F E AT U R E F E AT U R E

BLOCKING THE IMMUNE SYSTEM TREATMENT PATHWAY

IN RHEUMATOID ARTHRITIS
Early targeted therapy to rapidly control disease activity in
rheumatoid arthritis (RA) is crucial to limiting long-term joint damage.
A range of drugs are approved by the National Institute for Health
and Care Excellence (NICE) for use within the NHS.
SMALL MOLECULES
Rheumatoid arthritis is caused by the immune system attacking the body. It afflicts Janus kinase (JAK) inhibitors block JAK enzymes,
around 1% of people in the UK and is now treated with a variety of biologic drugs that part of the signal transducer and activation of
transcription (STAT) pathway, which is used by
dampen the immune system in different ways. By Janna Lawrence. immune cells to respond to cytokines. 1 DIAGNOSIS
Person diagnosed with rheumatoid arthritis.
Baricitinib
Cytokine Macrophage
Toficitanib

Cytokine 2 INITIAL TREATMENT

DRUG TARGETS BONE receptor Prescribe a combination of methotrexate and one
Neutrophils and JAK other oral DMARD. DMARDs take several weeks
Oral disease-modifying anti-rheumatic MISTAKEN IDENTITY B cells produce macrophages release
JAK to work so a short course of steroids is usually
The cells prescribed while the DMARDs take effect.
drugs (DMARDs), the mainstay of In rheumatoid arthritis, a
infiltrate the antibodies like digesting enzymes,
flaw in the immune system rheumatoid Pro-inflammatory
rheumatoid arthritis treatment, were allows some B cells and joint and release cytokines recruit
which contribute to STAT
factor, which joint damage,
the first drugs available that affected T cells to recognise tissue molecules called
target the joint. and prime other including cartilage
SYMPTOM
cytokines. immune cells, Reduce doses CONTROL
the immune system. But over the in the joints as foreign. and bone erosion and to level that
past 15 years, a multitude of new
including thickening of the YES DISEASE CONTROL? NO Pain relief:
macrophages maintains
synovial membrane.
biologic therapies have hit the and neutrophils, disease control. Prescribe
paracetamol,
market, which target specific B CELL to attack the joint.
codeine or
parts of the immune system. Th17 compound
New small molecules are also The inflammatory analgesics, or
Cartilage 3 FIRST-LINE BIOLOGIC non-steroidal
Th CD4 +
in development that target auto-immune
process takes Prescribe a biologic in combination with methotrexate anti-inflammatory
intracellular immune signalling. place primarily in (e.g., adalimumab, etanercept, certolizumab pegol, infliximab, drugs (NSAIDs) and
the synovial golimumab, tocilizumab or abatacept). Use the least expensive cyclo-oxygenase
Neutrophil
membrane, but drug first, taking account of administration and drug costs and (COX)-2 inhibitors
Cytokines Macrophage Synovial fluid at the lowest
also in the patient access schemes. Anakinra is not approved by NICE.
Tumour necrosis factor (TNF) inhibitors Synovial membrane synovial fluid. effective dose for
IL17 the shortest
Other biologics Joint capsule possible period
Pipeline drugs CD20 TNF Reduce doses
Muscle of time.
to level that
IL1 maintains YES DISEASE CONTROL? NO Flare-ups:
IL6 disease control. Prescribe
Rituximab Anakinra

£4.8bn
short-term
Obinutuzumab Osteoclast Inhibits pro- glucocorticoids
inflammatory for flare-ups.
Bind to a receptor called CD20 Secukinumab cytokine
on the surface of B cells, IL-1.
leading to cell lysis and the Inhibits pro- The total cost of 4 SECOND-LINE BIOLOGIC
depletion of B cell levels. inflammatory If there is an inadequate response or intolerance to other
cytokine rheumatoid arthritis drugs, including at least one TNF inhibitor, prescribe rituximab
Abatacept IL-17. Digesting Cytokines cause the (RA) to the UK economy in combination with methotrexate. If rituximab is
enzymes normal balance of per year, estimated by contraindicated, prescribe another biologic that has not been
CD28 CD80/86 bone destruction and
Adalimumab tried (e.g., adalimumab, etanercept, infliximab or abatacept).
Certolizumab pegol
Tociluzumab replacement by The National Audit
JOINTS AFFECTED Etanercept osteoclasts to become Office. A total of
Th APC Sirukumab dysregulated, leading
Rheumatoid arthritis most Infliximab 690,000 people in the
commonly starts in the small joints Sarilumab to bone erosion.
Binds to a receptor called CD80 Golimumab UK have RA, costing the
of the hands and feet. Larger joints
or receptor CD86 on the surface Infliximab biosimilars:
Inhibit pro- YES DISEASE CONTROL? NO
inflammatory
can be affected later in the course
of antigen presenting cells (APCs), Inflectra and Remsima cytokine NHS approximately Reduce doses
of the disease. It affects both sides Consider
of the body symmetrically. which prevents APCs from
Inhibit the
IL-6. £560m per year. to level that referral for
activating T helper cells that maintains surgery.
pro-inflammatory disease control.
express receptor CD28.
cytokine tumour
necrosis factor
(TNF).

73%
70%

Efficacy: Formulation: 2013: INFLIXIMAB

51%

DRUG DEVELOPMENT Probability of 20% BIOSIMILAR

62%
Tablet
symptom improvement Injection 2000: INFLIXIMAB 2006: RITUXIMAB
Brand: Remsima
The first breakthrough in rheumatoid

43%
Infusion Brand: Mabthera Manufacturer: Napp
Brand: Remicade 2009: GOLIMUMAB
40%

Probability of 50% Manufacturer: Roche

arthritis treatment was methotrexate.

72%
27%

Average dose: 3mg/kg,

38%
symptom improvement Manufacturer: MSD Average dose: 1,000mg two weeks
Since then, numerous biologics have Brand: Simponi repeated after two weeks,
Average dose: 3mg/kg, repeated apart, repeated after six months Manufacturer: MSD then four weeks then
been approved by the European after two weeks, then four weeks, Year 1 cost (2016): £6,985 Average dose:
57%

then every eight weeks 2009: CERTOLIZUMAB PEGOL every eight weeks

49%
Medicines Agency for use in Year 1 cost (2016): £10,071
50mg once monthly Year 1 cost (2016): £9,064
combination with methotrexate. The 2003: ADALIMUMAB Year 1 cost (2016): £9,156 Brand: Cimzia
56%

prices are high but efficacy is good

2007: ABATACEPT Manufacturer: UCB
Brand: Humira
33%

1983: Average dose: 400mg every

73%
Brand: Orencia
69%

for patients who have failed on Manufacturer: AbbVie two weeks for three doses, then

64%
METHOTREXATE Manufacturer: BMS 2013: INFLIXIMAB
SC: 58%

Average dose:
IV: 56%

methotrexate and other oral 200mg every two weeks

32%

2000: ETANERCEPT 40mg every two weeks Average dose: 750mg

DMARDs alone. The first biosimilars
Brand: generic
Year 1 cost (2016): £9,155 intravenously every two weeks
Year 1 cost (2016): £10,368 BIOSIMILAR
Manufacturer: multiple
2009: TOCILUZUMAB
46%

Brand: Enbrel for three doses, then monthly Brand: Inflectra

were approved in 2013, introducing Average dose: 15mg weekly

43%
40%
Manufacturer: or 125mg subcutaneous Manufacturer: Hospira
SC: 34%
IV: 32%

more price competition to the Year 1 cost (2016): £43 Pfizer Brand: RoActerma
injection weekly Average dose: 3mg/kg,
Average dose: Manufacturer: Roche Efficacy data are from a network meta-analysis, except
biologics market. Year 1 cost (2016): repeated after two weeks,
25mg twice weekly Prices don’t include monitoring costs, Average dose: for rituximab, infliximab and the infliximab biosimilars,
VAT or patient access schemes. £12,701 (intravenous [IV]) which are response rates from single trials. then four weeks then
or 50mg once weekly 8mg/kg every four weeks
£16,632 (subcutaneous [SC]) every eight weeks
Year 1 cost (2016): £9,295 Year 1 cost (2016): £10,250
Year 1 cost (2016): £9,064

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