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Therapeutic strategies for rheumatoid arthritis

Key Points

  • Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease that affects 0.5–1% of the population in the industrialized world and commonly leads to significant disability and consequently a reduction in quality of life.

  • Drug therapy for RA rests on two bases: symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). Whereas NSAIDs do not interfere with the underlying immuno-inflammatory events or retard joint destruction, DMARDs, the focus of this review, 'modify' the disease process in all these respects.

  • DMARDs are divided into small-molecule drugs and biological therapies. Approved agents, such as the small molecules methotrexate and leflunomide, and biological therapies, such as tumour-necrosis-factor (TNF) blockers and IL-1 blockers, are briefly reviewed, before considering approaches that could lead to novel agents.

  • Most new candidate small-molecule DMARDs are enzyme inhibitors, which target either secreted enzymes involved in tissue destruction, such as matrix metalloproteinases, enzymes liberating active cytokines from their precursor or membrane-associated forms, or kinases of various signal transduction cascades leading to the activation of transcription factors.

  • Potential approaches to developing novel biological agents that are discussed include targeting TNF, other proinflammatory cytokines and lymphokines; blocking chemokines and angiogenesis; anti-inflammatory cytokines; targeting T cells; targeting B cells and complement; targeting adhesion molecules; targeting Toll-like receptors; and targeting osteoclasts.

Abstract

Recent years have seen considerable advances in our understanding of both the clinical and basic-research aspects of rheumatoid arthritis. Clinical progress has come from a better recognition of the natural history of the disease, the development and validation of outcome measures for clinical trials and, consequently, innovative trial designs. In parallel, basic research has provided clues to the pathogenic events underlying rheumatoid arthritis, and advances in biotechnology have facilitated the development of new classes of therapeutics. Here, we summarize the fruits of these advances: innovative approaches to the use of existing, traditional disease-modifying antirheumatic drugs; novel agents approved very recently; and further avenues that are presently under investigation or which are of more distant promise.

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Figure 1: Schematic view of a normal joint and its changes in rheumatoid arthritis.
Figure 2: Schematic representation of events occurring in rheumatoid arthritis.
Figure 3: Data for recently approved antirheumatic agents.
Figure 4: Simplified overview of pathways involved in TNF-α and IL-1 signalling.
Figure 5: The inflammatory house of cards.

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Correspondence to Josef S. Smolen.

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DATABASES

LocusLink

αlB2

αvB3

BTK

CD40

CD40L

CD58

CD80

CD86

CTLA4

ICAM-1

ICE

IFN-γ

IL-1β

IL-1RI

IL-2

IL-2R

IL-2Rβ

IL-4

IL-5

IL-10

IL-12

IL-13

IL-15

IL-15R α-chain

IL-18

IκB

IKK-β

JNK

LCK

NF-κB

OPG

p38-MAPK

RANK

RANKL

TACE

TIMP-1

TNF-RI

VLA-4

Online Mendelian Inheritance in Man

Agammaglobulinaemia

Crohn's disease

FURTHER INFORMATION

Encyclopedia of Life Science

Rheumatoid arthritis

Glossary

NF-κB PROTEINS

NF-κB consists of homo- or heterodimers, and the most important of its components are the p50 and the p65 proteins.

TRANSCRIPTION FACTOR AP-1

The transcription factor AP-1 is composed of homo- or heterodimers of proteins that primarily belong to the JUN and FOS (but also other) families. Whereas JUN proteins can homodimerize, FOS proteins do not form stable homodimers but form heterodimers with JUN proteins. Once phosphorylated and dimerized, the AP-1 proteins gain enhanced DNA-binding capacity and modify transcriptional activity. AP-1 proteins are phosphorylated (and thereby activated) by the MAPK pathways.

CHEMOKINES

Chemokines are chemotactic cytokines and play a pathogenic role in various disorders, including inflammatory diseases. Many chemokine receptors, such as CCRs and CXCRs, have characteristic cell or tissue expression profiles.

INDUCTION THERAPY

Therapeutic approach that involves the initial application of an 'aggressive' regimen to, ideally, induce a remission-like state, followed by maintenance therapy with more traditional agents, such as MTX.

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Smolen, J., Steiner, G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2, 473–488 (2003). https://doi.org/10.1038/nrd1109

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