Agents targeting proinflammatory or immunomodulatory cytokines

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3.3.1. Anti-tumour necrosis factor-a Tumour necrosis factor-a (TNF-a) is a homo-trimeric protein, which exists in both transmembrane and soluble forms, the latter resulting from proteolytic cleavage and release (Schottelius et al., 2004). It has been recognized as a key molecule mediating inflammation in immunologically mediated diseases such as RA, Crohn's disease, and psoriasis. Several different agents that neutralize the proinflammatory cytokine TNF-a such as a humanized antibody (infliximab), a fully human antibody (adalimumab), a protein containing the TNF-a receptor (p75) TNF-aRII fused with a humanized immunoglobulin fragment (etanercept), a fully human (p55) TNF-aRI (onercept), and pegy-lated anti-TNF's (CDP870, certolizumab) are available or are currently being developed for the treatment of inflammatory diseases (Smolen and Steiner, 2003; Braun and Sieper, 2003b; Schottelius et al., 2004; Feldmann and Steinman, 2005). In addition to approved indications such as RA, psoriatic arthritis ankylosing spondylitis, and Crohn's disease, anti-TNF-a strategies proved to be extremely effective for the treatment of psoriasis (Mease et al., 2000; Mahadevan and Sandborn, 2001; Iyer et al., 2002; Gottlieb et al., 2003; Braun and Sieper, 2003b; Imperato et al., 2004; Numerof et al., 2005; Tobin and Kirby, 2005). Accordingly, etanercept recently has been approved for the treatment of psoriasis and approval for infliximab will follow in the near future.

Etanercept (Enbrel) is a fusion protein consisting of two TNF receptors fused to the Fc portion of human IgG antibody, which binds to TNF-a resulting in a decrease of active soluble TNF-a (Goffe and Cather, 2003). Etanercept has been used in more than 210,000 patients over the past 6 years for the treatment of psoriatic arthritis, anky-losing spondylitis, juvenile and adult RA, and psoriasis (Saini et al., 2005). According to clinical trials, etanercept also was highly efficacious in plaque type psoriasis resulting in 59% improvement in the psoriasis activity and severity index (PASI) score. Adverse events and infections were comparable to placebo. Discontinuation of eta-nercept was not associated with rebound (Papp et al., 2005; Papp, 2004; Gottlieb, 2004; Mease, 2004). There is also preliminary evidence that patients with dermatomyositis/polymyositis may profit from therapy with etanercept. In a pilot study of four patients with polymyositis refractory to conventional therapy, etanercept reduced the serum levels of creatinine phosphokinase and markedly improved clinical signs (Saadeyh, 2000). In a recent case report, etanercept also significantly reduced disease activity of a patient with pemphigus vulgaris during a 16 wk treatment (Lin et al., 2005). In contrast, etanercept (50mg/ wk) was not effective in an open-label study of 17 patients with moderate to severe alopecia areata (Strober et al., 2005) confirming an anectodal report of a patient with RA receiving etanercept and in whom alopecia areata recurred (Posten and Swan, 2005). Moreover, a pilot study with etanercept in 15 patients with primary Sjogren's syndrome failed to demonstrate any effects on sicc symptoms, glandular functions, and histologic findings (Zandbelt et al., 2004).

Infliximab (Remicade) is a humanized murine antibody targeting TNF-a which is indicated for the treatment of RA, psoriatic arthritis, and Crohn's disease, with more than 500,000 patients having been treated worldwide (Schottelius et al., 2004; Braun and Sieper, 2003a). Treatment of psoriasis with infliximab (5 mg/kg) resulted in a rapid (2-4 wk) and significant improvement of plaque type psoriasis. Up to 80% of the patients with severe psoriasis experienced a 75% improvement in the PASI score. However, relapses often occur in 6-8 wk after the last infusion. Infliximab may only need to be administered intravenously once in every 2-3 months for maintenance after induction. Nail psoriasis also responded to in-fliximab as shown by a study of 25 plaque-type and arthropathic patients with a nail psoriasis severity index (NAPSI) of> 14. After 22 weeks, complete clinical remission was achieved in all patients, which lasted for the subsequent follow-up time of 12 wk (Bianchi et al., 2005). In patients with psoriasis, infliximab monotherapy so far did not cause severe side effects. Due to the lack of adverse effects on liver function tests, infliximab may also be suitable in special clinical conditions, i.e. in patients with psoriasis and liver cirrhosis (Lehnen et al., 2005). However, adverse events such as mycobacterial infections, anaphylactic reactions, and autoimmune diseases have to be considered. Therefore, therapy guidelines developed for patients with RA have to be observed strictly (Gottlieb et al., 2002, 2003, 2004a; Winterfield and

Menter, 2004; Antoni et al., 2005). Similarly to etanercept, infiximab lacked any effect in a multi-centre randomized double-blinded study on 103 patients with primary Sjogren's syndrome (Mariette et al., 2004). Further studies will have to confirm the observed beneficial effect of infliximab on der-matomyositis/polymyositis as reported in two case reports (Hengstman et al., 2003; Labioche et al., 2004) as well as on severe pemphigus vulgaris as reported in one case (Pardo et al., 2005).

Adalimumab (Humira1) is a fully human monoclonal antibody, which specifically binds to TNF-a, blocking its interaction with the p55 and p75 cell surface TNF receptors (Bain and Brazil, 2003; Schottelius et al., 2004). Adalimumab was shown to be an effective treatment in RA either as mono-therapy or in combination with other disease-modifying antirheumatic drugs (Furst et al., 2003; Keystone and Haraoui, 2004). Adalimumab was further reported to be effective in treating refractory RA associated leg ulceration (Hirche et al., 2005). In a recent phase II clinical trial ad-alimumab was also effective in the treatment of moderate to severe psoriasis. At week 12, PASI 75 was achieved in 53% of patients in the low dose group, 80% in the high dose group, and 4% in the placebo group (Scheinfeld, 2004a; Chew et al., 2004). Adalimumab was well tolerated in this group of patients, and there were no new safety concerns identified in psoriasis patients when compared to the RA population (Scheinfeld, 2004a; Patel and Gordon, 2004). Although rare overall, it should be noted that under therapy with all the above anti-TNF strategies, side effects have been reported. In some cases, the development of lymphomas, mostly of the non-Hodgkin type with sometimes aggressive behaviour, have been associated with the use of anti-TNF-a therapy (Scheinfeld, 2004b).

The experience of using anti-TNF strategies for the treatment of LE are limited and have to be considered very carefully because of their potential to induce autoantibodies, which may cause exacerbation of the disease (Debandt et al., 2003; Eriksson et al., 2005; De Bandt et al., 2005). Of note, 10-16% of patients treated with infliximab developed de novo anti-ds DNA antibodies (Charles et al., 2000) and infliximab-induced cutaneous LE has been reported (High et al., 2005). However, one patient with RA and with subacute cutaneous LE was reported to be treated with etanercept, which resulted in a significant improvement of the previous therapy-resistant skin lesions within 15 days. After 6 months, the RA remained improved, there were no signs of active lupus, antinuclear antibodies were stable and no anti-ds DNA antibodies were present (Fautrel et al., 2002). Recently, in an open-label study, 6 patients with SLE (four with nephritis and three with arthritis refractory to other therapies) were treated with infliximab in addition to other immunosuppressive drugs (azathioprine or metho-trexate). Levels of antibodies to ds DNA and cardiolipin increased in four patients. However, the disease activity decreased and all the three patients with joint involvement experienced remission of arthritis. In the four patients with lupus nephritis, proteinuria decreased significantly (Aringer et al., 2004). Further controlled clinical trials ultimately will reveal the role of anti-TNF-a strategies in the treatment of LE.

3.3.2. Interleukin-1 receptor antagonist Targeting IL-1 represents a further promising approach for the treatment of inflammatory diseases. Accordingly, a recombinant human IL-1 receptor antagonist (anakinra) is currently being investigated for its efficacy in patients with RA (Schiff, 2000; Dinarello, 2004). Recently, the efficacy of anakinra in patients with SLE with joint involvement was reported. Treatment with ana-kinra resulted in a clinical as well as serological improvement and was safe and well tolerated (Moosig et al., 2004; Ostendorf et al., 2005).

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