monodermatomal and uncomplicated, and

treatment can be temporarily interrupted and

continued, in line with EULAR recommendations.

Patients should be up to date with all

vaccinations before starting JAKinibs, and

Major cardiovascular

events (MACE) and venous

thromboembolism (VTE)

in patients with RA and

SpA: what should we be

considering?

Dr Janet Pope

Patients with inflammatory arthritis are at

increased risk of MACE and VTE. Dr Janet

Pope reviewed the evidence of associated

risk of JAKinibs and MACE and VTE.

MTX is associated with a decreased risk of

cardiovascular events in RA that is not seen in

patients treated with corticosteroids. TNFi also

show a reduction in cardiovascular events.

all four licences recommend HZ immunisation.

Shingrix may be used to replace live-attenuated

vaccination. It is well tolerated, with patients

reporting only mild-to-moderate side-effects,

no suspected cases of HZ or discontinuation

of JAKinibs, and low rates of disease flares.

MACE

The risk of MACE with JAKinibs was not

increased in tofacitinib RCTs compared with

MTX, adalimumab or placebo in patients

with RA. However, in ORAL Surveillance, a

study undertaken at the request of the FDA

to investigate MACE and malignancies with

tofacitinib in patients at high cardiovascular

risk, the rate of MACE events was numerically

higher with 5 and 10 mg BID tofacitinib than

with adalimumab and etanercept. No increased

risk was observed for upadacitinib compared

with adalimumab or MTX in RA RCTs, or placebo

in AS. In SELECT COMPARE, upadacitinib

had a reduced risk compared with adalimumab

over 3 years.

EULAR’s recommendations emphasise the

importance of recognising the increased

TOFACITINIB

EAIR of HZ per 100 PY during Phase II and III trials incl. LTE

FILGOTINIB

EAIR of HZ per 100 PY during Phase II and III trials

IRs inhibitor for adjudicated MACE

IR/100 PY (95% CI)

HRs vs TNF inhibitor for adjudicated MACE

HR (95% CI)

TOFA 5 mg BID

TOFA 10 mg BID

2.3 (2.3–3.3)

0 1 2 3 4 5

3.7 (3.4–4.1)

BARICITINIB

EAIR of HZ per 100 PY (Phase Ib, Phase II, III, & LTE trials)

FILGO 200 mg QD

FILGO 100 mg QD

MTX 1.1 (0.4–3.0) Rate 2.4x

ADA

0.7 (0.2–2.8) vs ADA

1.7 (1.3–2.3)

1.1 (0.7–1.8)

0 1 2 3 4 5

UPADACITINIB

EAER of HZ per 100 PY during Phase III RA trials

Tofacitinib

5 mg BID

Tofacitinib

10 mg BID

Tofacitinib

doses combined

TNF inhibitor

0.91 (0.67, 1.21)

1.05 (0.78,1.38)

0.98 (0.79, 1.19)

0.73 (0.52, 1.01)

0 1 2

Tofacitinib

5 mg BID

Tofacitinib

10 mg BID

Tofacitinib

doses combined

0 1 2

1.24 (0.81, 1.91)

1.43 (0.94, 2.18)

1.33 (0.91, 1.94)

BARI 4 mg QD 3.8

PBO

1.0

MTX monotherapy pooled 0.8 (0.3–1.8) Rate 3.0x

ADA 40 mg EOW + MTX

1.1 (0.6–2.0)

vs ADA

UPA 15 mg pooled

3.3 (2.9–3.8)

TNF inhibitor

(n=1451; 5045.27 PY)

Tofacitinib 5 mg

(n=1455; 5166.32 PY)

Tofacitinib 10 mg

(n=1456; 4871.96 PY)

Tofacitinib combined doses

(n=2911; 10,038.28 PY)

0 1 2 3 4 5

0 1 2 3 4 5

All JAK inhibitors show an increased risk for HZ in RA compared with methotrexate, adalimumab, and placebo

ADA, adalimumab; BID, twice daily; EAIR, exposure-adjusted incidence rate; HZ, herpes zoster; LTE, long-term extension; PBO, placebo; PY, patient-year; QD, once daily

Adapted from Wollenhaupt J, et al. Arthritis Res Ther 2019;21:89 (tofacitinib), Smolen JS, et al. J Rheumatol 2019;46:7–18 (baricitinib), Genovese MC, et al.

EULAR 2020 (THU0202) (filgotinib), and Cohen S, et al. EULAR 2021 (POS0220) (upadacitinib).

Non-inferiority versus TNF inhibitor for incidence of MACE was not achieved with tofacitinib in

ORAL Surveillance

BID, twice daily; IR, incidence ratio; MACE, major adverse cardiovascular events; PY, patient-year

Adapted from Pfizer press release. Available at www.pfizer.com/news/press-release/press-release-detail/pfizer-shares-co-primary-endpoint-results-post-marketing


cardiovascular events in patients with

inflammatory disease, and monitoring risk

factors such as lipids and blood pressure.

VTE

There is no increased risk of VTE with JAKinibs

than with MTX, adalimumab or placebo, however,

in clinical trials, 4 mg baricitinib was associated

with an imbalance in VTEs compared with 2 mg

and comparators. The unlicensed 10 mg dose

of tofacitinib in ORAL Surveillance was stopped

due to an increased risk in PEs. A regulatory

safety warning for VTE was subsequently issued

for all JAKinibs. Across the global RA clinical

programme for baricitinib, rates of DVT and PE

remained stable over time, and use of baricitinib

did not increase incidence rates of AEs up to

8.4 years. No significant difference in VTE was

Malignancies in RA and SpA:

from risk factors to disease

management

Professor Maya Buch

Several complex inter-relationships exist

between inflammatory rheumatic diseases,

malignancies, and their treatments. While

some treatments increase the risk of

developing malignancy, others may control

it. Similarly, treatment of malignancy may

induce rheumatic disease or may support

its treatment.

Chronic inflammation in rheumatic disorders

may stimulate development of secondary

malignancies and the background risk of

malignancies, including lymphoproliferative

disorders and solid tumours such as lung cancer

is increased in patients with RA and AS. Some

csDMARDs, particularly cyclophosphamide

and azathioprine, are associated with an

increased risk that is not seen with MTX.

All JAKinibs include safety warnings for potential

increased risk of malignancy. Data suggest a

similar risk of malignancy for tofacitinib and

seen between tofacitinib and TNFi in daily

practice. In RCTs with 15 mg/day upadacitinib

and the unlicensed dose of 30 mg/day, no

increased risk of VTE was observed compared

with adalimumab or MTX in RA, adalimumab in

PsA, or placebo in AS. In SELECT COMPARE,

upadacitinib had a reduced risk of VTE compared

with adalimumab over 3 years. No mechanism

associating JAK inhibition and thrombosis has

been identified. Whether the observed increases

are a class effect, specific to an individual

JAKinib, or dose related is unknown.

Monitoring for VTEs in patients on JAKinibs

should include risk factors such as previous

VTE and disease activity. Recurrent VTE is

a contraindication to JAKinib use due to the

uncertainty around the mechanism underlying

the increased risk.

baricitinib in RA, but non-inferiority versus

TNFi was not achieved with tofacitinib in ORAL

Surveillance. In an integrated safety analysis

of RCT data for upadacitinib, no increased risk

of malignancy was observed compared with

adalimumab or MTX in RA or adalimumab in

PsA. In SELECT COMPARE, upadacitinib had a

reduced risk of VTE compared with adalimumab

over 3 years. Although data are generally

reassuring, ongoing studies are needed, and

further analysis of ORAL Surveillance results

is required to clarify whether there is an

increased risk with tofacitinib or a protective

effect of the comparators.

The risk of malignancy and patient history

should be considered when initiating and

continuing treatment with bDMARDs and

tsDMARDs in patients with RA and SpA.

Patients with a history of prior malignancy or

increased risk of skin cancer should undergo

periodic skin examination. Caution should

be exercised when starting TNFi in patients

with prior history, and continuation should be

re-evaluated in those who develop malignancy

during treatment. For patients with a current

malignancy, immunomodulators may increase

the risk of malignancies including lymphomas.

Striving for remission with JAK inhibition in the management

of rheumatoid arthritis

This symposium, sponsored by Abbvie, was co-chaired by Professors Phil

Conaghan and Gerd-Rüdiger Burmester, with presentations by Professor Hendrik

Schulze-Koops and Professor Grace C Wright. The reasons why it is important

to strive for remission in RA were discussed, as well as the different definitions,

how well it is achieved, and the role and safety profile of JAKinibs.

What defines remission

and how good we are at

achieving it?

Professor Hendrik Schulze-Koops

Remission, the primary aim of treatment for

RA, can be defined in different ways, and

rates of remission depend on the definition

used. Professor Schulze-Koops examined

the definitions of remission and the number

of patients who achieve it.

DAS28-CRP remission, the most commonly

used definition, considers SJC, TJC, extent of

systemic inflammation and PROs. ACR/EULAR

2011 Boolean remission is based on similar

characteristics and is more robust for clinical

studies and in the absence of PROs; however,

it is not widely used and is rarely achieved.

CDAI and SDAI, simplified variations of DAS28

remission, assessed through SJC, TJC and

PROs, are simple to administer in the clinic.

Remission definitions do have limitations.

None consider the systemic nature of the

disease, and rates vary depending on the

Remission rates vary depending on the criteria used

*Boolean requires CRP ≤1 mg/dl (10 mg/l) and PtGA of ≤1 on 0–10 scale (≤10 mm on 0–100 scale)

PhGA, physician global assessment; PtGA, patient global assessment; SJC, swollen joint count; TJC, tender joint count

criteria used: Boolean remission is achieved by

61–66% of patients who achieve SDAI or CDAI

remission but only 23–26% of patients who

achieve DAS28-CRP remission. Additionally,

remission does not necessarily translate to

disease control. In TEMPO, patients with

active RA who achieved DAS28 remission

with csDMARDs and/or bDMARDs frequently

still had tender and swollen joints.

At the time of early clinical trials with biologics,

remission in RA was not yet defined as a concept,

however approximately 25% of patients achieved

ACR70 responses with infliximab or adalimumab,

which approximates present-day remission.

A decade later, 25–30% of patients achieved

DAS28-ESR or -CRP remission with golimumab.

Recent data with sarilumab found that 26–40%

of patients achieved DAS28-CRP remission and

10–15% achieved CDAI remission. Real-world

data reflect similar findings, with one in four

patients achieving remission, and sustained

remission achieved less frequently. Rates of

remission remain disappointing despite advances

in therapy over the past 20 years; effective

treatments that lead to sustained clinical

remission or LDA remain an unmet need.

Endpoint Patient 1 Patient 2 Patient 3 Patient 4

SJC 2 0 0 0

TJC 2 1 0 1

CRP (mg/l)* 0.2 15.6 1.08 5.8

PtGA (0–100 mm)* 24 11 17 2

PhGA (0–100 mm)* 25 0 13 25

Remission

DAS28-CRP (<2.6) 2.5 2.7 1.5 2.2

CDAI (≤2.8) 9.9 2.7 3.0 3.7

SDAI (≤3.3) 9.2 3.7 3.1 4.3

Boolean (yes/no) No No No Yes


What’s the value of achieving

remission?

Dr Grace C Wright

Multiple factors drive the target of remission.

Remission reduces the comorbidities of

RA, which improves quality of life, as well

as reducing healthcare resource utilisation.

Patients, physicians, and payors therefore

increasingly expect remission to be the goal

in clinical trials and practice.

RA is associated with comorbidities that

increase the burden of disease on the patient,

their family, physicians, the healthcare system,

and wider society. There is also an economic

impact through a variety of direct, indirect, and

Patients in remission (DAS28 <2.6 or RAPID3 ≤3.0) have fewer hospital visits

Adapted from Bergman M, et al. EULAR 2020 (Abstract THU0546).

Burden of RA on the healthcare system

*Only DAS28 and RAPID3 were used to define remission. CDAI was not included due to lack of data.

RAPID3, Routine Assessment of Patient Index Data 3.

Adapted from Bergman M, et al. EULAR 2020 (Abstract THU0546).

intangible costs, including reduced productivity

at work and increased presenteeism.

Achieving remission can reduce comorbidities,

and improve quality of life outcomes, which also

reduces the burden for patients’ families.

Reductions in comorbidities associated with

achievement of, and sustained, remission

translates into fewer physician visits, inpatient,

outpatient and emergency department hospital

visits, as well as mortality.

Patients who achieve remission have improved

physical function, which reduces the impact on

work productivity and presenteeism. Patients who

achieve remission incur significantly lower annual

all-cause direct costs ($30,427 vs. $38,645), with

a saving in healthcare costs of $3,133 per year

between those with and without remission.

Resource Remission cohort (n=125) Non-remission cohort (n=210) Visit ratio (95% CI)

Overall

Patients (%) Mean (95% CI) Patients (%) Mean (95% CI)

Inpatient visits 13.6 0.23 (0.13–0.40) 26.2 0.63 (0.45–0.89) 0.36 (0.19–0.70)

Emergency department visits 22.4 0.36 (0.25–0.53) 39.5 0.77 (0.61–0.98) 0.47 (0.30–0.74)

Outpatient visits 100 20.73 (18.19–23.60) 991 28.45 (25.80–31.40) 0.73 (0.62–0.86)

RA related

Inpatient visits 10.4 0.15 (0.09–0.26) 16.7 0.22 (0.15–0.31) 0.67 (0.35–1.30)

Emergency department visits 4.0 0.04 (0.01–0.11) 8.6 0.13 (0.08–0.21) 0.31 (0.10–0.95)

Outpatient visits 90.4 5.37 (4.45–6.46) 85.2 7.41 (6.46–8.51) 0.72 (0.58–0.91)

Annual costs (US dollars)

45,000

40,000

35,000

30,000

25,000

20,000

15,000

10,000

5,000

0

30,427

Remission

Total costs

12,581

17,846

Annual all-cause direct costs

38,645

Non-remission

12,254

26,391*

Total costs excluding prescriptions

17,846

Remission

2,325

10,498

866

4,157

*

26,391

Non-remission

1,924

17,235*

1,833

5,399

Medical

Prescription

Inpatient

ED

Outpatient

Other

Can JAK inhibitors elevate

more patients to achieve

robust remission?

Professor Phil Conaghan

ORAL

Strategy

R-BEAM

FINCH-1

Patients (%)

Patients (%)

Patients (%)

60

40

20

0

60

40

20

0

60

40

20

SELECT-COMPARE

60

Patients (%)

0

40

20

0

DAS28-CRP <2.6

CDAI ≤2.8

31 28

21

24 30 35 10 14 13 14 19 17

6 months 12 months 6 months 12 months

Professor Phil Conaghan reviewed

evidence from several clinical trial

programmes to evaluate the remission

rate of different JAKinibs.

SDAI ≤3.3

10 13 13 14 16 16 7 8 9

6 months 12 months 6 months

TOFA 5 mg BID mono (n=384) TOFA 5 mg BID + MTX (n=376) ADA + MTX (n=386)

Week 52

34 32

40 39

4

Week 12

8

Week 24

2 8 7

Week 12

24 19

DAS28-CRP <2.6 1

*++

34

*

2424

9

Week 12

48

*

3536

16

Week 24

54

16

22 18

12

4

Week 24 Week 52

2 8 7

Week 12

PBO + MTX (n=488) BARI 4 mg QD + MTX (n=487) ADA + MTX (n=330)

43 46

Week 52

Week 12

Boolean remission

CDAI ≤2.8 1 SDAI ≤3.3 1 Boolean 2

*

*

21 *++ * + 19 17

12 11 6 8 3

Week 24

30

24 23

Week 52

13 9 7 3

Week 12

10 13 12

12 months

16 14

23 18

12 10

16 13

3

Week 24 Week 52

1 7 5

Week 12

3

Week 24 Week 52

DAS28-CRP <2.6 CDAI ≤2.8 SDAI ≤3.3 Boolean 2

+++

*

+

+

* + 30

23 * 25 24

*++

*

1817

7

Week 24

Week 52

+

* +

23

* + 19 * 1917

1413

10 *

7 5 2

5

Week 12

Week 24

Week 52

FIL 200 mg QD + MTX (n=475) FIL 100 mg QD + MTX (n=480) ADA 40 mg EOW (n=325) PBO + MTX (n=475)

###

**

29 ###

**

### 18

**

6

Week 12

DAS28-CRP <2.6

###

CDAI ≤2.8 SDAI ≤3.3 3 Boolean remission

**

##

41

### 38

##

**

###

###

##

##

27 28

**

**

###

#

##

### 25 ##

23

24 ### 25 ##

#

** 21

#

###

** ## **

###

17 ** **

##

13 14

17

18

###

#

**

###

## **

9

12 14

**

#

**

**

## ### **

##

15

** 8

3

6

**

** 7

10 10

3 5

** ** **

2 4 4

Week 26 Week 48 Week 12 Week 26 Week 48 Week 12 Week 26 Week 48 Week 12 Week 26 Week 48

PBO + MTX (n=651) UPA 15 mg QD + MTX (n=651) ADA 40 mg (Q2W) + MTX (n=327)

Remission rates for ORAL Strategy, R-BEAM, FINCH-1, and SELECT-COMPARE

*p<0.001 versus placebo, not adjusted for multiplicity and should be considered exploratory except for FIL200 and FIL100 versus placebo for DAS28(CRP) <2.6

at week 12. **p≤0.001 for comparison of UPA versus PBO. +p<0.05, ++p<0.01, +++p<0.001 versus ADA, not adjusted for multiplicity and should be considered

exploratory. # p≤0.05, ## p≤0.01, ### p≤0.001 for comparison of UPA versus ADA. multiplicity-controlled comparisons of UPA versus PBO.

ADA, adalimumab; BID, twice daily; EOW, every other week; Q2W, every two weeks; QD, once daily

Adapted from Fleischmann R, et al. Lancet 2017;390:457–468 (ORAL Strategy); Taylor PC, et al. N Engl J Med 2017;376(Suppl):652–662 (R-BEAM); ClinicalTrials.gov.

NCT01710358; Combe B, et al. Ann Rheum Dis 2021:annrheumdis-2020-219214; Jyseleca EU Summary of Product Characteristics 2020 (FINCH-1); Fleischmann R et al. Arthritis

Rheum 2019;71:1765–800; Fleischmann R, et al. EULAR 2020 abstract (THU0201); Fleischmann RM, et al. Annals of the rheumatic diseases. 2019 Nov 1;78(11):1454–62.


Trials with JAKinibs have been undertaken in

treatment-naïve patients with RA and patients

with inadequate response to csDMARDs,

bDMARDs and MTX. In ORAL Strategy, which

compared tofacitinib alone and in combination

with MTX, and adalimumab + MTX, similar

proportions of patients achieved remission

with both combination therapies, but fewer

with tofacitinib monotherapy.

RA-BEAM, which compared baricitinib + MTX,

adalimumab + MTX and MTX alone, found no

significant difference in remission rates by any

definition between the combination therapies.

FINCH-1 compared two doses of filgotinib

Understanding the risks:

the evolving safety profile

of JAK inhibitors in RA

Professor Gerd-Rüdiger Burmester

JAKinibs have a well-established safety

profile in RA, including in patients who are

MTX-naïve or have inadequate response to

csDMARDs and bDMARDs. Safety profiles

continue to emerge through post-marketing

studies, but some adverse events including

MACE, malignancies, VTE and infections

have raised concerns.

In 2019, Pfizer announced that all patients on

10 mg tofacitinib were to be switched to the 5 mg

dose, as the ORAL Surveillance study found a

higher risk of MACE and some malignancies

with 10 mg. An integrated safety summary over

9.5 years concluded that the incidence ratios

for MACE and malignancies (excluding NMSC)

were similar for both tofacitinib doses and

remained consistent over time. A post-approval

comparative safety study over 5 years found

that incidence rates for MACE were higher with

bDMARDs versus tofacitinib; malignancies

(excluding NMSC) were comparable. Rates of

(100 or 200 mg) + MTX, adalimumab + MTX,

and MTX alone followed by filgotinib. Higher

remission rates were seen with 200 mg

filgotinib + MTX but these were inconsistent

depending on the definition and timepoint

used. SELECT-COMPARE, which compared

upadacitinib + MTX, adalimumab + MTX

and MTX alone, demonstrated significantly

higher percentages of patients achieving

remission with upadacitinib + MTX versus both

comparators, irrespective of remission definition.

The significantly greater remission rates with

upadacitinib + MTX over adalimumab + MTX

were maintained for up to 3 years for DAS28-CRP

remission and up to 72 weeks for CDAI remission.

MACE and malignancies (excluding NSMC) were

comparable for upadacitinib and adalimumab

over 3 years in SELECT-COMPARE and in an

integrated safety study.

All approved JAKinibs have safety warnings

for VTE after an FDA review. Across the global

clinical programme for baricitinib in RA, rates

of DVT and PE remained stable over time, with

no increase in incidence rates up to 8.4 years.

Interim analysis of the ORAL Surveillance study

found an increased risk of VTE with tofacitinib

compared with TNFi, and the licence includes

cautions in patients with known risk factors and

ulcerative colitis at high risk of blood clots. In

SELECT-COMPARE and a long-term integrated

safety analysis, the risk of VTE was not elevated

with upadacitinib compared with adalimumab.

All approved JAKinibs also have safety

warnings for infections and viral reactivation.

In the tofacitinib global clinical programme, the

incidence of infections of interest was similar

for tofacitinib mono- and combination therapy,

and the incidence of serious infections remained

stable over time. In the SELECT integrated

safety analysis for upadacitinib, rates of serious

infections were higher with 15 mg upadacitinib

than MTX, but similar to rates with adalimumab.

In Darwin’s footsteps: Exploring the role of JAK Inhibitors

within the diverging RA treatment landscape

Professor Maxime Dougados chaired the Galapagos symposium with

presentations from Professor Rieke Alten, Professor Kevin Winthrop, and

Professor Ernest Choy. They discussed the chronic and evolving state of

disease in RA, efficacy and safety profiles of available treatment options

and how mechanisms of action translate to different outcomes.

Through the looking glass:

Living with rheumatoid arthritis

Professor Maxime Dougados

RA impacts many aspects of patient’s

lives, and has variable, often unpredictable

symptoms.

Great expectations:

Translating clinical features

of different treatments to

meet patient needs

Professor Rieke Alten and

Professor Kevin Winthrop

Using a patient case study example,

Professor Alten and Professor Winthrop

discussed the PRO data and long-term safety

profiles for JAKinibs that have emerged from

the Phase 1–3 clinical trials and LTE studies.

Treat-to-target recommendations used in clinical

practice advocate sustained remission or LDA

as the goal of RA. The treatment goal should be

a shared decision with the patient; this can be

a challenge in practice but open conversations

and education on the available treatment options

are key. Data from the SENSE study involving

patients with poorly controlled RA despite

DMARD treatment, showed patients preferred

oral therapies over intravenous and subcutaneous

options. According to patients with RA who took

part in a discrete choice experiment conducted

in Sweden, treatment efficacy followed by the

probability of severe side effects are the most

important attributes.

Patient assessments of disease activity are

dominated by pain and fatigue, even in clinical

remission to a degree. Patients expect treatments

to address pain and fatigue. Therefore, it is

important for clinicians to discuss treatment

goals and incorporate shared decision making

in their treatment plans.

What impact do JAKinibs have on

patient-important symptoms of fatigue

and pain?

The RA-BEAM study showed treatment with

baricitinib in MTX-IR not only significantly

increased the proportion of patients achieving

remission but rapidly reduced pain versus

adalimumab. This significant reduction in pain

is comparable across all the Phase III JAKinib

clinical trials.

JAKinibs report similar rates of AEs across

Phase I–III clinical trials and LTE studies. Rates

of MACE, VTE and malignancies (excluding

NMSC) across the pooled data are similar for all

approved JAKinibs. Due to the increased risk of

HZ infection associated with JAKinibs, clinicians

should consider vaccinating patients prior to

starting treatment. The effect of vaccinating

individuals who have already started treatment

with a JAKinib is not currently clear. Studies

on the effect of tofacitinib on influenza and

pneumococcal vaccines show that tofacitinib

diminishes the response to these vaccines,

which suggests that JAKinibs down-regulate

response in individuals with RA to some extent,

although it may not be clinically meaningful.

Data is awaited on the effect of JAKinib treatment

on the response to COVID-19 vaccination.



0 10 20 30 40 50

0

-5

-10

-30

-35

-40

††

*

‡

*

Pain VAS

Week

† ‡

* ‡

* † * ‡ ‡ ‡

* *

‡

* † ‡

BARI 4 mg QD + MTX (n=487)

ADA 40 mg q2w + MTX (n=330)

PBO + MTX (n=488)

Change from baseline in patient pain VAS

from RA-BEAM study

*P≤0.001 vs. placebo; †P≤0.001, ‡P≤0.01, ††P≤0.05 vs. ADA

(logistic regression without control for multiple comparisons).

Adapted from Taylor PC, et al. N Engl J Med 2017;376:652–662.


-15 *

-20 *

*

*

*

-25

0

-10

-20

-30

-40

-50

* * * * *

2 4 8 12 14 18 22 26

*

*

†

*

‡

Pain VAS

Week

UPA 15 mg QD + MTX (n=651)


PBO + MTX (n=651)


from SELECT-COMPARE study

*P≤0.001 vs. placebo; †P≤0.001, ‡P≤0.01, ††P≤0.05 vs. ADA;

Comparisons between UPA and ADA were controlled for multiplicity.

Adapted from Fleischmann RM, et al. Ann Rheum Dis 2019;78:1454–1462.

*

†

††

* *

‡ * *

‡ ‡

†


from ORAL standard study

*P≤0.0001, †P≤0.001, vs. placebo.

Adapted from Strand V, et al. Rheumatology (Oxford) 2016;55:1031–1041.

0 2 4 8 12 14 16 20 24 26 30 36 44 52

0


from FINCH-1 study

*P<0.001 vs. placebo+MTX; †P<0.01, ‡P<0.05 vs. ADA+MTX;

Comparisons between UPA and ADA were controlled for multiplicity.

Adapted from Kivitz A, et al. EULAR 2020. Poster FRI0128.

ADA, adalimumab; BID, twice a day; FACIT, Functional Assessment of Chronic Illness Therapy; IR, inadequate response; LSM, least squares mean; MCID, minimum

clinically important difference; PBO, placebo; PRO, patient-reported outcome; QD, once daily; q2w, every two weeks; VAS, visual analogue scale.



0 2 4 6 8 10 12

0

-5

-10

-15

-20

-25

-30

-35

-40

-5

-10

-15

-20

-25

-30

-35

-40

-45

* ‡

* *

*† * ‡

*

*†

*

*†

* *

*‡ Pain VAS

Months

* * **

†

*

TOFA 10 mg BID + MTX (n=197)

TOFA 5 mg BID + MTX (n=198)

ADA 40 mg Q2W + MTX (n=199)

PBO + MTX (n=104)

Pain VAS

Week

FIL 200 mg QD + MTX (n=475)

FIL 100 mg QD + MTX (n=480)


PBO + MTX (n=475)

Brave new world:

Exploring the impact of

treatment evolutions

Professor Ernest Choy

As the understanding of RA has evolved,

treatments have progressed from symptomatic

control to modifying disease activity. In the

last 20 years, treatment development has

accelerated, and has seen the introduction

of bDMARDs followed by tsDMARDs.

Professor Choy summarised the effects

of selective JAK inhibition in RA pathology.

JAKs are involved in signal transduction of type

I and II cytokine receptors. There are four JAK

isoforms: JAK1, JAK2, JAK3 and TYK2, which

act in different pairs depending on which cytokine

families are utilising the JAK isoforms for signal

transduction. Not only are JAKs important for

the immune system, but they are also critical to

homeostasis. There are very few cells in the body

that do not express JAKs, hence, it is important

not to block all JAKs. The aim of JAKinibs is to

reduce activity but not inhibit them completely.

JAK1 is essential for signalling for certain type I

and type II cytokines. It is also important for

IFN-α/β and IFN-γ interferon signalling. All

currently approved JAKinibs inhibit JAK1, which

has a pivotal role in cytokine signalling implicated

in the key pathogenic processes involved in RA.

Inhibition of JAK1 leads to suppression of the

Inhibition (%)

Time above

IC50, hours

100

80

60

40

20

STAT

inhibition, %

0

0 8 16 24

Time

(hours)

Filgotinib

100 mg 200 mg

5 15

37 53

Inhibition of JAK1/JAK2-mediated

IL-6/pSTAT1 signalling

0 8 16 24

Time

(hours)

Baricitinib

2 mg 4 mg

5 13

36 52

0 8 16 24

Time

(hours)

Tofacitinib

5 mg 10 mg

9 17

43 59

Inhibition of JAKs by different JAKinibs

0 8 16 24

Time

(hours)

Upadacitinib

15 mg 30 mg

13 21

55 69

cytokine activity in T cells, bone, and cartilage

cells, as well as decreased immune cell migration

and inflammation. In-vivo studies show JAKinibs

inhibit IL-6/pSTAT1 and IFN-ɒ/pSTAT5 signalling

at clinically meaningful doses, and that onset of

effect is fast and reduces rapidly over 24 hours.

JAKinibs may modulate inflammatory and

nociceptive pain, leading to greater pain

reduction versus inflammation control alone.

In a trial evaluating the relationship between

pain and inflammation among patients with RA,

baricitinib was associated with greater reductions

in non-inflammatory pain versus adalimumab.

Furthermore, the impact of JAKinibs on pain

may influence the fatigue experienced by

patients due to the strong relationship between

pain, fatigue, and mood in patients with RA.

The increased incidence of HZ infection

associated with JAKinib treatment may be due

to the inhibition of IFN-ɣ induced pSTAT signalling,

as IFN-ɣ plays an important role in antiviral

defence. However, it is also suggested that

proliferation of NK cells, which are responsible

for anti-viral response and signal through

JAK1 and JAK3, is hindered by JAK inhibition.

The different inhibition potential of JAKinibs

in the laboratory may not necessarily translate

to the clinic. Additional factors that affect

patient drug plasma levels – such as genetics,

obesity, systemic exposure, metabolism and

concomitant therapies – will influence the

clinical profile and treatment outcomes.

Inhibition (%)

Time above

IC50, hours

100

80

60

40

20

STAT

inhibition, %

0

0 8 16 24

Time

(hours)

Filgotinib

100 mg 200 mg

5 12

37 55

Inhibition of JAK1/TYK2-mediated

IFN-α/pSTAT5 signalling

0 8 16 24

Time

(hours)

Baricitinib

2 mg 4 mg

7 16

41 59

0 8 16 24

Time

(hours)

Tofacitinib

5 mg 10 mg

14 22

55 72

0 8 16 24

Time

(hours)

Upadacitinib

15 mg 30 mg

15 23

61 76

IC, inhibitory concentration; IFN, interferon, IL, interleukin.

Adapted from Traves PG, et al. Ann Rheum Dis 2021;Epub ahead of print.


Exploring global Olumiant experience in treating rheumatoid

arthritis: different continents, different circumstances

This Lilly symposium, chaired by Professor Roberto Caporali included

presentations from Professors Caporali, Peter Taylor, and Rieke Alten.

The implications for clinical practice of the increasing number of treatment

options and evolution of treatment guidelines were discussed, and a review

of the latest data from baricitinib clinical trials, real-world patient registries,

and patient case studies was provided.

Going beyond: long-term

treatment results with

Olumiant in RA

Professor Peter Taylor

Many patients with RA fail to achieve

significant clinical response with csDMARDs.

Baricitinib has shown efficacy and safety

in a large population; and patients with

inadequate response to MTX who achieved

LDA or remission at 1 year maintained this

for a further 2 years. Baricitinib has been

well tolerated up to 8.4 years of exposure.

% Patients

100

90

80

70

60

50

40

30

20

10

0

0 12 24 36 48 60 72 84 96 108 120 132 144

Year 1

NRI a

From Week 52 BARI 4 mg (+MTX) administered to all pts

Week c

Year 2 Year 3

Week

148:

38%

36%

34%

The efficacy and safety of baricitinib was

evaluated in the RA-BEAM RCT. Patients

with RA were randomised to baricitinib

4 mg once daily, placebo + MTX (switched

to rescue baricitinib after 16 weeks in adequate

responders), or adalimumab 40 mg every

two weeks + MTX. At Week 52, patients

could be switched to baricitinib 4 mg to

enter the open-label RA-BEYOND study.

In RA-BEAM, LDA rates were higher with

baricitinib + MTX at Weeks 12 and 52, and LDA

(SDAI ≤11) with baricitinib was sustained up to

3 years in RA-BEYOND. Remission (SDAI ≤3.3)

Proportion of patients with inadequate response to MTX who achieved and sustained LDA (SDAI ≤11 or

CDAI ≤10) with baricitinib through Week 52 in RA-BEAM and up to 3 years in RA-BEYOND

a

Discontinued patients were considered as non-responders. b Analysis based on patients with data available at the analysis timepoint. c Rescue was offered at Week 16;

All patients treated with placebo + MTX were switched to 4 mg baricitinib + MTX at Week 24.

ADA, adalimumab; NRI, non-responder imputation; PBO, placebo

Adapted from Taylor PC, et al. N Engl J Med 2019;376:652–662 (RA-BEAM) and Smolen JS, et al. Rheumatology 2020;Nov 17:keaa576 (RA-BEYOND).

100

90

80

70

60

50

40

30

20

10

0

0 12 24 36 48 60 72 84 96 108 120 132 144

Year 1

Observed b

From Week 52 BARI 4 mg (+MTX) administered to all pts

Week c

Year 2 Year 3

PBO (+MTX) to BARI 4 mg (N=488) ADA (+MTX) to BARI 4 mg (N=330) BARI 4 mg (+MTX) (N=487)

Week

148:

51%

49%

48%

was achieved in one third or more of the

patients taking baricitinib and was also

sustained up to 3 years. Normalised physical

function (HAQ-DI 0.5) is an important outcome

for patients and was achieved and maintained

in one third to one half of baricitinib patients

in RA-BEAM and RA-BEYOND. Only 3.6% of

patients discontinued due to lack of efficacy.

Inhibition of radiographic progression and

structural damage is another important

outcome, particularly in those with poor

prognostic disease. Two multicentre inception

cohorts in the UK, which collected data before

advanced therapies were widely available, show

that radiographic progression can advance

quickly for patients with the poorest prognosis

(≥8 Sharp points per year over 5 years). In

RA-BEAM and RA-BEYOND, most patients on

baricitinib showed no progression over 5 years

in terms of mTSS overall and its components

ES and JSN, with average progression of

2 Sharp points.

Long-term safety is an important consideration,

and trial data are available for more than

3770 patients with RA treated with baricitinib up

to 8.4 years, representing 13148 patient-years

of exposure. The incidence of serious infections

was comparable between placebo and

baricitinib, with no increase with cumulative

Olumiant RWE: across

continents and circumstances


Professor Rieke Alten reviewed the

real-world evidence for baricitinib from

rheumatology registries. Most patients

with RA from these registries who were

treated with baricitinib had refractory and

long-lasting disease.

The JAK-POT study is a collaboration of

registries of patients with RA from more than

17 countries. The 3804 patients prescribed

JAKinibs were similar in terms of age,

gender, disease duration, disease activity

and functional disability between countries.

exposure. A large imbalance in the incidence

of HZ was observed with both doses of

baricitinib in the placebo-controlled phase,

but the incidence was stable in the long

term, and most cases were non-serious and

monodermatomal. Rates of HZ were higher

in Asian countries, which may reflect genetic

differences. No obvious signals for increased

incidence of malignancy, excluding NMSC,

were seen in the placebo-controlled period or

with increasing exposure, although a numerical

trend to an increase in malignancy was seen

with baricitinib 4 mg.

The incidence of MACE may be lower than

expected in this population. VTE was more

common with baricitinib 4 mg than the 2 mg

dose or placebo, with no incremental rise in the

longer term. Analysis is complicated by the fact

that the incidence of VTE in patients with RA is

2–3 times higher than for patients without RA,

irrespective of treatment. VTE is more common

during the first year after diagnosis, and in

patients who have switched to b/tsDMARDs

compared with those treated with csDMARDs

or b/tsDMARD initiators. A baricitinib dose

response for VTE was not seen during extended

observation, rates were stable over time, and

all patients who experienced VTE during the

placebo-controlled period had a risk factor.

However, patients prescribed JAKs differed

in terms of seropositivity, previous bDMARDs,

and csDMARD co-medication. The data

identified interesting geographical anomalies:

>60% of patients in Germany were prescribed

JAKinib monotherapy and approximately

75% of patients in Romania were bio-naïve

when started on JAKinibs. Such differences

need to be considered when analysing the

real-life efficacy and safety of JAKinibs across

different countries in collaborative studies.

In the German RABBIT registry, ACR20 response

was achieved by 46% of patients compared

with 56% from the RA-BEACON study.

Treat-to-target goals of remission and LDA

were achieved more often in the real-world

RABBIT population than in the RCT.


% of patients

60

50

40

30

20

10

0

Remission

LDA

ACR20 response

DAS28-ESR

≤2.6

≤3.2

Remission and LDA were achieved more often in the real-world RABBIT population than in the BEACON RCT

ESR, erythrocyte sedimentation rate

Adapted from Melliner Y, et al. Poster presented at DGRh 2018 (Abstract RA.05) and Genevose MC, et al. N Engl J Med 2016;374:1243–1252.

In the SCQM RA registry, baricitinib was

prescribed to significantly older patients with

longer disease duration and more previous

treatment failures. Drug maintenance was

significantly higher with baricitinib than TNFi

and was similar for bDMARD-naïve patients

and the overall population. In the Spanish ORBIT

study patients had refractory and long-lasting

disease, and most started treatment with 4 mg

baricitinib in combination with csDMARDs.

Persistence with treatment was highest in

patients without previous bDMARD failure.

High remission and LDA rates were observed

from 6 to 12 months, irrespective of the

remission definition used.

In the UK BSRBR-RA registry, almost two-thirds

of patients who received baricitinib had received

prior b/tsDMARDs. Baricitinib had good efficacy

and tolerability, with 74.9% of patients who

completed the first follow-up remaining on

SDAI

≤3.3

≤11

CDAI

≤2.8

≤10

RA-BEACON LDA

RA-BEACON remission

RABBIT LDA

RABBIT remission

baricitinib. Efficacy was also good in all

subgroups studied, including patients with

and without prior b/tsDMARD experience.

Data from Japanese post-marketing surveillance

up to Week 24 of baricitinib in 3445 patients

indicated that more than half of patients were

older than 65 years, and body weight and

BMI were low (56 kg and 22.67 mg/kg/m 2 ,

respectively). AEs and SAEs were low, and

74% of patients continued baricitinib to

Week 24. HZ and hepatic function disorder

were the joint most common AEs (2.9%),

reiterating the importance of HZ vaccination

prior to initiation of JAKinibs. The high rate

of hepatic function disorder may reflect

concomitant MTX use (56%), as low body

weight in Japanese populations has been a

problem with MTX. Dose reduction was needed

in a small number of patients. No new safety

concerns were identified.

In Darwin’s footsteps: continuing evolution of RA patient care

as we adapt to a changing environment

This discussion-based symposium, sponsored by Galapagos, was chaired by

Professor Laure Gossec and featured Professor Peter Taylor, Professor Peter

Nash and Ailsa Bosworth, a patient with RA, who is national patient champion

for the National Rheumatoid Arthritis Society in the UK. How treatment and

holistic care for patients with RA has adapted to the COVID-19 pandemic

was described, and future challenges and opportunities in a post-COVID-19

environment were addressed.

Evolving strategies: bringing

together HCP and RA patient

priorities in a changing

environment

Discussion led by Professor Peter Nash

Telehealth has multiple benefits including

reducing the cost of healthcare, increasing

efficiency, keeping patients engaged with

healthcare, and supporting improved

knowledge and education for patients and

HCPs. Professor Peter Nash led a discussion

with the faculty on the use of telehealth

during the COVID-19 pandemic and how

treating RA may evolve to include more

virtual management.

The COVID-19 pandemic has necessitated

rapid uptake of telehealth, whether expansion

of existing services, acceleration of planned

service redesign, or introduction where remote

consultations were not already in place. In a

telephone survey that explored the impact of

COVID-19 on the daily practice of physicians

from five European countries, 66% of

rheumatologists reported moving to video

or telephone consultations since COVID-19,

as well as limiting physical contact during

consultations (58%), and limiting appointments

to patients with more severe disease (47%).

A total of 30% changed how they use

medications, including administration route,

duration of dosing, drug, and drug class.

In the UK, strict data protection and privacy

rules initially prohibited use of platforms such

as Skype and Facetime, while some clinics

had to use hospital-based systems. Older

patients struggled with access to digital

communications and subsequently were

not always available for planned calls, or

much of a call was spent familiarising them

with the technology. Challenges have arisen

even where digital care was already well

established. In Australia, where telemedicine

has been in place for a decade, referrals from

primary care were often reduced and follow-up

appointments and investigations postponed.

For some patients, advanced treatments were

at threat of being stopped by the authorities,

as it was not possible to comply with

administrative requirements for reimbursement,

such as joint counts. Some patients ceased

immunosuppressive medicines due to worries

about COVID-19 outcomes, which led to

disease flare.

Lack of hands-on physical examination is a

concern, as this is key to patient assessment

and decision-making. Clinicians may need to

seek history more explicitly than in a traditional

appointment and patients may need to be better

prepared. Patients can be invited to attend clinic

when face-to-face assessment is needed.

For patients concerned about visiting hospitals

due to infection risk, remote telehealth has been

well accepted, although they have concerns

about physical examination and the continued

need for some face-to-face review. Tools that

include PROs and outcomes important to

patients, such RAID score, provide additional

information for clinicians and can reassure

patients that their perspective is understood.


‘How has COVID-19 impacted your patient management for RA?’

(N=274 rheumatologists from France, Germany, Italy, Spain and the UK)

Moving to video/telephone consultation 66%

Limiting physical contact during consultations

Fewer visits made by individual patients

Fewer visits made by individual patients

Only allowing more severe patients’ appointments

Fewer new patients referred from primary care

Fewer tests/investigations performed

Changed the way I choose and prescribe medication

Moving to remote completion of questionnaires

Other

COVID-19 has not impacted patient management 1%

2%

6%

30%

38%

42%

47%

58%

57%

56%

The butterfly effect: how small

changes in communication can

optimise outcomes for patients

with RA in a virtual world

Discussion led by Professor Peter Taylor

Professor Peter Taylor led a faculty

discussion on how telemedicine may

increase patient empowerment, improve

convenience for patients and clinicians, and

improve efficiency for healthcare systems.

The importance of involving patients in

decision-making in all aspects of their care

is emphasised in EULAR guidance, which

recommends that clinicians and patients work

together to ensure alignment of short- and

long-term goals, adherence, and satisfaction

with decisions. The pandemic has further

highlighted the importance of shared

decision-making to support remote patient

management, reduce demands on healthcare

services and reduce potential exposure

to COVID-19.

Broader use of telemedicine can empower

patients, allowing them to book their own

follow-up appointments, offering easier

access to flare clinics, and avoiding some

of the practical issues with attending hospital

appointments. Telehealth offers the opportunity

for increased peer support, such as patient

buddy systems and virtual patient group

meetings. It also offers efficiencies in the

management of healthcare resources. For

example, disease scores can be prepared

in advance of follow-up appointments, so

a decision can be made about whether a

face-to-face appointment is needed or if

remote consultation will suffice.

Telephone survey exploring how COVID-19 impacted on daily practice of 82 HCPs in France,

Germany, Italy, Spain and the UK

AT, advanced therapy.

Adapted from Adelphi Real World RA XII Disease Specific PRogramme, COVID-19 telephone survey, Galapagos, Data on file 2020

Tele-rheumatology triage tool

Condition Disease state Candidate for

telehealth

Diagnosis/disease

well established

Stable

Flaring

Needs

procedure

Yes

Maybe

Diagnosis/disease complex Complex No

Screening prior to

in-person visit

Any

No

Yes

No

Clinical example

Stable well-established disease (RA/PsA/SLE) on DMARD or biologic therapy

needing routine drug monitoring (laboratory analyses for toxicity, etc)

Well-established disease (RA/PsA/SLE) experiencing flares requires

escalation of therapy or short course of systemic steroids to control symptoms,

but no procedure needed

Requiring arthrocentesis or MSK ultrasound to guide therapy

Complex multi-organ disease (i.e., scleroderma/dermatomyositis/vasculitis) with

worsening symptoms where diagnosis/treatment cannot be delayed or missed

Primary care provider calling for initial work up recommendations or

management questions

If modality will lead to prolonged delay in follow-up of complex disease

Filed prior telehealth visit – No Prior bad experience or failure with modality

Natural adaptation: catalysing

positive change to achieve

holistic care

Professor Laure Gossec, Professor

Peter Taylor, Professor Peter Nash,

and Ailsa Bosworth

The faculty were joined by a patient for a

discussion on remote consultation and how

many of the changes to rheumatology care

prompted by COVID-19 have been positive

and may be beneficial long term.

Remote consultations will continue to work

well for most patients after the pandemic,

provided they are combined with face-to-face

appointments when required. Patients will

need access to clinicians, especially if

intervals between appointments are prolonged.

Systems and resources will need to be in place

so that clinicians can respond promptly and

appropriately to requests for remote contact

from patients needing support. Patients will

also need to be more proactive in seeking

support if their disease flares or they are

struggling to cope.

In the future, it will be important to optimise

use of the MDT and nurse practitioner and

to listen to patients about the outcomes that

matter most to their daily lives. Patients must

still be examined in person, at least at the initial

appointment and when changes in disease

status occur or new treatments are required,

and comorbidities outside of the joint must

still be considered. PROs should be included

in the treat-to-target approach to ensure that

patient-important outcomes are managed

satisfactorily. Online programmes can be

useful for non-pharmacological management

of comorbidities, such as mindfulness apps to

help with anxiety. Social media also provides

a new way to engage with patients and offer

patient education opportunities.

Hard of hearing or

poor engagement

– No Poor ability to participate in care

MSK, musculoskeletal; PsA, psoriatic arthritis; SLE, systemic lupus erythematosus

Adapted from Kulscar Z, et al. Sem Arthritis Rheum 2016;46:380–385.


COVID-19 and the management of patients with rheumatic

musculoskeletal diseases

Professor Leonard Calabrese chaired the Lilly symposium, with presentations

from Professor Kimme Hyrich, Professor Robert Landewé, and Professor Chris

Edwards. The symposium provided insights from global registries on COVID-19

in patients with RMD, reviewed treatment guidelines and considerations for

vaccination in these patients, and considered how strategies used during the

pandemic may affect future management.

COVID-19 global registries:

What have we learned?

Professor Kimme Hyrich

At the outset of the pandemic, it was not

known whether RMDs or their treatments

might increase the risk of developing

severe COVID-19. National and international

databases were established to rapidly

capture outcomes from patients with

RMD who acquired SARS-CoV-2 to better

understand the risks to the patient.

Professor Hyrich reviewed the current

data captured by the Global COVID-19

Rheumatology Alliance and EULAR COVID-19

database that were launched in parallel and

pooled to make the Global Case Database.

Factors associated with being hospitalised

in patients with RMD

According to the data collected, lower rates

of hospitalisation were observed in patients

with RMD on biologics versus csDMARDs and

glucocorticoids. Patients on glucocorticoids

were more likely to be hospitalised versus

patients on DMARDs or none. Patient

characteristics associated with hospitalisation

or death among people with RMDs are similar

to those without RMDs, such as race, ethnicity,

and age.

Factors associated with death in patients

with RMD

Patients with RMD who were older than

75 years, male, had previously smoked and

had moderate to high disease activity had higher

odds of death versus those who were younger,

female, non-smokers and had LDA. Pre-existing

comorbidities such as hypertension, CVD, lung

disease, chronic kidney disease and diabetes

were also associated with higher odds of death.

Few therapies were associated with higher

odds of death compared to MTX, and the

roles of patient-related factors, disease activity

and drug is unclear. Patients who had initiated

treatment with rituximab within the last

12 months had higher odds of death versus

those on MTX, however, patients on rituximab

are typically those that have failed other

treatments and have higher disease activity.

A higher risk of death was also seen in patients

receiving >10 mg of prednisone or equivalent.

A surprising association is the increased risk

of death seen with sulfasalazine treatment. In

stratified analysis, this was only associated with

smokers and was not significant in complete

case analysis; further investigation is needed.

Control of disease activity should remain a

priority. Patients with severe COVID-19 were

more likely to have high disease activity when

they acquired infection compared to those

with mild COVID-19.

Treatment guidance for

patients with RMD in the

COVID-19 era

Professor Robert Landewé

Professor Landewé reviewed the EULAR

provisional recommendations for the

management of RMDs in the context of

COVID-19, first published in June 2020,

and provided updates on recently

published evidence.

The provisional EULAR recommendations

were drafted at the beginning of the COVID-19

pandemic and aimed to provide guidance

to patients with RMD and physicians on the

implications of COVID-19. A task force of

20 members was convened by EULAR and five

overarching principles and 13 recommendations

were agreed in the absence of published

evidence covering (i) general measures and

prevention of COVID-19 infection, (ii) the

management of RMD when local measures

of social distancing are in effect, (iii) the

management of COVID-19 in the context

of RMD, and (iv) the prevention of infections

other than COVID-19.

As of April 2021, the overarching principles

remain unchanged. Patients with RMD are at

no increased risk of contracting COVID-19 than

individuals without RMD. Whilst a potential

shortage of sDMARDs and bDMARDs was

COVID-19 vaccination

for patients with RMD:

Experience from the UK

Professor Chris Edwards

Uncertainty remains about the use of

vaccines to prevent COVID-19 in patients

with RMDs. Professor Edwards tackled

the key questions that remain around

COVID-19 vaccines using case experience

from the UK.

predicted, this has not manifested. It was

recommended that physicians follow their

country guidelines and this is still the case.

Similarly, if a patient with RMD shows no

symptoms of COVID-19, they should continue

with their current RMD treatment.

Patients should continue to avoid visits to the

hospital or the office, and remote physician

monitoring of RMD is still considered safe

for the majority of patients. If a hospital or

patient visit is necessary, precautions by the

physician and patient should be taken. PCR

tests are recommended upon contact with a

COVID-19 positive patient. If a patient with

RMD and symptoms is chronically treated

with glucocorticoids, this treatment should

be continued at the lowest possible dose. In

patients with mild symptoms of COVID-19, treat

on a case-by-case basis. If symptoms worsen,

expert advice should be sought immediately,

and local treatment recommendations followed.

Physicians should always be aware of diseases

that may mimic COVID-19 such as pneumonia.

Vaccine recommendations were not included

in the original EULAR recommendations as

none were available at the time of publication.

Consequently, EULAR published ‘viewpoints

on SARS-CoV-2 vaccination in patients with

RMDs’ in December 2020, and recommended

patients are vaccinated. They noted that the risk

of ‘wait and see’ outweighs the risk of a severe

but rare adverse event in a population-wide

vaccination programme.

Do vaccines for COVID-19 work?

Data from the real-world SIREN study which

included 23,324 healthcare workers in England

showed a single dose of BNT162b2 vaccine had

efficacy of 70% (95% CI, 55–85) 21 days after

first dose and 85% (95% CI, 74–96) 7 days after

two doses. Similarly, a Scottish study of 1,331,993

people with comorbidities including RA, showed

that the BNT162b2 mRNA vaccine was 91%

effective and the ChAdOx1 vaccine 88% effective

at reducing COVID-19 hospital admission at

28–34 days post-vaccination with first dose.


SARS-CoV-2 vaccines licensed or in Phase 3 clinical trials

Vaccine Type Number of doses Stage of development (all Phase 3 trials continue)

Pfizer/BioNtech mRNA 2 doses at least 21 days apart Emergency approval 16+ yrs by MHRA, EMA and FDA Dec 2020

AZ/Oxford Chimp adenovirus vector 2 doses 4–12 weeks apart

Emergency approval 18+ yrs by MHRA Dec 2020

and EMA/FDA Jan 2021

References

1. Russell SM, et al. Science 1995;270:797–800.

2. Nash P, et al. Ann Rheum Dis 2021;80:71–87.

3. Finckh A, et al. RMD Open 2020;6:e001174.

MODERNA mRNA 2 doses 28 days apart

Emergency approval in 18+ yrs by FDA Dec. 2020

and MRHA/EMA Jan 2021

Abbreviations

SputnikV Human adenovirus vector 2 doses 21 days apart Phase 3 trials, approved in Russia

Novavax Recombinant nanoparticle 2 doses 21 days apart Phase 3 trials

Janssen Human adenovirus vector 1 dose

Adapted from A Mason et al. Lupus 2021; DOI: 10.1177/09612033211024355.

Are vaccines for COVID-19 safe?

Due to their disease activity and

immunosuppressed state, patients with RMD

are more at risk of developing severe COVID-19.

EULAR stated there is no reason to withhold

vaccines from patients with RMDs as well as

in patients receiving drugs that influence the

immune system. The ACR stated there are no

known additional contraindications to COVID-19

vaccination for AIIRD patients and the expected

response on immunomodulatory therapies is likely

to be blunted. Theoretical risk exists for AIIRD

flare following COVID-19 vaccination, however

benefit outweighs the risk in these patients. The

Arthritic and Musculoskeletal Alliance suggested

patients should not stop immunosuppression,

but patients receiving rituximab and corticosteroid

therapies may potentially have a reduced

response to COVID-19 vaccines. Clinicians

are encouraged to report a vaccination to

the EULAR COVAX Database which captures

outcomes of vaccines in patients with RMDs.

Factors associated with hospitalisation for

COVID-19: Who needs vaccination most?

Data from the COVID-19 Global Rheumatology

Alliance registry show patients aged over

Emergency approval 18+ yrs by FDA Feb. 2021.

2 dose use in Phase 3

CoronaVac Inactivated virus 2 doses 2–4 weeks apart Phase 3 trials

BBIBP- CoV Inactivated virus 2 doses 3–4 weeks apart Phase 3 trials

Wuhan Inactivated virus 2 doses 21 days apart Phase 3 trials

65 years, who have hypertension or CVD,

lung disease, diabetes, chronic renal

insufficiency or end-stage renal disease,

are on csDMARDs or greater than

prednisone-equivalent a day are at greater

risk of hospitalisation from COVID-19.

Vaccine uptake in the UK appears to be

high in over 65s and clinically extremely

vulnerable groups, with 92.6% vaccinated

with at least one dose and 69.9% with a

second dose at the time of the congress.

What future strategies are being considered?

There are several clinical trials being run

in the UK to evaluate different aspects of

vaccination such as the COM-COV study

that is comparing COVID-19 vaccine schedule

combinations, the COMFLU COV study

assessing the combination of the COVID-19

and flu vaccinations, and COV-BOOST study

evaluating COVID-19 booster injections.

Of particular interest is the OCTAVE study,

investigating the effectiveness of COVID-19

vaccines used in the UK in 2021 in people

with impaired immune systems, led by

Professor Iain McInnes at the University

of Glasgow.

AIIRD – autoimmune inflammatory

rheumatic disease

ATP - adenosine triphosphate

bDMARD – biologic disease-modifying

antirheumatic drug

BRASS – Brigham and Women’s Hospital

Rheumatoid Arthritis Sequential Study

CDAI – Clinical Disease Activity Index

csDMARD – conventional synthetic

disease-modifying antirheumatic drug

CVD – cardiovascular disease

DAS28(CRP) – Disease Activity Score

in 28 Joints

DVT – deep vein thrombosis

ES – erosion score

GRAPPA – Group for Research

and Assessment of Psoriasis and

Psoriatic Arthritis

HAQ-DI – Health Assessment

Questionnaire - Disability Index

HZ – herpes zoster

IMID – immune-mediated inflammatory

disease

IR – inadequate responder

JAK – Janus kinase

JAKinib – JAK inhibitors

JSN – joint space narrowing

LDA – low disease activity

LTE – long-term extension

MACE – major cardiovascular events

NMSC – nonmelanoma skin cancer

NNH – number needed to harm

NNT – number needed to treat

OMA – other modes of action

PE – pulmonary embolism

PhGA – physician global assessment

of disease activity

PK – pharmacokinetics

PRO – patient reported outcome

PtGA – patient global assessment

of disease activity

RAID - Rheumatoid Arthritis Impact of

Disease

RMDs – rheumatic musculoskeletal

diseases

SDAI – Simplified Disease Activity Index

SJC – swollen joint count

TJC – tender joint count

TNFi – tumour necrosis factor inhibitor

tsDMARD – targeted synthetic

disease-modifying antirheumatic drug

VTE – venous thromboembolism

This EULAR symposium review was sponsored by Lilly

www.cytokinesignalling.com

info@cytokinesignalling.com

Cytokine Signalling Forum

Cytokine Signalling Forum

@CytokineForum

Developed under the auspices of the

University of Glasgow

CSF EULAR Symposium Review

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