Clinical Effects of IL10 Therapy in Psoriasis

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The powerful immunomodulatory properties of IL-10 and the promising results from IL-10 delivery on the course of several inflammatory diseases in experimental models induced the interest on clinical application of recombinant human (rh) IL-10 (ilodecakin / Tenovil; Schering-Plough Corp., USA) After promising data from phase 1 trials in was used in several indications including in psoriasis. The first administration of human recombined IL-10 in human was performed in 1995.9 Overall, these studies showed that IL-10 is well tolerated without serious side effects at doses up to 25 Mg/kg; mild to moderate flu-like symptoms were observed in a fraction of recipients at doses up to 100 Mg/kg.10 Therapeutic effects of IL-10 in psoriatic patients has been studied in 7 trials so far (Table 2).

Figure 2. Clinical effects of short course IL-10 therapy in established psoriasis.11 Example of a patient showing good response towards IL-10 therapy. Typical skin lesions before (A), during (B - day 15) and at the end of therapy (C- day 50) are shown. The patient received IL-10 injections in a dosage of 20 [ig/kg 3 times per week. © American Medical Association.

Figure 2. Clinical effects of short course IL-10 therapy in established psoriasis.11 Example of a patient showing good response towards IL-10 therapy. Typical skin lesions before (A), during (B - day 15) and at the end of therapy (C- day 50) are shown. The patient received IL-10 injections in a dosage of 20 [ig/kg 3 times per week. © American Medical Association.

Table 2. Clinical effects of IL-10 therapy in psoriasis27

Study

Design, Patients and Interventions Outcome and Remarks

Ref.

Pilot study in exacerbated psoriasis vulgaris

Pilot study in exacerbated psoriasis vulgaris

Phase II in exacerbated psoriasis vulgaris

Phase II in exacerbated psoriasis vulgaris

Open label, not placebo controlled; 3 patients with moderate to severe psoriasis; 8 ^g/kg/d s.c. over a 24 day period

Open-label; not placebo controlled; 10 patients with moderate to severe psoriasis: 4 |ig/kg/d s.c. over 42 days

Open-label; not placebo controlled; 10 patients with moderate to severe psoriasis; 8 |ig/kg daily (n=5) or 20 |ig/kg three times per week (n=5) s.c. over 49 days

Open-label, not placebo-controlled; 15 patients with moderate to severe disease; 4 |ig/kg/d s.c. over 42 days

Safe, clinical and histological confirmed improvement

Safe, good to moderate response, 12 histological confirmed; significant mean decrease in PASI by 40% after 3 weeks and 68% after 6 weeks. These patients are a subgroup of the study Reich et al, 2001 (see below).

Safe, good to moderate response, 11 histological confirmed; significant mean decrease in PASI by 55% after 7 weeks

Safe, good—moderate response 13 histological confirmed; 14 patients evaluated, mean decrease in PASI by 50% after 4 weeks and 59% after 6 weeks.

Phase II in psoriatic arthritis

Phase II in exacerbated psoriasis vulgaris

Placebo-controlled, double-blind; 29 patients with psoriatic arthritis, dose-escalating with 1, 5, or 10 |ig/kg s.c. daily for 28 days

Well tolerated, significant clinical improvement in skin (> 30% PASI reduction: 50% in IL10 group (10 |ig/kg ) vs 10% in placebo after 4 weeks. No decrease in articular disease activity.

Randomized, double-blind, placebo Modest trend towards improvement 14 controlled; 28 patients with moderate after 6 and 8 weeks (mean decrease to severe psoriasis; 20 |ig/kg three times per week for 12 weeks in PASI by 31% and 35% in IL10 group versus 7% and 13% in placebo group, respectively), but no significant difference at week 12 (17% vs 13% in placebo group).

Phase II in psoriasis vulgaris in remission

Placebo-controlled, double-blind; 17 patients with moderate to severe psoriasis in remission; 10 |ig/kg; IL-10 (n=7) or placebo (n=10) 3 x week for 4 month

Well tolerated; 90% relapse in the placebo group versus 28% in the IL-10 treated group; Significant prolongation of relapse-free interval (101 days vs 66 in placebo).

In our pilot trial starting in 1997, daily injections of 8 ^g rhIL-10 /kg body weight directly under a psoriatic plaque over a 24 day period led to complete clearance of the plaque in one of two patients.5 Moreover, some systemic antipsoriatic effects were observed in all 3 patients treated in this pilot trial (subcutaneous injections under nonlesional skin in the third patient).

In a second trial (open-label phase II), ten psoriatic patients received subcutaneously rhIL-10 over a 7 week period in a dosage of 8 ^g/kg daily (n=5) or 20 ^g/kg three times per week (n=5), respectively.11 Patients were followed up for an additional 7 weeks. The treatment was well tolerated. We found antipsoriatic effects in 9 out of 10 patients resulting in a significant decrease of the psoriasis area and severity index (PASI) by 55.3 ± 11.5% (mean ± SEM, p<0.02). The antipsoriatic effect was confirmed by histological examination. Heterogeneity in the effectiveness was found among the patients, but seemed to be independent of the dosage regime11

Similar clinical effectiveness of IL-10 application has been reported by Reich et al.12 In this open-label phase II trial ten patients were treated subcutaneously with 4 ^g/kg rhIL-10 daily. The mean of the disease activity score PASI decreased by 67.9% after 6 weeks of treatment and was associated with improvement of histological parameters.13 The clinical response was associated with a significant decrease of cutaneous cell infiltration and the lesional expression of type1 cytokines (IFNy, TNF), IL-17 IL-8, and IL-8 receptor CXCR2. There was some evidence that genetic factors are involved in the response to IL-10.13

In a more recent study14 28 patients with moderate-to-severe psoriasis received rhIL-10 (20 ^g/kg) or placebo subcutaneously 3 times weekly for 12 weeks in a randomized, double-blind manner. Remarkably, treatment with rhIL-10 resulted in only temporary clinical improvement after 6 and 8 weeks, despite sustained systemic decreases in proinflammatory and type 1 cytokine production.

The effect of IL-10 in psoriatic arthritis patients has been investigated by McInnnes and coworkers. IL-10 was given sc for 28 consecutive days in a double blind, placebo-controlled study including 29 patients (0, 1, 5, or 10 ^g/kg). Modest, but significant clinical improvement in skin, but not articular disease activity scores with only minor adverse effects was ob-served.15

More recently, we investigated the effects of long-term IL-10 application on the immune system and duration of psoriasis remission.16 We performed a placebo-controlled, double-blind, phase II trial using IL-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either IL-10 (10 ^g/kg body weight; n=7) or placebo (n=10) 3 times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only 2 out of 7 patients (28.6%) relapsed in the IL-10-treated group. Kaplan Meier analysis revealed a significantly lower relapse incidence in the IL-10 than in the placebo group (p=0.02). The mean relapse-free interval time was 101.6 ± 12.6 days in the IL-10 group in comparison to 66.4 ± 10.4 days in the placebo group (Fig. 3).

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