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Interleukin 10 Treatment of Psoriasis
Clinical Results of a Phase 2 Trial
Khusru Asadullah, MD;
Wolf-Dietrich Döcke, MD;
Merle Ebeling;
Markus Friedrich, MD;
Gudrun Belbe;
Heike Audring, MD;
Hans-Dieter Volk, MD;
Wolfram Sterry, MD
Arch Dermatol. 1999;135:187-192.
ABSTRACT
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Objective To determine the safety and clinical effects of interleukin 10 (IL-10) treatment of psoriasis.
Design and Methods In an open-label phase 2 trial, 10 patients with psoriasis subcutaneously received recombinant human IL-10 over a 7-week period in a dosage of 8 µg/kg daily (n=5) or 20 µg/kg 3 times per week (n=5). Patients were followed up for an additional 5 weeks.
Results The treatment was well tolerated. Antipsoriatic effects were found in all but 1 patient. A significant decrease of the psoriasis area and severity index by 55.3% ± 11.5% (mean ± SEM) was observed (P<.02). The antipsoriatic efficiency was confirmed by histological examination. Heterogeneity in the effectiveness was found among the patients, but seems to be independent of the dosage regimen. However, a tendency to a better response was found in the patients who received 20-µg/kg IL-10 3 times per week. Decreasing response in the delayed-type hypersensitivity reaction against recall antigens indicated immunosuppressive effects. Moderate effects on hematopoietic cells were observed.
Conclusions Our data suggest that IL-10 therapy for psoriasis is safe and possibly clinically effective. Consequently, its value in psoriasis and similar immune diseases should be further determined. Dose-finding, placebo-controlled, double-blind trials are necessary now.
INTRODUCTION
PSORIASIS IS a chronic relapsing cutaneous disorder characterized by inflammation and increased epidermal proliferation with a prevalence of 2% to 3% in the general population.1 It has been shown that T cells and cytokines are of major pathophysiological importance.2-6 These observations are supported by the beneficial effects of systemic administration of immunosuppressive drugs such as cyclosporine,7 tacrolimus (FK 506),8 and fumaric acid esters.9-10 However, these and other conventional therapies may cause severe side effects and/or may fail in certain patients. This indicates the demand for novel therapeutic strategies.
According to the predominant expression of interleukin (IL) 2 and interferon (IFN)– and the lack of IL-4 in skin lesions, psoriasis is believed to be characterized by a type 1 cytokine pattern.4-5 Moreover, the involvement of other proinflammatory cytokines such as IL-1, IL-6, IL-8, and tumor necrosis factor  has been demonstrated.11-13 In contrast, recent investigations showed that the cutaneous expression of the type 2 cytokine IL-10 is lower in psoriasis than in other inflammatory dermatoses.14-16
Several lines of evidence support our hypothesis that the IL-10 deficiency in psoriasis might be a central phenomenon10, 16-17: (1) Several effective antipsoriatic treatment modalities, eg, UV radiation, induce an increase of IL-10 production by several cell types. (2) Cyclic adenosine monophosphate–elevating drugs (eg, iloprost, pentoxifylline) up-regulate IL-10 expression. Interestingly, there are sporadic reports that these substances are effective in the treatment of psoriasis. (3) Inhibitors of the  -adrenergic receptor (eg, propranolol) or the cyclooxygenase (eg, indomethacin) may lead to exacerbation of psoriasis. These drugs diminish intracellular cyclic adenosine monophosphate formation, presumably associated with IL-10 decrease. (4) Direct support of a type 1 cytokine pattern by IFN- or IFN- application as well as IFN-–elevating drugs such as lithium are also known to provoke or to exacerbate psoriasis, and it is well established that IFN- inhibits IL-10 expression. (5) Pregnancy often leads to depression of type 1 cytokines, and the majority of psoriatic women who become pregnant experience an improvement in their disease activity (reviewed in Asadullah et al16).
Because of its considerable anti-inflammatory and immunosuppressive capacities, IL-10 became a candidate for the therapy of several immune diseases. Intravenous injection of IL-10 was well tolerated in a single dose up to 25 µg/kg in healthy volunteers.18 Moreover, the first clinical IL-10 application in patients with Crohn disease, another "type 1 disease," showed beneficial effects.19 The second clinical trial in which kidney transplant recipients were pretreated with IL-10 to reduce secretion of tumor necrosis factor following OKT-3 therapy was also effective and safe.20 To investigate the effect of IL-10 in psoriasis might be of particular importance, since it may serve as a model for hyperinflammatory autoimmune diseases. Moreover, in contrast to several other disorders such as Crohn disease, disease activity is clearly visible and therapeutic effects can be monitored easily.
Recently, we started to investigate the therapeutic effect of IL-10 in psoriatic patients.16 Daily injections of 8-µg/kg body weight of IL-10 directly under a psoriatic plaque over a 24-day period led to complete clearance in 1 of 2 patients. Moreover, some systemic antipsoriatic effects were observed in all 3 patients treated in this pilot trial. The immunosuppressive effects (decrease of monocytic HLA-DR expression, IL-12 plasma levels, and responsiveness to recall antigens) as well as a shift toward a type 2 cytokine pattern (increasing proportion of IL-4–, IL-5–, and IL-10–producing T cells and increase in IgE serum levels) that we found in the 3 patients might be the basis of the antipsoriatic activity of IL-10. Since these findings suggested that IL-10 treatment is safe and might be effective, we further investigated its antipsoriatic effect in this open-label prospective trial, comparing 2 different therapeutic regimens.
PATIENTS AND METHODS
PATIENTS
Ten patients with moderate or severe chronic plaque psoriasis, aged 20 to 54 years, were chosen for treatment with IL-10 and were divided into 2 groups receiving 2 different IL-10 therapeutic regimens: 8 µg/kg daily (3 men and 2 women; mean ± SEM age, 30.0 ± 4.3 years) and 20 µg/kg 3 times per week (4 men and 1 woman; mean ± SEM age, 37.6 ± 4.7 years). The mean ± SEM psoriasis area and severity index (PASI) score before therapy was 16.3 ± 2.2 for the 8-µg/kg daily group and 19.9 ± 5.9 for the 20-µg/kg thrice weekly group. No significant differences between the groups were found regarding PASI score before therapy, age, sex, or onset of the disease (P>.05, Mann-Whitney U test). There was no systemic antipsoriatic treatment, including methotrexate, cyclosporine, fumaric acid derivates, or phototherapy during the 7 weeks preceding the study and no treatment with any standard topical therapy for psoriasis other than with bland emollients during the 3 weeks preceding the study. The patients had no clinical evidence of infection 3 weeks prior to the study; no anti-DNA, anti–hepatitis B virus, anti–hepatitis C virus, or anti–human immunodeficiency virus antibodies; a platelet count of 100 x 109/L; and no history or presence of cancer. Pregnancy was also an exclusion criterion.
IL-10 APPLICATION PROTOCOL
Patients were randomized into 2 groups and received subcutaneous applications of recombinant human IL-10 (SCH 52000; Essex Pharma, Munich, Germany/Schering Plough Research Institute, Kenilworth, NJ) over a period of 49 days. One group received a daily dosage of IL-10, 8 µg/kg of body weight (5 patients), and the other group received IL-10, 20 µg/kg of body weight, 3 times per week (5 patients). These different application regimens resulted in a similar weekly dosage of IL-10 (56 vs 60 µg/kg). Interleukin 10 was injected in nonlesional subcutaneous tissue. After the treatment period (days 1-49), patients were observed for an additional 5 weeks (days 50-85). There was no systemic treatment other than with IL-10 and no topical treatment other than with bland emollients during the whole treatment and observation period.
The study was approved by the institutional review board of the medical faculty, and written informed consent was obtained from all patients.
CLINICAL AND HISTOLOGICAL INVESTIGATIONS
Clinical examination was performed at least once a week. Activity and severity of psoriasis were assessed from day -6 (6 days before therapy) up to 5 weeks after the end of therapy (day 85) by the PASI21 and photodocumentation. Laboratory investigations included the determination of transaminases, creatinine, urea, -amylase, hemoglobin, hematocrit, white blood cell count, differential blood count, thrombocyte count, glucose, and albumin. All patients were evaluated for adverse events by personal interview at each visit. An adverse event was defined as any change in the patient's baseline condition, which occurred during the course of the study, regardless of whether the event was related to treatment. Each event was graded to be mild, moderate, or severe.
Before (day -6), during (days 15 and 43), and 21 days after the end of treatment (day 71), delayed-type hypersensitivity (DTH) reaction was determined using the Multitest Mérieux test system (Institut Mérieux GmbH, Leimen, Germany). The DTH response to recall antigens reflects a type 1 cytokine-mediated immune reaction.22
Skin biopsy specimens (4 mm punch biopsies) were obtained 7 days before IL-10 therapy (day -6), on days 15 and 50 (first day after end of therapy), and on day 71 (3 weeks after end of therapy) for histological examination. The histological investigations included the evaluation of the main psoriatic parameters such as acanthosis, hyperkeratosis and parakeratosis, the mitotic activity of the epidermis, papillary edema, dilation and tortuosity of capillaries, and number of neutrophils in the dermis, stratum spinosum, and horny layer.
STATISTICAL ANALYSIS
Data are presented as mean ± SEM. Statistical analysis was performed using the Wilcoxon signed rank test for paired values and the Mann-Whitney U test for the comparison of groups. Differences were considered significant at P<.05.
RESULTS
ANTIPSORIATIC EFFECTS
Clinical effectiveness was found in all but 1 patient. A significant decrease of the overall PASI score was observed (Figure 1). This resulted more from a decrease of skin infiltration and squamation than from the decrease of the plaque area. The degree of the antipsoriatic effect, however, was heterogeneous. At the end of treatment (day 50), almost complete healing was reached in 3 patients (>90% reduction of initial PASI score) (Figure 2). In 6 other patients, the skin clearly improved during the treatment period by 35% to 65% (Figure 3). A good response was particularly seen in the patients receiving IL-10 three times per week ( Figure 1): a significant mean reduction of the PASI score by 65% (P<.05; day 50 vs day 1) was detected in this patient group, whereas it was less pronounced and nonsignificant (P=.08) in the patients receiving daily injections (45%). This resulted from 1 patient who continuously showed disease progression before, during, and after the treatment period. However, no significant differences in the PASI score were found between the 2 patient groups at any time. All patients reported the loss of skin itching. No rebound effect was observed in any patient during the immediate posttreatment period. However, a slight reincrease was detected in 4 of the 5 patients who received daily injections during the observation period. Similarly, 3 patients of the thrice-weekly group showed mild disease progression after cessation of the therapy ( Figure 1).
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Figure 1. Psoriasis area and severity index (PASI) score during interleukin 10 (IL-10) therapy. The PASI21 was determined in 10 patients with psoriasis undergoing 2 different regimens of subcutaneous IL-10 therapy for 49 days. Data are mean ± SEM. Asterisk indicates P<.05; dagger, P=.08 (Wilcoxon signed rank test vs day 1).
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Figure 2. Antipsoriatic effects in a patient. Typical skin lesions are shown before (A), during (B) (day 15), and at the end of interleukin 10 (IL-10) therapy (C) (day 50) in a patient who received IL-10, 20 µg/kg of body weight, 3 times per week. Almost complete healing was reached in this patient as in 2 other cases (>90% reduction of initial psoriasis area and severity index score at the end of therapy [day 50]).
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Figure 3. Antipsoriatic effects in a patient. Typical skin lesions are shown before (A), during (B) (day 15), and at the end of therapy (C) (day 50) in a patient who received interleukin 10, 8 µg/kg of body weight, daily. Clear improvement but no complete healing (between 35% and 65% reduction of initial psoriasis area and severity index score at the end of therapy [day 50]) was found in this patient as in 5 other cases.
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Histologically, a decrease in epidermal thickness, parakeratosis, Munro abscesses, and number of mitoses was observed, whereas the morphological characteristics of the papillary vessels were the same as before. The quantity of the infiltrate decreased. So, overall evaluation of the main psoriatic parameters clearly indicated decreasing disease activity with IL-10 therapy in 8 of 10 patients Table 1). There was no evidence of a different response between the groups. Figure 4 shows typical histological changes in 1 patient.
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Histological Parameters for Psoriatic Disease Activity During Interleukin 10 Therapy*
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Figure 4. Intralesional skin biopsy specimens from a typical patient obtained before (A), during (B) (day 15), at the end of interleukin 10 therapy (C) (day 50), and 3 weeks after treatment (D) (day 71). A decrease in epidermal thickness, parakeratosis, and Munro abscesses as well as a reduction of the infiltrate is demonstrable (hematoxylin-eosin, original magnification x20).
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IMMUNOSUPPRESSIVE EFFECTS
Direct evidence of in vivo depression of the type 1 immune response was obtained by investigating the DTH response to 7 recall antigens (Multitest Mérieux) in healthy skin at 4 different time points. Before treatment, 6 of the 10 patients showed responsiveness to the recall antigens tested. These 6 patients lost at least 2 positive reactions during IL-10 treatment. Moreover, a reduction in the size of erythema was found (Figure 5). Interestingly, a reincrease of both parameters (number of positive reactions and intensity of reaction) was observed 2 weeks after cessation of therapy. These findings indicate immunosuppressive effects of IL-10 therapy, confirming our recently published data.16 There was no evidence of differences in the cellular immune responses with respect to the clinical response as well as the dosage regimen. Four patients were anergic during the whole observation period, including the patient with disease progression, as were patients with good clinical response.
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Figure 5. Depression of the cellular immunity by interleukin 10 therapy. The mean diameter of the erythemas determined by the summation of all positive reactions from 6 patients, who were positive for delayed-type hypersensitivity reaction before treatment, and the number of the positive reactions are shown. Data are mean ± SEM. Asterisk indicates P<.05, Wilcoxon signed rank test vs before therapy.
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CONSTITUTIONAL SYMPTOMS
The treatment was well tolerated. Only 1 patient developed flulike symptoms (cough, hoarseness, mild headache, and rhinorrhea), while 2 other patients reported fever, with a temperature up to 38.9°C, fatigue, and headache during the treatment period. These symptoms were of minor severity and did not require interruption of the IL-10-therapy. It seems unlikely that their occurrence during the long treatment and observation period (7 + 5 weeks) is related to the IL-10 administration since the symptoms reversed within 1 to 2 weeks despite continuation of the treatment. Moreover, at the same time, relatives of the patients had similar symptoms, suggesting an infectious origin. Two patients repeatedly (up to 4 times) showed mild local inflammation in the injection area that persisted 2 to 6 days.
Moderate effects on the hematopoietic system were found (Figure 6). Hemoglobin, hematocrit, and erythrocyte counts significantly decreased beginning on day 4 of treatment. We also found that thrombocyte counts transiently decreased immediately after the first injection and returned to normal after 2 weeks. At the end of the therapy, they counterregulatorily increased. In concordance with observations in the IL-10–treated patients with Crohn disease,19 we also recognized a short-lived increase of leukocytes ( Figure 6). Neutrophils are particularly responsible for this increase. There was no evidence of differences in the effects on hematopoietic cells observed between the 2 patient groups.
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Figure 6. Effects of interleukin 10 (IL-10) therapy on hematopoietic cells. Blood was obtained from 10 patients with psoriasis undergoing IL-10 treatment for 49 days (days 1-49). The blood was drawn in the morning and at 2 PM on the first day of treatment (1+6 h). Data are mean ± SEM values relative to the pretreatment levels (100%). The absolute pretreatment values were as follows: hemoglobin, 141.2 ± 3.5 g/L; erythrocytes, 4.76 ± 0.13 x1012/L; leukocytes, 7.26 ± 0.64 x109/L; and thrombocytes, 244 ± 21.5 x109/L. Asterisk indicates P<.05; dagger, P<.01 vs day 1 (Wilcoxon signed rank test).
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Additional laboratory parameters monitored excluded renal and hepatic toxic effects.
COMMENT
Psoriasis is a chronic self-perpetuating disease in which relative IL-10 deficiency seems to be of crucial importance.16 In the present study, we showed clinical safety in all patients and therapeutic efficiency of IL-10 treatment in 9 of 10 patients. This suggests that IL-10 therapy is a useful novel approach for treatment of psoriasis.
Using 2 different low-dose treatment protocols of IL-10, we observed a good clinical response in patients treated over a 49-day period, almost regardless whether they received IL-10, 8 µg/kg of body weight, daily or IL-10, 20 µg/kg of body weight, 3 times per week. Since the latter regimen is more convenient for the patients, it should be favored in subsequent trials.
The antipsoriatic effect, indicated by the significant decrease of the PASI score, resulted mainly from a reduction of the skin infiltration and scaling, but not from a total disappearance of skin lesions. Although a significant improvement was observed, the majority of patients still showed skin lesions at the end of the therapy (day 50). The lack of a total clearance in 7 of 10 patients strongly argues for the use of IL-10 therapy in combination with local antipsoriatic agents. One interesting candidate for combination might be the local antipsoriatic agent calciprotriol, since its capacity for the induction of IL-10 receptor expression on keratinocytes has been demonstrated recently.23 Interestingly, the patients responded extraordinarily well to standard antipsoriatic therapies performed after the observation period. It might be that long-lasting immunological effects contributed to this phenomenon.
No dramatic rebound effect was seen after termination of the therapy; however, a moderate disease relapse was found in 7 patients during the posttreatment observation period (days 50-85) (Figure 1). Therefore, it is of particular interest whether a low-dose long-term IL-10 maintenance treatment would be able to prevent the frequent relapse of skin lesions in patients with severe psoriasis after an intensive antipsoriatic therapy during hospitalization, including UV radiation. This is of particular importance since it may reduce cost-intensive morbidity and hospitalization. It has to be determined whether the long-term safety profile of IL-10 is superior to other alternatives currently in use, such as cyclosporine or methotrexate.
Based on recent data,16 we favor the concept that IL-10 exerts its antipsoriatic activity by effects on different cell populations. These include T cells, antigen-presenting cells, and keratinocytes as well as their interactions. Psoriasis is a T-cell dependent (auto)immune disease,2 probably initiated by presentation of so far unknown "psoriasis-related antigens" by specialized cutaneous antigen-presenting cells.24-25 Interleukin 10 is able to suppress the antigen-presenting cell activity of monocytes, macrophages, and dendritic cells.25-27 Presentation of antigens and/or superantigens activates effector T cells.24, 28 In particular, type 1 cytokine-producing T cells seem to play an important role in the pathogenesis of psoriasis.4-5,22, 28 Administration of IL-10 leads to a lasting type 1/type 2 shift in vivo.16 Our finding that IL-10 therapy depressed the DTH reaction further supports this. Finally, direct effects of IL-10 on keratinocytes may have contributed to the clinical response observed. It has been shown that IL-10 in high concentrations inhibits the proinflammatory cytokine synthesis29 and the proliferation30 of keratinocytes.
Taken together, our data suggest that IL-10 might be a new important antipsoriatic agent. Long-term, dose-finding, double-blind trials are necessary to further evaluate the value of IL-10 therapy in the treatment of psoriasis, particularly in combination treatment protocols. Moreover, the value of IL-10 treatment in other immune diseases characterized by a type 1 cytokine pattern22 should be defined.
AUTHOR INFORMATION
Accepted for publication August 10, 1998.
This work was partly supported by grant Ste 366/7-1 from Deutsche Forschungs gemeinschaft and Essex Pharma, Munich, Germany/Schering Plough Research Institute, Kenilworth, NJ.
Recombinant human IL-10 was kindly provided by Essex Pharma, Munich/Schering Plough Research Institute, Kenilworth, NJ.
Reprints: Khusru Asadullah, MD, Department of Dermatology, University Hospital Charité, Berlin Humboldt University, D-10098 Berlin, Germany.
From the Department of Dermatology (Drs Asadullah, Friedrich, Audring, and Sterry, and Ms Ebeling) and Institute of Medical Immunology (Drs Döcke and Volk, and Ms Belbe), University Hospital Charité, Berlin Humboldt University, Berlin, Germany.
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