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Published on 1 November 2003

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Systemic management of severe psoriasis

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Aldo F Finzi
MD
Professor and Chairman
Department of Dermatology
University of Milan
Italy
E:aldo.finzi@unimi.it

The treatment of psoriasis needs to be adapted on the basis of the characteristics of the disease (type, extension and localisation) and those of the patient (age, sex, health status, type of occupation and psychological state). In 70–80% of cases psoriasis is mild to moderate, with stable lesions localised to typical sites; in these cases it is sufficient to use local treatments, such as UV rays, dithranol, corticosteroids, calcipotriol and tazarotene.

Systemic therapies should be reserved for the more severe forms of psoriasis. They are firstline for erythrodermal, pustular and active arthropathic psoriasis, and secondline in the case of extensive plaque psoriasis unresponsive to topical treatments. In patients with severe psoriasis requiring prolonged systemic therapy, the different regimens should be rotated every 6–12 months to reduce the risks of chronic toxicity associated with each individual drug. All of the licensed systemic treatments that have proved to be efficacious in psoriasis act on the immune system in some way.(1)

Photochemotherapy or PUVA therapy
This involves the administration of photosensitising substances (8-methoxypsoralen given orally, followed by the application of UVA rays with a maximum wavelength of about 360nm). The main indication for PUVA therapy is very widespread plaque psoriasis; the contraindications are, above all, photosensitivity, inverted psoriasis and some general conditions, such as liver disease and cataracts.

In patients receiving long-term phototherapy, there have been reports of mainly cutaneous, but sometimes visceral, neoplasms. Currently, one of the most important problems concerning PUVA therapy is its cost: it is certainly not a cost-effective treatment (particularly bath PUVA) because of the time involved and the considerable investment required in adequate facilities and medical and nursing staff.

Retinoids
The retinoids used in psoriasis are etretinate and acitretin. The main negative aspect of etretinate is its teratogenic effect, which, together with its persistent presence in adipose tissue, hampers its use in women of childbearing age. Acitretin, whose presence in the circulation seems to be less, can be transformed into etretinate in many cases, particularly in patients with hepatic alterations. At equivalent doses, the therapeutic efficacy of acitretin is slightly less than that of etretinate.

Retinoids mainly act by inhibiting neutrophilic chemotaxis, and, by stimulating the maturation of immature keratin cells, they have a direct effect on keratinocyte differentiation. The principal indication for the use of retinoids is pustular psoriasis, the prognosis of which they significantly modify. However, they are also used in combination with photochemotherapy in the treatment of psoriasis vulgaris.

The main contraindications are the possibility of pregnancy and paediatric use, insofar as retinoids are teratogenic and capable of causing the early calcification of growth cartilage and endocranial hypertension. Their side-effects include increased triglyceride and cholesterol levels, which limit their use in the elderly and in dyslipidaemic patients. An additional and more or less constant side-effect is the so-called “retinoid-induced skin syndrome”, which is characterised by a dryness of the skin and mucosa that is extremely irritating at the level of the labial semimucosa and, in some cases, of the tunica conjunctiva.

Methotrexate
Methotrexate is probably one of the most efficacious systemic drugs in psoriasis and psoriatic arthritis. It is an antimetabolite of folic acid that was initially (and mistakenly) used at very high dosages in the hope of blocking the proliferation of psoriatic keratinocytes. It is now administered at minimal doses: 7.5–15mg orally given once a week.

Given its cytostatic nature, the contraindications to the use of methotrexate are pregnancy and being of childbearing age; it should not be administered to men who want to reproduce because it may also have a mutagenic effect on spermatozoa. Furthermore, it must be used with caution in subjects with concomitant lymphopenia or thrombocytopenia. When it is administered for very long periods, it may cause hepatic necrosis: in this regard, the total lifelong dosage should not exceed 1,500–2,000mg, after which it is prudent to perform a needle biopsy to evaluate the condition of the liver.

Ciclosporin A
Like methotrexate, this is one of the most efficacious drugs in the treatment of psoriasis. It is active in all forms of psoriasis, particularly erythrodermal psoriasis and psoriatic arthritis. It is not cytostatic and therefore does not act on keratinocyte proliferation, but on the production of lymphokines and cytokines, especially those produced by T-lymphocytes. Ciclosporin exerts its effect by acting on a specific cytoplasmatic receptor and blocking the transcription of the RNA for interleukin-1 (IL-1), IL-2, tumour necrosis factor-alpha (TNF-alpha), granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma). It also reduces the activity of Langerhan’s cells and phospholipase A2. At above-therapeutic dosages it has been hypothesised that ciclosporin A may directly inhibit keratinocyte mitosis and have anti-inflammatory activity. The average recommended dosage is 3mg/kg/day or, in an adult weighing 70kg, a fixed dose of 200mg/day of micronised ciclosporin A. The main side-effects are those secondary to immunosuppression (eg, infectious diseases, hepatitis) and, only in the case of long-term treatment, nephrosclerosis secondary to a renal artery spasm, which regresses upon a dosage reduction or the discontinuation of treatment. Patients being treated with ciclosporin A must therefore be carefully monitored, particularly in terms of creatininaemia and arterial blood pressure.

Fumaric acid
Fumaric acid undoubtedly has a certain efficacy and acts on keratinocytes (by inhibiting their reproduction) and on T-lymphocytes. The most common reported adverse event is gastrointestinal upset.

Biological immunotherapies
A large number of studies of new biological immunotherapies based on murine, humanised or entirely human monoclonal antibodies, fusion proteins, cytokines or recombinant DNA receptors are currently being carried out with the aim of selectively inhibiting (by means of blockade or competition) individual cytokines or receptors (see Figure 1). Some of these drugs have already been marketed for use in patients with rheumatoid arthritis or Crohn’s disease and are used experimentally in the treatment of severe psoriasis.(2,3)

[[HPE11_fig1_19]]

Antisense oligonucleotides
These are inhibitors of the cytoplasmic RNA transcription of various cytokines. Some of them have been tested as topical psoriasis treatments with the aim of suppressing the expression of ICAM-1 and insulin-like growth factor (IGF) receptor. Only modest results have so far been achieved.

Recombinant IL-10
This increases the activity of B-lymphocytes but reduces that of antigen-presenting cells (APC), CD4-Th1 and endothelial cells. The results indicate slight, transient or no effect. Side-effects are frequent and consist of flu-like symptoms and fever. In some cases, a major anergy of cell-mediated immunity has been observed.

Peptide T
This is a synthesised octapeptide that was initially created as an antagonist of the binding between HIV and CD4 cells. It increases the CD4-Th2 production of IL-10, and its possible therapeutic activity should be similar to that of IL-10. There has been a chance observation of its curative efficacy in psoriasis.(4)

Anti-CD4
A number of anti-CD4 chimeric monoclonal antibodies have been studied (OKT4A, higG1-CD4), but all of them have considerable side-effects and an unfavourable risk/benefit ratio.

Alefacept (Anti-CD2)
Alefacept is a recombinant fusion protein that combines LFA3 with the Fc portion of a human immunoglobulin G1 (IgG1). It competitively inhibits the interaction between the LFA3 receptor of the APCs and the CD2 antigen on the surface of T-lymphocytes, thus inhibiting its activation. It also causes the apoptosis of CD45RO+T-lymphocytes. The results in psoriasis are promising, with an optimal risk/benefit ratio. The product has been FDA approved in the USA (January 2003), and clinical development is underway in Europe.

Anti-IL-2r (CD25)
Blocking CD25 (IL-2 receptor) halts the recruitment, reproduction and activation of T-lymphocytes, thus reducing cell-mediated immunity. It comes in the form of a fusion toxin, DAB389 IL-2, and two monoclonal antibodies, basiliximab and daclizumab. These are widely used in transplantations and have also been used in rheumatoid arthritis, Crohn’s disease and psoriasis, with rapid but transient effects. They can cause the production of neutralising IgGs.

Anti-TNF-alpha

TNF-alpha is mainly produced by macrophages and monocytes and acts on all aspects of phlogosis, especially in psoriasis. Blocking TNF-alpha leads to a reduction in the levels of other proinflammatory cytokines (IL-1, IL-6 and IL-8). Some anti-TNF-alpha antibodies have already been introduced and marketed in various European countries: the chimeric anti-TNF monoclonal antibody infliximab, and anti-receptor TNF p75 IgG etanercept. Both are marketed for rheumatoid arthritis but have been used in psoriatic arthritis, Crohn’s disease and psoriasis, with fair results. As they induce neutralising antibodies, they should be combined with methotrexate or ciclosporin A. Others are in an advanced phase of development: antihuman TNF monoclonal antibody (adalimumab: D2E7; antihumanised TNF Fab PEG: CDP 780; receptor TNF-p55 PEG: PEG-sTNF-r; soluble TNF receptor: onercept).

Anti-CD11
Efalizumab is a chimeric anti-CD11 monoclonal antibody that blocks the interaction between ICAM-1 of the APCs and T-lymphocytes and seems to be efficacious in treating psoriasis. It has major side-effects and, if the weekly dosage of 2mg/kg is exceeded, causes a worsening in the disease.

Anti-CD80
IDEC-114 is a monoclonal antibody against the CD80 surface receptor expressed by APCs that binds to CD28 and CTLA4, both of which are antigens expressed by T-lymphocytes. The CD80-CD28 interaction activates T-lymphocytes, whereas that between CD80 and CTLA4 reduces the immune response. IDEC-114 seems to inhibit only the CD80–CD28 interaction, thus leaving the CD80–CTLA4 function unchanged. A single dose of 10mg/kg has been found to be efficacious in psoriasis.(5)

Anti-IL-8
AbX-IL-8 is a chimeric monoclonal antibody against IL-8, a lymphokine produced by T-lymphocytes. IL-8 has major effects in psoriasis, in particular the activation of keratinocytes and polymorphonucleate neutrophils and the stimulation of angiogenesis.

Anakinra (Anti-IL-1r)
Blocking the IL-1 receptor halts the recruitment, reproduction and activation of T-lymphocytes by APCs, thus reducing cell-mediated immunity. Anakinra is a recombinant form of IL-1r that competitively replaces the natural IL-1 receptor, thus preventing binding to endogenous IL-1. It has so far been studied in rheumatoid arthritis.

Conclusion
The existing and officially recognised systemic treatments for severe psoriasis are effective and have a good cost/benefit ratio.The new biological immunotherapies that are currently being developed have a number of interesting characteristics:

  • Rapid action.
  • Specific targets.
  • Considerable speculative interest.
  • Represent a last resource in desperate cases.

On the other hand, they raise a number of still unsolved problems:

  • They can induce tachyphylaxis.
  • They can induce anaphylactic or immunocomplex reactions.
  • They cause immunosuppression (TB, neoplasms, lymphomas).
  • They are very expensive.

References

  1. Finzi AF, Marinovich M. Dermofarmacologia. Torino, Italy: UTET Ed; 1998.
  2. Gottlieb AB, Bos JD. Recombinantly engineered human proteins: transforming the treatment of psoriasis. Clin Immunol 2002;105:105-16.
  3. Gniadecki R, Zachariae C, Calverley M. Trends and developments in the pharmacological treatment of psoriasis. Acta Derm Venereol 2002;82:401-10.
  4. Marcusson JA, Lazega D, Pert CB, et al. Peptide T and psoriasis. Acta Derm Venereol 1989;146:117-21.
  5. Gottlieb AB, Lebwohl M, Totoritis MC, et al. Clinical and histologic response to single-dose treatment of moderate to severe psoriasis with an anti-CD80 monoclonal antibody. J Am Acad Dermatol 2002;47:692-700.


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