Use of g class immunoglobulins for the topical treatment of atopic dermatitis

ES 2 187 635 T3

DESCRIPTION

Use of class G immunoglobulins for the topical treatment of atopic dermatitis.

The present invention relates to a new therapeutic use of class G immunoglobulins, particularly immunoglobulins for intravenous use (abbreviated IVIG) or for intramuscular use (abbreviated IMIG). More particularly, the present invention relates to the topical use of class G immunoglobulins which are normally administered intravenously or intramuscularly for the therapeutic treatment of dermatitis, particularly acne, contact dermatitis, atoeic dermatitis, eczema and ichthyosis, psoriasis, papulosquamous skin diseases (seborrheic dermatitis, erythroderma, etc.), as well as infectious dermatitis due to fungi, parasites, by bacteria and viruses.

Pharmaceutical compositions comprising class G immunoglobulins as active ingredient are already known.

International patent application WO-A-94/15640 describes compositions comprising the immunoglobulins IgA, IgB and IgM for the treatment of wounds (particularly surgical wounds) and burns that are effective for the prevention or neutralization of infection thereof caused by bacteria and viruses.

As is well known, the term "immunoglobulins for intravenous use" indicates a product based on human proteins, at least 90% of which have the electrophoretic mobility of gamma globulin (IgG), at least 90% of IgG is made up of monéomers. Traces of IgA and IgM may also be present. The distribution of IgG subclasses is similar to that found in normal serum.

Various commercial preparations for intravenous use are currently available on the immunoglobulin market, for example, under the trademarks VENOGLOBULIN '', GAMMIMUNE®, SANDOGLOBULIN®, GAMMAGARD®, GAMMAR®, and IVEGAAM®.

"Immunoglobulins for intramuscular use" differ from intravenous immunoglobulins in their low degree of purity. Various commercial preparations for intramuscular use are currently available on the immunoglobulin market, for example, under the trademarks GLOBUMAN®, GAMMABULIN®, LIOGAMMA®, BOEHRIGAMMA® and UMANGAMMA®.

The skin interacts, more than any other bodily organ, continuously and intimately with a wide range of environmental agents. The environment comes into contact with the body in the form of substances or forces (physical, chemical, biological) and through different routes: radiation, air, food, direct contact with the skin, injections, or psychosocial interactions. All of these agents can lead to skin diseases (Ring, J :, "The skin and the environment", Hautarzt, 44: 625-35, 1993). Atoepic dermatitis (AD for short) is a multifactorial skin disease with a chronic or chronic recurrent duration, which often sets in during childhood. The etiology of this annoying skin condition is still obscure, but an immunological disorder of the immune response of Testéa cells is probably involved in its pathogenesis (Wuthrich, B., "Atopic dermatitis", Ther. Usmch., 51: 45 - 54, 1994).

Recent discoveries have revealed several key factors in the maintenance of the vicious circle of DA, associated with an elevated activation of T lymphocytes, hyperstimulating Langerhans cells, an immunity mediated by abnormal cells and an overproduction of IgE by B cells ( Cooper, KD, "Atopic dermatitis: recent trends in pathogenesis and therapy", J. Invest. Dermatol., 102: 128 37, 1984). Insitute hybridization has revealed that, compared to normal control skin or unaffected skin of those with AD, acute and chronic skin lesions had a significantly higher number of cells that were positive for IL-4 mRNA e IL-5 (Hamid, Q., et al. "Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis", J. Clin. Invest., 94: 870-6, 1994. E^and These and other data suggest the activation of a selected population of helper T cells that produce a type of Th2 cytokines relative to IL-4 and IL-5 but not to IL-2 and interferon-γ (abbreviated IFN-γ) in DA (Kagi, MK et al., "Differential cytokine profiles in peripheral blood lymphocyte supernatants and skin biopsies from patients with different forms of atopic dermatitis, psoriasis and normal individuals", Int. Arch. Allergy Immunol., 103: 332-40, 1994 ). Microorganisms of the cutaneous flora can also be an additional stimulus for allergy skin reactions. Colonization of abnormal bacteria is a typical feature of AD. Staphylococcus aureus (abbreviated Staph. Aureus) is the most common pathogen and has proven useful in some cases.

ES 2 187 635 T3 an antimicrobial and antifungal treatment (Ring, J., et al., "Atopic ezcema: role of micro-organisms on the skin surface", Allergy, 47: 265-9, 1992).

Conventional therapy remains the mainstay of treatment for atopic dermatitis, but it is often unsatisfactory. New therapies based on the concepts outlined above are now being tested in clinical trials, and for this purpose trials with parenterally administered biological response modifiers such as interferon-γ, cyclosporin A, or thymopentin have been suggested (Cooper, KD, “ Atopic dermatitis: recent trends in pathogenesis and therapy ”, J. Invest. Dermatol., 102: 128-37, 1994).

Until now, the accepted use of IVIG and IMIG has been as antibody replacement in immunodeficiency states to treat and / or prevent infectious diseases (Newland AC, "The use and mechanism of action of intravenous immunoglobulin", Br. J. Haematol. , 72: 301-5, 1989). In addition, there is growing evidence that intravenous infusion of large amounts of Polymeric Immunoglobulin causes more than simple antibody replacement and may have a marked effect on the reticuloendothelial system. IVIG and IMIG can alter the function of B and T lymphocytes and cause a short-term blockage of phagocytic function with a regulation towards a lower immunological activity (Newland, A. C., Macey et al., "Intravenous immunoglobulin: mechanism of action and their clinical application) in" Immunotherapy with intravenous immunoglobulins ", edited by P. Imbrach, Academy Press, London, 1991, pp. 14-25). Conceptually it is important to emphasize that, in many diseases, more than one mechanism of action is possible and that the therapeutic effect may be due to several concomitant actions rather than any simple mechanism. In any case, IVIG and IMIG preparations have so far been developed to allow systemic administration.

With regard to skin diseases, an improvement in AD has been observed in patients with both AD and Kawasaki disease and idiopathic thrombocytopenia, but immunoglobulins were administered, as always, intravenously and at high doses ( Kimata, H., "High dose gammaglobulin treatment for atopic dermatitis" Arch. Dis. Child., 70: 335-6, 1994).

Surprisingly, however, it has been found that class G immunoglobulins, and in particular IVIG or IMIG, in solution or in the form of ointments or gels, or in liposomes (or other formulations) at concentrations between 1 and 25% are potentially effective for the prophylaxis and treatment of AD or other skin diseases characterized by a very poorly regulated immune response and / or by abnormal bacterial, viral or fungal colonization.

The efficacy of immunoglobulins has been tested in various studies in man. Some of these studies will be described in this specification. The local administration of immunoglobulins at the indicated doses produces the remission of inflammatory processes without causing any toxic or unwanted side effects.

Studies in man

Study N ° 1

In this study, the authors selected 8 patients suffering from AD in whom the blood levels of total lymphocytes as well as CD3, CD4 and CD8, and the CD4: CD8 ratio were studied. These parameters were determined in two clinical phases, that is, in the acute phase (pre-treatment) and in another phase in which the lesions remit (post-treatment). IVIGs were administered topically in the form of a 25% solution. IVIGs were applied to skin lesions three times a day for a period of 14 days. The purpose of this work was to study the changes in these subpopulations of lymphocytes in each of the phases. The authors also studied a control group consisting of 8 healthy patients to reinforce the results obtained. The authors found no significant differences between the results obtained in the two phases or when compared with the control group (Table 1). These data indicate that IVIG when applied topically in the form of a 25% solution, do not modify the subpopulations of lymphocytes in the peripheral blood. Its therapeutic efficacy is thus attributed to a local effect.

ES 2 187 635 T3

TABLE 1

Absolute number of lymphocytes in peripheral blood: percentages of CD3, CD4 and CD8 cells and CD4: CD8 ratio

<td></td><td colspan="2">Lymphocytes</td><td>CD3</td><td>CD4</td><td>CD8</td><td>CD4: CD8</td><td>Stats</td>

<td>Patients</td><td>Before</td><td> 1870 ± 324</td><td> 67 ± 13</td><td> 41 ± 8</td><td> 27± 0</td><td> 1,6</td><td>ne</td>

<td></td><td>After</td><td> 1920 ± 376</td><td> 72 ± 15</td><td> 88 ± 6</td><td> 16± 7</td><td> 1,4</td><td>ne</td>

<td>Controls</td><td>Before</td><td> 1903 ± 411</td><td> 70 ± 12</td><td> 49 ± 10</td><td> 29 ± 9</td><td> 1,4</td><td>ne</td>

<td></td><td>After</td><td> 1928 ± 407</td><td> 70 ± 8</td><td> 40± 11</td><td> 28 ± 8</td><td> 1,4</td><td>ne</td>

Study N ° 2

In this study, IVIGs were administered topically as a 0.1% solution and applied to skin lesions three times daily for a period of 14 days. A total of 6 patients with acute lesions of AD were treated. No other treatment was allowed. The authors used in situ hybridization, as previously described (Hamid, Q., et al., “Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis,” J. Clin. Invest., 94: 870-6, 1994) to examine the expression of the messenger RNA (abbreviated mRNA) of interleukin 4 (abbreviated IL-4) and interleukin 5 (abbreviated IL-5) in skin biopsies. In comparison with pretreatment, skin lesions were no longer present and a significantly lower number of cells positive for IL-4 mRNA (P &lt;0.01) and IL-5 (P &lt;0.01) were detected. ) (table 2). These data indicate that acute lesions of the DA are associated with an increase in the activation of the genes of IL-4 and IL-5, and that treatment with IVIG follows a reduced expression of IL-4 and of IL-5 locally.

TABLE 2

Differential expression in situ of the cytokine gene in skin biopsies before and after treatment. The results are expressed by the mean number of positive cells per high-power field (0.202 mm²)

<td></td><td>Pretreatment</td><td>Aftercare</td><td>Statistics</td>

<td>IL-4 mRNA</td><td> 22 ± 4</td><td> 4±2</td><td>P &lt;0.01</td>

<td>IL-5 mRNA</td><td> 14 ± 5</td><td> 2±1</td><td>P &lt;0.01</td>

Study N^° 3

In this study, the authors evaluated the expression of Th1-type cytokine and interferon-γ in three AD patients in whom Staph superinfection had been observed clonically. aureus and confirmed microbiologically by culture of the skin biopsy. Compared with normal skin (3 volunteers), the expression of interferon-γ was increased in the lesions of the DA. After treatment with IVIGs in the form of a 5% suspension 4 times a day for 16 days, the lesions disappeared and the increase in the expression of interferon-γ mRNA proved to be significantly controlled towards lower levels (Table 3). These data indicate that the therapeutic efficacy of IVIGs was associated with reduced colonization by microorganisms and with modulation of interferon-γ mRNA expression.

TABLE 3

Differential in situ expression of the interferon-γ gene in skin biopsies before and after treatment in patients and controls. The results are expressed as the mean number of positive cells per high power field (0.202 mm²)

<td></td><td>Pretreatment</td><td>Aftercare</td><td>Stats</td>

<td>Patients</td><td> 30 ± 6</td><td> 14± 5</td><td>P &lt;0.02</td>

<td>Control</td><td> 7±3</td><td> 8±5</td><td>ns</td>

ES 2 187 635 T3

Compositions suitable for the treatment of dermatitis (solutions, ointments, creams, gels, liposomes, etc.) can be prepared using conventional methodologies and excipients, for example as described in "Remington's Pharmaceutical Sciences Handbook", Mack Pub. Co. , New York, USA, XVIII Ed., 1984, as would be self-evident to any person skilled in the art.

In addition to suitable excipients, these compositions may also contain antibiotics, antiviral agents, antifungal agents, vitamins, anti-inflammatory, antipruritic and / or antimicrobial agents, unsaturated fatty acids and immunosuppressive agents.