DMARDs in Development

Drugs in
development for Rheumatoid Arthritis

Used here with permission


Disease-modifying anti-rheumatic drugs
(DMARDs) make up a large family of drugs used to treat rheumatoid
arthritis (RA). In order to be classified as a DMARD, a drug must be
shown to improve the symptoms of RA for at least one year and must act
in a different way than corticosteroids or non-steroidal
anti-inflammatory drugs (NSAIDs). DMARDs improve joint function and,
since they work by different processes than NSAIDs, they generally are
prescribed in combination with NSAIDs.

Until recently, little was known about
how these drugs work to alleviate the symptoms of RA. However, we now
have a better understanding of the biology of RA and some insight into
how these drugs work. As a result, a new generation of DMARDs is being
developed that are more effective and have fewer side effects.�

Experimental DMARDs can be organized
into six categories:�

  1. Anti-metabolites���
    Cytokine inhibitors��
    Protease inhibitors���
    Chemotaxis inhibitors��
    Complement inhibitors���

1) Anti-metabolites

Anti-metabolite DMARDs work by blocking
various metabolic steps required to make DNA or other important
molecules involved in building new cells. When immune cells are
activated to attack the joints in RA patients, the immune cells undergo
massive growth. Thus the effect of anti-metabolite DMARDs is to block
DNA production and cell growth in immune cells. However, since DMARDs
inhibit DNA production in all cells, not just immune cells, these drugs
are associated with serious side effects. The best known among this
group of drugs is methotrexate.�

The following drugs are
anti-metabolites in development:

Pentostatin injection�

2) Cytokine inhibitors

Cytokines are a group of proteins that
regulate the immune system’s activity. In general, cytokines can either
stimulate or stifle the immune response. Two important cytokines, Tumor
Necrosis Factor (TNF)-alpha and Interleukin-1 (IL-1), help orchestrate
the active phases of RA. Interestingly, these cytokines are found in the
joints of all RA patients. Research aimed at inhibiting the activity of
these cytokines has resulted in a number of promising drugs.�

The following drugs are cytokine
inhibitors in development:

EF-5, Diacerein, IGF-1, IL-1 Hy1 and IL-1Hy2, ICE Inhibitors, VX-740,
D2E7, IL-1ra, KB-R7785, CDP870, Teva TNF-Alpha Inhibitor, and Scios
P38-Kinase Inhibitors.�

3) Chemotaxis inhibitors

Chemotaxis inhibitors are DMARDs that
work by interfering with the chemical signals that attract inflammatory
cells to joints, thereby limiting the damaging effects they can cause.
If inflammatory cells are prevented from detecting these chemical
signals they will be less likely to migrate to and damage the joints.
Although still in the early stages of development, chemotaxis inhibitors
will hopefully play a role in the treatment of RA.�

The following drugs are chemotaxis
inhibitors in development:

CCR1 antagonist
CXCR3 Antagonist

4) Complement inhibitors

Complement inhibitors are a class of
DMARDs that interfere with the complement system, a key component of the
body’s immune defenses. The complement system consists of proteins that
interact through a cascade of complex reactions, the final product of
which can destroy bacteria and foreign cells. During these complex
reactions, small proteins are generated that have inflammatory effects
on blood vessels. These small complement proteins also recruit immune
cells to the joints of the RA patient, thereby contributing to the
inflammatory process. Activation and progression of this complement
cascade normally proceeds in a tightly regulated fashion. When this
process proceeds without the normal level of regulation, it may result
in the destruction of healthy cells and may also contribute to ongoing
inflammation. Although still in the early stages of development, drugs
directed against various components of the complement system may play a
role in the reduction of damage to the joints and other tissues of RA

The following�drug�is a
complement inhibitor in development:


6) Others�

This subset includes DMARDs that are in
development and have mechanisms of action that are diverse and
incompletely understood.�

The following drugs are
miscellaneous DMARDs: