Rheumatoid Arthritis Treatment Options from University of Portsmouth

Treatment for Rheumatoid Arthritis

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Learning Objectives
On completion of this session you should be able to

• Understand the goals of RA treatment, including
  symptom relief and prevention of joint damage.
• Identify the main treatment options, including DMARDs,
  NSAIDs/COX inhibitors, and corticosteroids.
• Explain the importance of early treatment to slow disease
  progression and improve quality of life.

Goals of Rheumatoid Arthritis Treatment

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Goals of Treatment

• Reduce inflammation and pain
• Prevent joint damage and deformity
• Improve function and quality of life
• Slow or halt disease progression

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Conventional Synthetic DMARDs (csDMARDs)

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A. Disease-Modifying Anti-Rheumatic Drugs (DMARDs) (First-line)
Conventional Synthetic DMARDs
(csDMARDS)

• Methotrexate (MTX) - First-line drug, inhibits
  folate metabolism, reduces T-cell activation.
• Leflunomide - Inhibits pyrimidine synthesis,
  suppresses T-cell proliferation.
• Sulfasalazine - Anti-inflammatory, reduces
  cytokine production.
• Hydroxychloroquine - Modulates immune
  response, often combined with other DMARDs.
  Conventional synthetic DMARDs are the first-line
  treatment for Rheumatoid Arthritis, aiming to slow
  disease progression and prevent joint damage.
  Methotrexate (MTX) is the gold standard, inhibiting
  folate metabolism to reduce T-cell activation.
  Leflunomide blocks pyrimidine synthesis, suppressing
  T-cell proliferation.
  Sulfasalazine has anti-inflammatory effects and
  reduces cytokine production.
  ]
  Hydroxychloroquine modulates the immune
  response and is often combined with other DMARDs
  for enhanced effectiveness.
  ] These drugs work slowly but effectively to control RA
  and prevent long-term disability.

Biologic and Targeted Synthetic DMARDs

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A. Disease-Modifying Anti-Rheumatic Drugs (DMARDs) (First-line)
Biologic and targeted synthetic DMARDs offer more precise
treatment by targeting specific immune pathways in Rheumatoid
Arthritis.
TNF-a inhibitors like Infliximab, Adalimumab, and Etanercept
block TNF-a, a key driver of inflammation.
IL-6 inhibitors, such as Tocilizumab, reduce cytokine signaling and
inflammation.
> B-cell depleting therapy with Rituximab lowers antibody
production and immune activation.
> T-cell co-stimulation blockers, like Abatacept, prevent T-cell
activation, reducing immune response.
For patients who do not respond to biologics, we have targeted
synthetic DMARDs (tsDMARDs):
> Janus kinase (JAK) inhibitors, such as Tofacitinib and Baricitinib,
block intracellular signaling pathways to reduce immune activation.
These advanced therapies are used when conventional DMARDS
fail, offering more targeted and effective disease control.
Biologic DMARDs (bDMARDs) (Targeted
Therapy)

• TNF-a Inhibitors - e.g., Infliximab,
  Adalimumab, Etanercept.
• IL-6 Inhibitors - e.g., Tocilizumab.
• B-cell Depleting Therapy - Rituximab.
• T-cell Co-stimulation Blockers -
  Abatacept.
  Targeted Synthetic DMARDs (tsDMARDs)
• Janus kinase (JAK) inhibitors - e.g.,
  Tofacitinib, Baricitinib.

Biologics: TNF-alpha Inhibitors

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Biologics; inhibitors of TNF-a, the new DMARDS
inflammation
TNFa
Activated Th1
-
Activated macrophages
Mouse challeged with antigen
Spleen Cells
Myeloma Cells
Fusion
Hybridomas
Culture in HAT Medium
Select for positive cells
Harvest monoclonal
antibodies
Macromolecule TNF Inhibitors
Chi meric
monoclonal
antibody
Human
monoclonal
antibody
Human recombinant
receptor/Fo fusion
protein
Fc
Infliximab
Adalimumab
Etanercept
Anakinra; an IL-1 receptor antagonist.

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The application of TNFa blockade to treat RA is a major success story. Animal models of disease
confirmed the predicted effect of targeting TNFa. Three biologic therapies designed to inhibit TNFa
are licensed. These include two monoclonal antibodies (mabs). One is infliximab (Remicade), which is
a chimeric human/mouse mab, having mouse Fab (Fragment antigen-binding) (mouse anti-human
TNFa) and human Fc (Fragment crystallizable) regions. The other, Adalimumab, is fully humanised.
The third biologic, is a fusion protein of the extracellular domain of the TNF a receptor with the
constant Fc domains of human IgG. They all have the ability to neutralise soluble TNFa and have
significant positive therapeutic effect in RA. Monoclonal antibodies are typically made by fusing
myeloma cells (immortal cancer cells) with the antibody-producing spleen cells from a mouse that has
been immunized with the desired human antigen.
❖
Early on, a major problem for the therapeutic use of monoclonal antibodies in medicine was that initial
methods used to produce them yielded mouse, not human antibodies. While structurally similar,
differences between the two were sufficient to invoke an immune response when mouse mabs were
injected into humans and resulted in their rapid removal from the blood, systemic inflammatory effects,
and the production of human anti-mouse mabs.
❖
In an effort to overcome this obstacle, approaches using recombinant DNA have been explored since
the late 1980s. In one approach, mouse DNA encoding the binding portion of a monoclonal antibody
was merged with human antibody-producing DNA in living cells, and the expression of this chimeric
DNA through cell-culture yielded half-mouse, half-human monoclonal antibody. The descriptive term
'humanised' monoclonal antibody reflects the amount of human DNA used in the recombinant process.
❖
Anakinra is an IL-1 receptor antagonist, a competitive inhibitor of IL-1 binding to its receptor,
preventing IL-1 mediated inflammation. Biologics are given together with DMARDs.

Immunosuppressants and DMARD Mechanisms

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Immunosuppressants;
methotrexate
Glucocorticoids
T
CD4
Tho
Activated
Th1 cell
Th17 cell
Macrophage
Anti-IL 1
agents
IL-1
TNF-Q
Anti-TNF
agents
Osteoclast
Fibroblast
Release of other
inflammatory
cytokines and
chemokines
Metalloproteinases
(e.g. collagenase)
Influx of
inflammatory cells
Erosion of cartilage and bone
JOINT DAMAGE
DMARDS:
Sulfasalazine, penicillamine, gold compounds,
chloroquine
Mechanism of
action:
not clearly knownDisease-modifying anti-rheumatic drugs (DMARDs) and NSAIDs are most frequently used in RA.
DMARDs relieve symptoms, (the number of swollen and painful joints and levels of rheumatoid factor)
and may halt or reverse the disease process. The clinical effect of DMARDs may take months, but can
reduce the use of NSAIDs and corticosteroids. Their mechanism of action is not precisely known.
Sulfasalazine; First choice DMARD. A combination of sulfonamide and a salicylate that can produce
remission in RA. It is broken down in the gut to release 5-amino salicylic acid, which can scavenge
reactive free radicals produced by neutrophils that contribute to tissue damage.
Gold compounds, such as sodium aurothiomalate (intramuscular) and auranofin (oral) accumulate in
synovial cells in inflamed joints and in other tissues and are thought to inhibit cytokine synthesis.
Penicillamine, a metal chelator, decreases immune response and IL-1 synthesis. Effective in 75% of
patients.
Hydroxychloroquine, an anti-malarial, last choice for therapy, effective in 50% of patients. Multiple
effects, inhibits T and B-cell activation, and restores Treg/Th17 balance. Immunosuppressants;
Methotrexate is a folic acid antagonist with cytotoxic and immunosuppresant activity. Inhibits purine and
DNA synthesis and T-cell proliferation.
Immunosuppresant drugs that act during the induction of the immune response, and inhibit IL-2
synthesis and T-cell proliferation include ciclosporin and tacrolimus, and steroids. They inhibit cytokine
synthesis by other cells (corticosteroids) and have anti-inflammatory effects.
Azathioprine interferes with purine synthesis and is cytotoxic to dividing cells, and inhibits T-cell
proliferation during induction of immune response. Leflunomide has specific inhibitory effects on
activated T-cells.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) & COX Inhibitors

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B. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs & COX Inhibitors)

• COX inhibitors are commonly used in
  Rheumatoid Arthritis for symptomatic relief by
  reducing pain, swelling, and stiffness.
• Non-selective COX inhibitors, like Ibuprofen,
  Naproxen, and Diclofenac, block both COX-1 and
  COX-2, but come with a higher risk of GI ulcers.
• Selective COX-2 inhibitors, such as Celecoxib and
  Etoricoxib, have a lower GI risk but an increased
  cardiovascular risk.
• While these drugs help manage symptoms, they
  do not slow disease progression and should be
  used alongside DMARDs for effective RA
  management.
  Examples: Ibuprofen, Naproxen, Diclofenac (Non-Selective
  COX Inhibitors); Celecoxib, Etoricoxib (Selective COX-2
  Inhibitors)
• Mechanism: Inhibits COX enzymes, reducing
  prostaglandin synthesis -> Decreases pain, swelling,
  and stiffness.
• Limitations:
  · Non-Selective COX Inhibitors (e.g., Ibuprofen, Naproxen) ->
  Increased GI ulcer risk.
  · Selective COX-2 Inhibitors (e.g., Celecoxib) -> Lower GI risk but
  increased cardiovascular risk.
• Used for: Symptomatic relief only (does not slow disease
  progression).

COX Inhibitors for RA Treatment

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COX inhibitors to treat RA
1) COX-1 is constitutively expressed in all cells. Inhibitors of COX-1 are
generally associated with unwanted side effects, especially in the gut.
1) COX-2 is induced in inflammatory cells when activated and responsible
for increased PGE2 in inflammatory disease including RA. Specific
inhibition of COX-2 reduces vasodilation, oedema and pain, although
with little effect on disease progression itself.
Drugs used in RA include celecoxib (Cox-2:COX-1 = 300:1). Effective
in RA but some concerns over prothrombotic cardiovascular side
effects. Rofecoxib (Cox-2:COX-1 = 1000:1), also known as Vioxx, was
withdrawn in 2004.

NSAID Side Effects and COX-2 Selectivity

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NSAIDs reduce the symptoms of RA but do not slow or reverse the disease
process, or alter the immunologic abnormalities.
❑
COX-1 is widely expressed and inhibitors of COX-1 are usually associated with side
effects in the gut as prostaglandins have a protective role in the gut. Prostaglandins
are present throughout the gastrointestinal (GI) tract and bring about various
actions, including the control of acid secretion, bicarbonate secretion, mucus
production, and mucosal blood flow.
❑
The aim is to preferentially target COX-2 to reduce the synthesis of PGE2.
❑
We saw in the last lecture that both chondrocytes and osteoblasts are activated by
IL-17 to release PGE2, which increases the damage to cartilage and bone and
limits the repair process.
❑
Cardiovascular side effects and increased numbers of heart attacks may be
associated by a parallel decrease in PGI2 (prostacyclin) with the use of COX2
inhibitors, since PGI2 is both a potent vasodilator and reduces platelet activation
and aggregation.
❑
This led to the withdrawal of Vioxx, and a decrease in the number of prescriptions
for celecoxib.