Intervention with Pleiotropic Cytokine Pathways

One of the major breakthroughs in the development of efficacious medicines against various autoimmune diseases including rheumatoid arthritis and Crohn's disease (CD) has been the introduction of the anti-TNF-a principle (Taylor 2007; Salfeld and Kupper 2007). One of the key mediators of autoimmune inflammation is TNF-a, a multipotent cytokine occurring both in a soluble and a non-soluble, membrane-bound form. Produced mainly by macrophages and T cells, TNF-induces a variety of further cytokines, resulting in a pleiotropic biological role in inflammation, host defence including mycobacteria, and cancer immunity (Beutler 1999). With the introduction of TNF-a inhibitors, the therapeutic arsenal against RA and other autoimmune diseases was amended by a potent new mechanism of action. Three drugs are licensed, two monoclonal antibodies (infliximab, Remicade, and adalimu-mab, Humira) and one fusion protein consisting of the extracellular portion of the p75 TNF receptor fused to the Fc part of human IgG1 (etanercept, Enbrel). Remi cade was the first monoclonal antibody against TNF-a to be licensed in Europe, and therefore a relatively large safety database exists for this product. Remicade was first licensed in the EU for the treatment of severe, active Crohn's disease under "exceptional circumstances" (European Medicines Agency 2006a) due to promising efficacy in this frequently severe autoimmune disease. Remicade was licensed for treatment of patients who have not responded despite a full and adequate course of conventional treatment such as a corticosteroid and/or an immunosuppressant. However, after marketing authorization in this second line setting (i.e. requiring an immunosuppressor OR corticosteroids), the "efficacy" of Remicade became apparent also in a negative sense, since due to the strong inhibition of TNF- serious adverse events were also observed, such as reactivation of tuberculosis (TB), severe infections, and sepsis. Occurrence of serious infections is the key safety problem. Data suggest that TNF- plays a physiological role in the formation and maintenance of granulomas, a host defence mechanism against intracellular pathogens that cannot be killed by other mechanisms (e.g. mycobacteria) (Wallis and Ehlers 2005). Treatment with TNF-a inhibitors apparently leads to delayed formation of these granulomas or the disruption of existing ones, resulting in reduced or even abolished host defence against certain pathogens like mycobacteria. Accordingly, cases of tuberculosis reactivation and other opportunistic infections have been reported in the post-marketing setting. Such reports have also been reported in Germany, as illustrated in the reports in 2004 of opportunistic infections to the competent national authority responsible for these kinds of products, the Paul-Ehrlich Institut (Table 16.1). These data from the reporting period of 2004 are representative results. A recent report in the literature describes a clinical case of a patient who developed widespread pulmonal TB during long-term treatment with infliximab for ankylosing spondylitis despite a 9-month isoniazide prophylaxis, showing a delayed response even to a five-drug anti-tuberculosis treatment (Vlachaki et al. 2005). Cases of patients like this, which are very difficult to treat, illustrate that the use of biologics like Remicade needs to be thoroughly considered on a case-by-case basis. Based on the observations on serious infections and also other safety issues in the time after marketing authorisation, an expert panel had convened at the European Agency for the Evaluation of Medicines (EMEA), and in early 2002

Table 16.1. Opportunistic infections with infliximab (Remica-de) during February to August 2004 reported to the Paul-Ehrlich Institut, Germany

Pathogen

No. of reports

Deaths

Crohn's

RA

Othe

Pneumocystosis

13

2

0

11

2

Atypical mycobacteri

a 8

0

1

5

2

TB

92

11

13

55

24

Histoplasmosis

8

3

1

7

0

Listeriosis

3

0

1

1

1

Aspergillosis

2

0

1

1

0

Coccidioidomycosis

15

2

0

14

1

CMV

14

6

3

7

4

Systemic candidiasis

9

4

6

1

2

Blastomycosis

2

1

1

0

1

Toxoplasmosis

1

0

0

1

0

Nocardia

5

0

2

1

2

Herpes

25

1

6

18

1

Total

200

50

35

122

39

the indication for the treatment of CD was restricted. This was implemented by the EMEA's scientific committee, the Committee for Proprietary Medicinal Products (CPMP, now CHMP, see below), by an urgent safety restriction (European Medicines Agency 2006a). The resulting indication was a restriction on patients not responding to a full and adequate course of treatment with a corticosteroid AND an immunosuppressant (instead of "and/or"), resulting in a restriction to a third line indication. Narrowing the patient population to a more restricted subset is a strong regulatory measure, and one of the regulatory principles intended to ensure safe use of medicines only for patients where the benefits clearly outweigh the risks. To further enhance patient safety and also awareness both of patients and prescribers, a patient alert card was introduced in 2002, which has proven to represent a powerful tool for this purpose. Meamwhile, the indication for Remicade in the treatment of Crohn's disease has been changed back to a second line indication, based on a more solid database that has emerged over the years.

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