Therapeutic Indications

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TNF-a antagonists are used in inflammatory conditions that are characterized by elevated TNF-a levels at the site of inflammation as well as systemically increased levels. For instance, increased TNF-expression has been detected in lesional skin of psoriatic patients (Johansen et al. 2006) or in the inflamed intestine in Crohn's disease patients (Raddatz et al. 2005). Thus, treatment of these inflammatory conditions with TNF- antagonists results in the binding, neutralization and elimination of surplus TNF-from the blood circulation and from sites of inflammation and translates into clinical benefit for the patient.

Infliximab is the only TNF- antagonist that is administered directly into the circulation by intravenous (i.v.) infusions; other TNF-a antagonists like eta-nercept and adalimumab are administered by subcutaneous (s.c.) injections. While subcutaneous injections maybe more convenient to the patient, subcutaneously administered drugs have to be absorbed from the injection site into the circulation before they can reach sites of inflammation and can become active. Thus, based on the different routes of administration, TNF-a antagonists present with different pharmacokinetics characterized by either a more even steady-state concentration of the subcutaneous drugs adalimumab or etaner-cept, or a serum profile characterized by peaks and troughs as for infliximab.

The presence of peak concentrations of TNF-a antagonist in the serum following infusions raises concern about the increased susceptibility of patients to infections by eliminating TNF- below a perceived safety window for an undefined time. However, accumulated data from registries that follow patients for extended period of times do not show differences in the infection rates between subjects receiving TNF-a blockers by either s.c. or i.v. administration (Wolfe et al. 2006). Rather, increased rates of serious infections appear to be linked to elevated susceptibility of patients due to their disease (Askling et al. 2005) or concomitant medications (Wolfe et al. 2006; Westhovens et al. 2006; Lichtenstein et al. 2006). In contrast, high concentrations of TNF-a antagonist in serum and peripheral tissue following administration might provide the opportunity for a rapid clinical response. Indeed, a clinical response to infliximab treatment was detected as early as 2 weeks following the first infusion in patients suffering from rheumatoid arthritis, Crohn's disease and ulcerative colitis (Maini et al. 1999; Rutgeerts et al. 2005; Targan et al. 1997; Kavanaugh et al. 2000).

Infliximab is currently (2006) approved for the treatment of six chronic inflammatory conditions:

1. For the reduction of signs and symptoms as well as improvement in physical function in patients with rheumatoid arthritis (RA)

2. For severe and active Crohn's disease in patients who do not respond to corticosteroid or immunosuppressant therapy or those with fistulating, active Crohn's disease

3. For ulcerative colitis in patients who do not respond to conventional therapy

4. For ankylosing spondylitis in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy

5. For active and progressive psoriatic arthritis in combination with methotrexate

6. For moderate to severe plaque psoriasis in patients who are intolerant to other systemic therapies

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