drug treatment for rheumatoid arthritis - nice pathways · drug treatment for rheumatoid arthritis...

Drug treatment for rheumatoid arthritisDrug treatment for rheumatoid arthritis

NICE Pathways bring together everything NICE says on a topic in an interactiveflowchart. NICE Pathways are interactive and designed to be used online.

They are updated regularly as new NICE guidance is published. To view the latestversion of this NICE Pathway see:

http://pathways.nice.org.uk/pathways/rheumatoid-arthritisNICE Pathway last updated: 08 January 2020

This document contains a single flowchart and uses numbering to link the boxes to theassociated recommendations.

Rheumatoid arthritisRheumatoid arthritis© NICE 2020. All rights reserved. Subject to Notice of rights.

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Drug treatment for rheumatoid arthritisDrug treatment for rheumatoid arthritis NICE Pathways


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1 Adult with rheumatoid arthritis

No additional information

2 Treat-to-target strategy

Treat active rheumatoid arthritis in adults with the aim of achieving a target of remission or low

disease activity if remission cannot be achieved (treat-to-target).

Consider making the target remission rather than low disease activity for people with an

increased risk of radiological progression (presence of anti-CCP antibodies or erosions on X-ray

at baseline assessment).

In adults with active rheumatoid arthritis, measure C-reactive protein and disease activity (using

a composite score such as DAS28) monthly in specialist care until the target of remission or low

disease activity is achieved.

Rationale and impact

See why we made the recommendations on treat-to-target strategy and how they might affect

practice [See page 19].

Quality standards

The following quality statement is relevant to this part of the interactive flowchart.

2. Treatment

3 Initial treatment

Monotherapy

For adults with newly diagnosed active rheumatoid arthritis:

Offer first-line treatment with cDMARD monotherapy using oral methotrexate, leflunomideor sulfasalazine as soon as possible and ideally within 3 months of onset of persistentsymptoms.

Consider hydroxychloroquine for first-line treatment as an alternative to oral methotrexate,



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leflunomide or sulfasalazine for mild or palindromic disease.

Escalate dose as tolerated.

Consider short-term bridging treatment with glucocorticoids (oral, intramuscular or intra-

articular) when starting a new cDMARD.

Step-up strategy

Offer additional cDMARDs (oral methotrexate, leflunomide, sulfasalazine or

hydroxychloroquine) in combination in a step-up strategy when the treatment target (remission

or low disease activity) has not been achieved despite dose escalation.

Rationale and impact

See why we made the recommendations on cDMARDs [See page 20] and short-term bridging

treatment with glucocorticoids [See page 23] and how they might affect practice.

Quality standards

The following quality statement is relevant to this part of the interactive flowchart.

2. Treatment

4 Inadequate response to conventional DMARDs

Biologicals

Sarilumab

The following recommendations are an extract from NICE technology appraisal guidance on

sarilumab for moderate to severe rheumatoid arthritis.

Sarilumab, with methotrexate, is recommended as an option for treating active rheumatoid

arthritis in adults whose disease has responded inadequately to intensive therapy with a

combination of conventional DMARDs, only if:

disease is severe (a DAS28 of more than 5.1) and

the company provides sarilumab with the discount agreed in the patient access scheme.



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http://www.nice.org.uk/guidance/TA485


Sarilumab can be used as monotherapy for people who cannot take methotrexate because it is

contraindicated or because of intolerance, when the criteria above are met.

Continue treatment only if there is a moderate response measured using European League

Against Rheumatism (EULAR) criteria at 6 months after starting therapy. After an initial

response within 6 months, withdraw treatment if at least a moderate EULAR response is not

maintained.

These recommendations are not intended to affect treatment with sarilumab that was started in

the NHS before this guidance was published. People having treatment outside these

recommendations may continue without change to the funding arrangements in place for them

before this guidance was published, until they and their NHS clinician consider it appropriate to

stop.

See why we made the recommendations on sarilumab [See page 18].

NICE has written information for the public on sarilumab.

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and

abatacept

The following recommendations are from NICE technology appraisal guidance on adalimumab,

etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for

rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only

have failed.

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept,

all in combination with methotrexate, are recommended as options for treating rheumatoid

arthritis, only if:

disease is severe, that is, a DAS28 greater than 5.1 and

disease has not responded to intensive therapy with a combination of conventionalDMARDs and

the companies provide certolizumab pegol, golimumab, abatacept and tocilizumab asagreed in their patient access schemes.

Adalimumab, etanercept, certolizumab pegol or tocilizumab can be used as monotherapy for

people who cannot take methotrexate because it is contraindicated or because of intolerance,

when the criteria above are met.



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http://www.nice.org.uk/guidance/TA485/informationforpublic







Against Rheumatism (EULAR) criteria at 6 months after starting therapy.

After initial response within 6 months, withdraw treatment if a moderate EULAR response is not

maintained.

Start treatment with the least expensive drug (taking into account administration costs, dose

needed and product price per dose). This may need to be varied for some people because of

differences in the mode of administration and treatment schedules.

People whose treatment with adalimumab, etanercept, infliximab, certolizumab pegol,

golimumab, tocilizumab or abatacept is not recommended in this NICE guidance, but was

started within the NHS before this guidance was published, should be able to continue

treatment until they and their NHS clinician consider it appropriate to stop.

NICE has written information for the public on adalimumab, etanercept, infliximab, certolizumab

pegol, golimumab, tocilizumab and abatacept.

Anakinra

On the balance of its clinical benefits and cost effectiveness, anakinra is not recommended for

the treatment of rheumatoid arthritis, except in the context of a controlled, long-term clinical

study.

Patients currently receiving anakinra for rheumatoid arthritis may suffer loss of wellbeing if their

treatment were discontinued at a time they did not anticipate. Therefore, patients should

continue therapy with anakinra until they and their consultant consider it is appropriate to stop.

Do not offer the combination of TNF-α inhibitor therapy and anakinra for RA.

Therapeutic monitoring of TNF-alpha inhibitors

See monitoring and review.

Other immunomodulatory therapies

Tofacitinib


tofacitinib for moderate to severe rheumatoid arthritis.



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Tofacitinib, with methotrexate, is recommended as an option for treating active rheumatoid

arthritis in adults whose disease has responded inadequately to intensive therapy with a

combination of conventional DMARDs, only if:


the company provides tofacitinib with the discount agreed in the patient access scheme.

Tofacitinib can be used as monotherapy for adults who cannot take methotrexate because it is





maintained.

These recommendations are not intended to affect treatment with tofacitinib that was started in




stop.

See why we made the recommendations on tofacitinib [See page 17].

NICE has written information for the public on tofacitinib.

Baricitinib

The following recommendations are an extract from NICE's technology appraisal guidance on

baricitinib for moderate to severe rheumatoid arthritis.

Baricitinib, with methotrexate, is recommended as an option for treating active rheumatoid

arthritis in adults whose disease has responded inadequately to intensive therapy with

conventional DMARDs, only if:


the company provides baricitinib with the discount agreed in the patient access scheme.

Baricitinib can be used as monotherapy for people who cannot take methotrexate because it is

contraindicated or because of intolerance, when the above criteria are met.




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maintained.

These recommendation are not intended to affect treatment with baricitinib that was started in

the NHS before this guidance was published. Adults having treatment outside these



stop.

See why we made the recommendations on baricitinib [See page 17].

NICE has written information for the public on baricitinib.

5 Inadequate response or intolerance to biological DMARDs, andrituximab is suitable

Rituximab


adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid

arthritis after the failure of a TNF inhibitor.

Rituximab in combination with methotrexate is recommended as an option for the treatment of

adults with severe active rheumatoid arthritis who have had an inadequate response to, or are

intolerant of, other DMARDs, including at least one TNF inhibitor. Treatment with rituximab

should be given no more frequently than every 6 months.

Treatment with rituximab in combination with methotrexate should be continued only if there is

an adequate response following initiation of therapy and if an adequate response is maintained

following retreatment with a dosing interval of at least 6 months. An adequate response is

defined as an improvement in DAS28 of 1.2 points or more.

When using DAS28, healthcare professionals should take into account any physical, sensory or

learning disabilities, communication difficulties, or disease characteristics that could adversely

affect patient assessment and make any adjustments they consider appropriate.

A team experienced in the diagnosis and treatment of rheumatoid arthritis and working under

the supervision of a rheumatologist should initiate, supervise and assess response to treatment



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with rituximab.

NICE has written information for the public on adalimumab, etanercept, infliximab, rituximab and

abatacept.

6 Inadequate response or intolerance to biological DMARDs, andrituximab is not suitable

Biologicals

Sarilumab




arthritis in adults whose disease has responded inadequately to or who cannot have other

DMARDs, including at least 1 biological DMARD, only if:


they cannot have rituximab and


Sarilumab can be used as monotherapy for people who cannot take methotrexate because it is





maintained.





stop.




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Adalimumab, etanercept, infliximab and abatacept


adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid

arthritis after the failure of a TNF inhibitor.

Adalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate, are

recommended as treatment options only for adults with severe active rheumatoid arthritis who

have had an inadequate response to, or have an intolerance of, other DMARDs, including at

least one TNF inhibitor, and who cannot receive rituximab therapy because they have a

contraindication to rituximab, or when rituximab is withdrawn because of an adverse event.

Adalimumab monotherapy and etanercept monotherapy are recommended as treatment options

for adults with severe active rheumatoid arthritis who have had an inadequate response to, or

have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot

receive rituximab therapy because they have a contraindication to methotrexate, or when

methotrexate is withdrawn because of an adverse event.

Treatment with adalimumab, etanercept, infliximab and abatacept should be continued only if

there is an adequate response (an improvement in DAS28 of 1.2 points or more) 6 months after

initiation of therapy. Treatment should be monitored, with assessment of DAS28, at least every

6 months and continued only if an adequate response is maintained.

When using DAS28, healthcare professionals should take into account any physical, sensory or

learning disabilities, communication difficulties, or disease characteristics that could adversely

affect patient assessment and make any adjustments they consider appropriate.

A team experienced in the diagnosis and treatment of rheumatoid arthritis and working under

the supervision of a rheumatologist should initiate, supervise and assess response to treatment

with rituximab, adalimumab, etanercept, infliximab or abatacept.

NICE has written information for the public on adalimumab, etanercept, infliximab, rituximab and

abatacept.

Golimumab

The following recommendations are from NICE technology appraisal guidance on golimumab

for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-



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rheumatic drugs.

Golimumab in combination with methotrexate is recommended as an option for the treatment of

rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to other

DMARDs, including a TNF inhibitor, if:

it is used as described for adalimumab, etanercept, infliximab, rituximab and abatacept(NICE technology appraisal guidance 195), and

the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mgdose, agreed as part of the patient access scheme.

When using the DAS28, healthcare professionals should take into account any physical,

sensory or learning disabilities, communication difficulties, or disease characteristics that could

adversely affect patient assessment and make any adjustments they consider appropriate.

NICE has written information for the public on golimumab.

Certolizumab pegol

The following recommendations are from NICE technology appraisal guidance on certolizumab

pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor.

Certolizumab pegol, in combination with methotrexate, is recommended as an option for

treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or

who cannot tolerate, other DMARDs including at least 1 TNF-alpha inhibitor, only if:

disease activity is severe and

rituximab is contraindicated or not tolerated and

the company provides certolizumab pegol with the agreed patient access scheme.

Certolizumab pegol, as monotherapy, is recommended as an option for treating active

rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot

tolerate, other DMARDs including at least 1 TNF-alpha inhibitor, only if:

disease is severe and

rituximab therapy cannot be given because methotrexate is contraindicated or not toleratedand

the company provides certolizumab pegol with the agreed patient access scheme.

Continue treatment only if there is at least a moderate response measured using European

League Against Rheumatism (EULAR) criteria at 6 months. After an initial response within 6



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months, withdraw treatment if at least a moderate EULAR response is not maintained.

This guidance is not intended to affect the position of patients whose treatment with

certolizumab pegol was started within the NHS before this guidance was published. Treatment

of those patients may continue without change to whatever funding arrangements were in place

for them before this guidance was published until they and their NHS clinician consider it

appropriate to stop.

NICE has written information for the public on certolizumab pegol.

Tocilizumab

The following recommendations are from NICE technology appraisal guidance on tocilizumab

for the treatment of rheumatoid arthritis.

Tocilizumab in combination with methotrexate is recommended as an option for the treatment of

rheumatoid arthritis in adults if:

the disease has responded inadequately to DMARDs and a TNF inhibitor and the personcannot receive rituximab because of a contraindication to rituximab, or because rituximab iswithdrawn because of an adverse event, and tocilizumab is used as described foradalimumab, etanercept, infliximab and abatacept (NICE technology appraisal guidance195) or

and the manufacturer provides tocilizumab with the discount agreed as part of the patientaccess scheme.

People currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet

the criteria for treatment should have the option to continue treatment until they and their

clinicians consider it appropriate to stop.

NICE has written information for the public on tocilizumab.

Therapeutic monitoring of TNF-alpha inhibitors

See monitoring and review.

Other immunomodulatory therapies

Tofacitinib





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Tofacitinib, with methotrexate, is recommended as an option for treating active rheumatoid

arthritis in adults whose disease has responded inadequately to, or who cannot have, other




the company provides tofacitinib with the discount agreed in the patient access scheme.

Tofacitinib can be used as monotherapy for adults who cannot take methotrexate because it is





maintained.

These recommendations are not intended to affect treatment with tofacitinib that was started in




stop.

See why we made the recommendations on tofacitinib [See page 17].

NICE has written information for the public on tofacitinib.

Baricitinib



Baricitinib, with methotrexate, is recommended as an option for treating active rheumatoid

arthritis in adults whose disease has responded inadequately to or who cannot have other




the company provides baricitinib with the discount agreed in the patient access scheme.

Baricitinib can be used as monotherapy for people who cannot take methotrexate because it is



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contraindicated or because of intolerance, when the above criteria are met.




maintained.

These recommendation are not intended to affect treatment with baricitinib that was started in

the NHS before this guidance was published. Adults having treatment outside these



stop.

See why we made the recommendations on baricitinib [See page 17].

NICE has written information for the public on baricitinib.

7 Inadequate response to rituximab and other biological DMARDs

Sarilumab




arthritis in adults whose disease has responded inadequately to rituximab and at least 1

biological DMARD, only if:






maintained.






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stop.



Tocilizumab


tocilizumab for the treatment of rheumatoid arthritis.

Tocilizumab in combination with methotrexate is recommended as an option for the treatment of

rheumatoid arthritis in adults if:

the disease has responded inadequately to one or more TNF inhibitor treatments and torituximab

and the manufacturer provides tocilizumab with the discount agreed as part of the patientaccess scheme.

People currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet

the criteria for treatment should have the option to continue treatment until they and their

clinicians consider it appropriate to stop.

NICE has written information for the public on tocilizumab.

8 Monitoring and review

See Rheumatoid arthritis / Managing rheumatoid arthritis / Monitoring and review

9 Symptom control and managing flares

Symptom control

Consider oral NSAIDs (including traditional NSAIDs and cox II selective inhibitors) when control

of pain or stiffness is inadequate. Take account of potential gastrointestinal, liver and cardio-

renal toxicity, and the person's risk factors, including age and pregnancy.

When treating symptoms of rheumatoid arthritis with oral NSAIDs:



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https://pathways.nice.org.uk/pathways/rheumatoid-arthritis/managing-rheumatoid-arthritis#content=view-node%3Anodes-monitoring-and-review


offer the lowest effective dose for the shortest possible time

offer a PPI, and

review risk factors for adverse events regularly.

If a person with rheumatoid arthritis needs to take low-dose aspirin, healthcare professionals

should consider other treatments before adding an NSAID (with a PPI) if pain relief is ineffective

or insufficient.

See why we made the recommendations on symptom control and how they might affect practice

[See page 24].

Managing flares

Offer short-term treatment with glucocorticoids for managing flares in adults with recent-onset or

established disease to rapidly decrease inflammation.

In adults with established rheumatoid arthritis, only continue long-term treatment with

glucocorticoids when:

the long-term complications of glucocorticoid therapy have been fully discussed, and

all other treatment options (including biological and targeted synthetic DMARDs) have beenoffered.

10 See what NICE says on medicines optimisation

See Medicines optimisation



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Why we made the recommendations on baricitinib

Clinical trials showed baricitinib plus conventional DMARDs to be more effective than

conventional DMARDs alone for treating severe active rheumatoid arthritis that has not

responded adequately to conventional or biological DMARDs. Some trial evidence also

suggests that in people who have not previously had DMARDs, baricitinib works as well when

taken alone as it does when taken with conventional DMARDs.

Baricitinib plus conventional DMARDs was also shown to have similar effectiveness to the

biological DMARD adalimumab in people whose disease has responded inadequately to

conventional DMARDs. Because there are no trials which compare baricitinib with other

biological DMARDs, the company did an indirect comparison. Baricitinib was shown to work as

well as most of the biological DMARDs which NICE has already recommended in this indication.

Based on the health-related benefits and costs compared with conventional and biological

DMARDs, baricitinib plus conventional DMARDs was recommended as a cost-effective

treatment, in line with previous recommendations in NICE technology appraisal guidance on:

certolizumab pegol (after a TNF-alpha inhibitor)

adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab andabatacept (after conventional DMARDs)

tocilizumab

golimumab (after DMARDs)

adalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha inhibitor).

For more information see the committee discussion in the NICE technology appraisal on


Why we made the recommendations on tofacitinib

Clinical trial evidence shows tofacitinib plus conventional DMARDs is more effective than

conventional DMARDs alone for treating moderate and severe active rheumatoid arthritis that

has not responded adequately to conventional or biological DMARDs.

Clinical trial evidence also shows that tofacitinib plus methotrexate is not worse in effectiveness

than the biological DMARD adalimumab plus conventional DMARDs in people whose disease

has responded inadequately to conventional DMARDs. Because there are no trials comparing

tofacitinib with other biological DMARDs, the company did an indirect comparison. This shows



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http://www.nice.org.uk/guidance/ta415






http://www.nice.org.uk/guidance/ta466/chapter/3-Committee-discussion


that tofacitinib works as well as most of the biological DMARDs which NICE has already

recommended in this indication.


DMARDs, tofacitinib plus conventional DMARDs is recommended as a cost-effective treatment

for severe active rheumatoid arthritis, in line with previous recommendations in NICE technology

appraisal guidance on:

baricitinib



tocilizumab



Tofacitinib for moderate active rheumatoid arthritis that has responded inadequately to

conventional DMARDs is not cost effective based on what NICE normally considers acceptable,

that is, £30,000 per quality-adjusted life year gained.

For more information see the committee discussion in the NICE technology appraisal on


Why we made the recommendations on sarilumab

Clinical trials showed sarilumab plus methotrexate or conventional DMARDs to be more

effective than methotrexate or conventional DMARDs for treating moderate to severe active

rheumatoid arthritis that has not responded adequately to conventional DMARDs. The trials also

showed that for treating severe active rheumatoid arthritis that has not responded adequately to

conventional DMARDs, sarilumab alone is more effective than adalimumab alone.

Because there are no trials comparing sarilumab with other biological DMARDs, the company

did an indirect comparison. This showed that sarilumab with conventional DMARDs (including

methotrexate) or alone works as well as most of the biological DMARDs that NICE has already

recommended.


DMARDs, sarilumab plus methotrexate or sarilumab alone is recommended as a cost-effective



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http://www.nice.org.uk/guidance/TA480/chapter/3-Committee-discussion


treatment for severe active rheumatoid arthritis, in line with previous recommendations in NICE

technology appraisal guidance on:

baricitinib



tocilizumab

tofacitinib



Rationale and impact: treat-to-target strategy

Rationale

Strategy and treatment target

Evidence showed that a treat-to-target strategy was more effective than usual care for

managing rheumatoid arthritis and improved outcomes at no additional cost. The committee

agreed that this approach was more likely to achieve rapid and sustained disease control.

No evidence was identified to indicate whether a target of remission or low disease activity was

more effective. However, the committee agreed that remission (for example, a DAS28 score of

less than 2.6) is the most appropriate target for most people, but for some who are unable to

achieve remission despite a treat-to-target approach with appropriate escalation, low disease

activity (for example, a DAS28 score of less than 3.2) is acceptable. It was agreed that for those

identified as being at risk of poor prognosis, a target of remission may be more appropriate

Frequency of monitoring for active disease

No studies were identified that compared different frequencies of monitoring specifically in

people with active disease. The committee noted that the 2009 guideline recommended monthly

monitoring and that this was used in some of the studies of a treat-to-target strategy. The

committee agreed that monthly monitoring of C-reactive protein and disease activity was most

appropriate for active disease. This allows dose escalation of DMARDs, checking the need for

short-term bridging treatment with glucocorticoids and whether people are tolerating the drug

regimen, assessing side effects, providing support and encouraging adherence.



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People at risk of poor outcomes

There was no evidence that people with a poor prognosis should have different management in

terms of the treatment target or the frequency of monitoring. However, in the committee's

experience rheumatoid arthritis often responds less well to standard management in this group.

The committee agreed that the recommendations on treat-to-target with monthly monitoring

should ensure that people with a poor prognosis receive effective treatment, but they decided to

make a research recommendation to inform future guidance for managing rheumatoid arthritis

in this group.

Impact

A treat-to-target strategy is current best practice in most NHS settings. The 2016 National

Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis indicated that healthcare

professionals set a treatment target for about 90% of their patients. Although the 2018

recommendation specifies a target of remission or low disease activity, rather than a disease

level previously agreed with the person, the committee agreed that these are the targets

commonly used and so this is unlikely to involve a significant change in practice.

Monthly monitoring was recommended in the 2009 guideline, but the committee acknowledged

that many clinics do not monitor active disease this often. A regional survey (Tugnet 2013)

reported that about two-thirds of people with rheumatoid arthritis received monthly C-reactive

protein monitoring but only a quarter had monthly monitoring of disease activity (with about 40%

in dedicated early arthritis clinics) until disease control was achieved. The committee were

unsure whether these rates reflected practice across England and noted that practice had

improved since the survey was conducted in 2011. However, the committee agreed that monthly

monitoring would likely involve a change in practice in some clinics.

Full details of the evidence and the committee's discussion are in evidence review C: Treat-to-

target.

Rationale and impact: cDMARDs

Rationale

First-line treatment

Evidence showed that starting treatment with more than 1 cDMARD was no more effective than



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http://www.nice.org.uk/guidance/ng100/evidence



starting with a single cDMARD. The committee agreed that cDMARD monotherapy might have

fewer side effects and recommended cDMARD monotherapy as first-line treatment. This

differed from the 2009 guideline which recommended combination therapy. The difference is

largely a result of inclusion of different evidence and a different approach to analysing that

evidence.

Many of the studies included in the 2009 guideline used cDMARDs that are no longer

commonly used in UK practice (for example, ciclosporin), and these studies were excluded from

the evidence for the 2018 update. In addition, the 2018 update included new evidence

published after the 2009 guideline. Further, a different approach to analysing the evidence was

taken, with the 2018 update aiming to identify the most effective cDMARD strategy

(monotherapy, sequential monotherapy, step-up therapy, step-down therapy or parallel

combination therapy) as well as which cDMARD should be used. The 2009 guideline compared

treatment strategies only, regardless of the particular cDMARDs, and combined evidence

according to treatment strategy.

The evidence included in the 2018 update was therefore different to that included in 2009 and

supported cDMARD monotherapy as first-line treatment.

Evidence from randomised controlled trials in people who had never had a DMARD showed no

consistent differences in the effectiveness of methotrexate, leflunomide and sulfasalazine as

monotherapies. The drugs also had similar costs. The committee agreed that any of these

drugs can be used as first-line treatment.

Hydroxychloroquine was less effective, but fewer people stopped treatment because of side

effects. The committee agreed that hydroxychloroquine could be considered for people with mild

or palindromic disease.

People at risk of poor outcomes

Evidence for different first-line treatment in people with a poor prognosis was limited so the

committee decided not to make a separate recommendation for this group. They agreed that

the recommendation for dose increases and treating to target (with the aim of keeping disease

activity low) should ensure adequate treatment for these people. Given the limited evidence in

this area, the committee also decided that the possible benefit of managing rheumatoid arthritis

with a poor prognosis with a different strategy was a priority for future research.



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Further treatment

Evidence supported adding another cDMARD when needed (step-up strategy) rather than

replacing the cDMARD with another (sequential monotherapy). The committee acknowledged

that more side effects were possible with a step-up strategy, but in their experience these could

be managed by drug monitoring and were outweighed by the clinical benefit of combination

treatment when monotherapy was inadequate. A published economic analysis supported a

step-up approach rather than sequential monotherapy.

Subcutaneous methotrexate

No evidence was found for subcutaneous methotrexate, but the committee agreed that the

effects may be superior and side effects fewer than with oral cDMARDs. However, because

subcutaneous methotrexate is significantly more expensive than other cDMARD options, the

committee was not able to recommend this without evidence of clinical benefit and cost

effectiveness relative to oral cDMARDs. The committee decided to make a research

recommendation to inform future guidance.

Impact

The 2009 guideline recommended a combination of cDMARDs (including methotrexate and at

least 1 other cDMARD) for newly diagnosed rheumatoid arthritis and emphasised the

importance of starting effective cDMARD therapy as soon as possible.

The 2009 recommendation to start with combination therapy was not widely adopted. The 2016

National Clinical Audit for Rheumatoid Arthritis and Early Inflammatory Arthritis reported that

only 46% of people with rheumatoid arthritis received combination cDMARDs at any time.

Currently there is variation in practice regarding the choice of cDMARD(s) and treatment

strategy, with many healthcare professionals preferring to start with monotherapy and only use

combination therapy when response is inadequate.

The 2018 recommendations to start with monotherapy and add drugs when the response is

inadequate are unlikely to have a substantial impact on practice or resources, as they align with

the current approach taken by many healthcare professionals. However, the recommendations

should result in a more consistent treatment strategy and reduce the number of people

prescribed combination therapy on diagnosis.

The 2009 guideline recommended methotrexate as one of the first drugs used in combination



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therapy. The 2018 recommendations do not specify which cDMARD should be used at any

stage of treatment. Again, this will be unlikely to have a significant impact on practice, and

methotrexate is likely to remain one of the most commonly prescribed drugs.

The recommendations on dose escalation and reduction have not changed substantially from

the 2009 guideline and reflect current clinical practice. The committee clarified that dose

reduction and the use of a step-down strategy should only be considered after a person has

maintained the treatment target for at least 1 year without the use of glucocorticoids.

Full details of the evidence and the committee's discussion are in evidence review F: DMARDs.

Rationale and impact: short-term bridging treatment with glucocorticoids

Rationale

Evidence from randomised controlled trials on the use of short-term bridging treatment with

glucocorticoids to relieve symptoms while people are waiting for a new DMARD to take effect

was limited. There was some evidence that fewer people withdrew from the studies due to

inefficacy or adverse events when they were taking glucocorticoids, although there was no

evidence that glucocorticoids were effective in terms of disease activity score, quality of life or

function, as studies did not report these outcomes. In the committee's experience people with

active arthritis may benefit from the anti-inflammatory effects of glucocorticoids. However, for

others with less active disease this additional treatment may not be needed. The committee

agreed that short-term glucocorticoids could be considered on a case-by-case basis.

Because of the lack of good quality evidence, the committee decided to make a research

recommendation to determine the effectiveness of short-term glucocorticoids for adults taking a

new DMARD, including the most effective regimen.

Impact

Most healthcare professionals offer short-term bridging treatment with glucocorticoids to adults

starting a new DMARD. They can continue to offer this but the recommendation encourages

them to consider whether this additional treatment is always needed. Therefore this is unlikely

to result in additional spending for the NHS.

Full details of the evidence and the committee's discussion are in evidence review H:

Glucocorticoids.



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Rationale and impact: symptom control

Rationale

Evidence suggested that NSAIDs may offer a small benefit in relieving symptoms for adults with

rheumatoid arthritis (including pain and stiffness). The committee agreed that this was likely to

outweigh the increase in gastrointestinal adverse events associated with NSAIDs. To minimise

adverse events, the committee agreed that NSAIDs should be used at the lowest doses and for

the shortest possible time, with a PPI, and that risk factors for adverse events should be

reviewed regularly.

There was limited evidence on paracetamol, opioids and tricyclic antidepressants and no

evidence for nefopam, gabapentinoids or selective serotonin reuptake inhibitor (SSRI) and

SSNRI antidepressants. The committee acknowledged that the 2009 guideline had

recommended analgesics other than NSAIDs for pain control. However, the 2009 guideline

indicated that the evidence on analgesia other than NSAIDs was 'sparse'. No further evidence

on these drugs was identified since the publication of the 2009 guideline. The committee for the

2018 guideline decided to make a research recommendation rather than a practice

recommendation on analgesia other than NSAIDs.

Impact

Current practice regarding the choice of analgesic is variable, with paracetamol, compound

analgesics and NSAIDs all commonly used to control symptoms. Choice of analgesic tends to

be based on individual effectiveness as well as the person's risk profile, tolerance, and side

effects. In particular, there are some groups of people for whom NSAIDs are unsuitable because

of contraindications, comorbidities or tolerability, and other people who are currently benefiting

from analgesic drugs other than NSAIDs. The current approach is likely to continue but there

may be an increase in prescribing of NSAIDs instead of other analgesic drugs for people with

newly diagnosed rheumatoid arthritis.

Full details of the evidence and the committee's discussion are in evidence review G:

Analgesics.



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Glossary

bridging treatment

glucocorticoids used for a short period of time when a person is starting a new DMARD,

intended to improve symptoms while waiting for the new DMARD to take effect (which can take

2 to 3 months)

CCP

cyclic citrullinated peptide

cDMARD

conventional disease-modifying anti-rheumatic drug: synthetic drugs that modify disease rather

than just alleviating symptoms; they include methotrexate, sulfasalazine, leflunomide and

hydroxychloroquine, but do not include biological DMARDs and targeted synthetic DMARDs

DAS28

disease activity score

DMARD

disease-modifying anti-rheumatic drug

DMARDs

disease-modifying anti-rheumatic drugs

HAQ

Health Assessment Questionnaire

NSAIDs

non-steroidal anti-inflammatory drugs



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palindromic

inflammatory arthritis that causes attacks of joint pain and swelling similar to rheumatoid

arthritis; between attacks the joints return to normal

PPI

proton pump inhibitor

step-down strategy

during treatment with 2 or more DMARDs, tapering and stopping at least 1 drug once disease is

adequately controlled

step-up strategy

additional DMARDs are added to DMARD monotherapy when disease is not adequately

controlled

synovitis

soft tissue joint swelling

TENS

transcutaneous electrical nerve stimulators

TNF

tumour necrosis factor

treat-to-target

a strategy that defines a treatment target (such as remission or low disease activity) and applies

tight control (for example, monthly visits and respective treatment adjustment) to reach this

target. The treatment strategy often follows a protocol for treatment adaptations depending on

the disease activity level and degree of response to treatment.



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Sources

Rheumatoid arthritis in adults: management (2018) NICE guideline NG100

Sarilumab for moderate to severe rheumatoid arthritis (2017) NICE technology appraisal

guidance 485

Tofacitinib for moderate to severe rheumatoid arthritis (2017) NICE technology appraisal

guidance 480

Baricitinib for moderate to severe rheumatoid arthritis (2017) NICE technology appraisal

guidance 466

Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha

inhibitor (2016) NICE technology appraisal guidance 415

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept

for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only

have failed (2016) NICE technology appraisal guidance 375

Tocilizumab for the treatment of rheumatoid arthritis (2012) NICE technology appraisal guidance

247

Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-

modifying anti-rheumatic drugs (2011) NICE technology appraisal guidance 225

Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid

arthritis after the failure of a TNF inhibitor (2010) NICE technology appraisal guidance 195

Your responsibility

Guidelines

The recommendations in this guideline represent the view of NICE, arrived at after careful

consideration of the evidence available. When exercising their judgement, professionals and

practitioners are expected to take this guideline fully into account, alongside the individual



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http://www.nice.org.uk/guidance/NG100















needs, preferences and values of their patients or the people using their service. It is not

mandatory to apply the recommendations, and the guideline does not override the responsibility

to make decisions appropriate to the circumstances of the individual, in consultation with them

and their families and carers or guardian.

Local commissioners and providers of healthcare have a responsibility to enable the guideline

to be applied when individual professionals and people using services wish to use it. They

should do so in the context of local and national priorities for funding and developing services,

and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to

advance equality of opportunity and to reduce health inequalities. Nothing in this guideline

should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable

health and care system and should assess and reduce the environmental impact of

implementing NICE recommendations wherever possible.

Technology appraisals

The recommendations in this interactive flowchart represent the view of NICE, arrived at after

careful consideration of the evidence available. When exercising their judgement, health

professionals are expected to take these recommendations fully into account, alongside the

individual needs, preferences and values of their patients. The application of the

recommendations in this interactive flowchart is at the discretion of health professionals and

their individual patients and do not override the responsibility of healthcare professionals to

make decisions appropriate to the circumstances of the individual patient, in consultation with

the patient and/or their carer or guardian.

Commissioners and/or providers have a responsibility to provide the funding required to enable

the recommendations to be applied when individual health professionals and their patients wish

to use it, in accordance with the NHS Constitution. They should do so in light of their duties to

have due regard to the need to eliminate unlawful discrimination, to advance equality of

opportunity and to reduce health inequalities.






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https://www.nice.org.uk/about/who-we-are/sustainability





Medical technologies guidance, diagnostics guidance and interventional proceduresguidance

The recommendations in this interactive flowchart represent the view of NICE, arrived at after

careful consideration of the evidence available. When exercising their judgement, healthcare

professionals are expected to take these recommendations fully into account. However, the

interactive flowchart does not override the individual responsibility of healthcare professionals to

make decisions appropriate to the circumstances of the individual patient, in consultation with

the patient and/or guardian or carer.

Commissioners and/or providers have a responsibility to implement the recommendations, in

their local context, in light of their duties to have due regard to the need to eliminate unlawful

discrimination, advance equality of opportunity, and foster good relations. Nothing in this

interactive flowchart should be interpreted in a way that would be inconsistent with compliance

with those duties.






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