Table of Contents   This Chapter   All Chapters

OTHER IMMUNOMODULATORY, IMMUNOSUPPRESIVE, AND CYTOTOXIC THERAPIES

These agents are grouped together, as most of their use is in similar situations in dermatology, for a variety of severe inflammatory dermatoses, for vasculitis, and for immunobullous diseases. However, the range of agents to consider is wide, and some have widespread application while others are used for only a small number of indications. The main features of the more widely used of this group of agents are summarized in Table 4.1.

Malignancy risk

Many immunosuppressive drugs carry an actual or a potential risk of increased frequency of malignant disease, due to suppression of immune surveillance. This will not be discussed for all the following drugs, as the same principles apply to most of them. In general, as with immunosuppression for renal transplant purposes, the main concern is skin cancers, cervical carcinoma, and lymphomas. Of particular relevance in dermatology is the potential that previous natural sunlight or psoralen ultraviolet A (PUVA) therapy for psoriasis (Ch.7) may increase the risk of skin cancer: there is a disproportionate increase in squamous cell carcinoma (more than the normally commoner basal cell carcinoma). Additionally, although rare as a sporadic neoplasm, long-term immunosuppressive therapy carries a very significantly increased risk (about 80-fold greater than in the general population) of Merkel cell carcinoma (Fig. 4.11).

Opportunistic infections

As with malignancy risk, all immunosuppressive agents have at least a theoretical risk of predisposing to opportunistic infection. Herpes infection, cytomegalovirus infection, candidiasis, and fungal infections should all be considered in the event of unusual or unexplained symptoms in patients on such therapies.

Pregnancy and lactation

Most of these agents are at least relatively contraindicated in these situations. Men are advised not to father children while taking methotrexate, although the evidence for this is from hematologic doses that are much larger than those used for dermatologic indications. Individual summary of product characteristics (SPC) data sheets should be consulteds.

PRACTICE POINTS

Ciclosporin (cyclosporin A, cyclosporine)

This drug is used for treatment of the following conditions.

Ciclosporin has a number of side effects, some of which are potentially serious and which require careful monitoring. The most important or frequent are the following.

Mycophenolate mofetil

This is a newer agent that selectively inhibits lymphocyte proliferation.

    It is likely that it will share many of the therapeutic indications for ciclosporin, as listed earlier. It is mainly used as a steroid-sparing drug, but there is interest in its use in conjunction with ciclosporin. This combination has been used in psoriasis, for example, and is beneficial, as the two drugs have a different spectrum of side effects, and lower doses of each may be achievable. It is generally well tolerated, although gastrointestinal upset is relatively common. The most important dose-related side effect is bone marrow suppression.

 

Table  4.2  SOME DRUG INTERACTION WITH CICLOSPORIN

.

Type of drug	Examples	Effect
Antimicrobials	Macrolides Doxycycline Azole antifungals Aminoglycosides Quinolones Rifampin	Increased ciclosporin levels Increased ciclosporin levels Increased nephrotoxicity Increased ciclosporin levels Increased nephrotoxicity Decreased ciclosporin levels
Rheumatologic	Non-steroidal antiinflammatory drugs Methotrexate	Increased nephrotoxicity Increased ciclosporin and methotrexate levels
Cardiac	Some calcium channel blockers Statins Digoxin	Increased ciclosporin levels Increased risk of myopathy Increased digoxin toxicity
Anticonvulsants (some)	Carbamazepine Phenytoin Barbiturates	Decreased ciclosporin levels Decreased ciclosporin levels Decreased ciclosporin levels
Hormonal	Oral contraceptives Danazol	Increased ciclosporin levels Increased ciclosporin levels
Others	Bromocriptine Metoclopramide Grapefruit juice	Increased ciclosporin levels Increased ciclosporin levels Increased ciclosporin levels

Figure. 4.12  Papular facial lesions associated with immunosuppression include sebaceous hyperplasia and non-melanoma skin cancers. The flesh-colored papules illustrated appear to be specifically related to ciclosporin, and have been reported as ciclosporin-related folliculodystrophy

 

Figure 4.13  Bullous pemphigoid. Although corticosteroids are usually first-line treatment, azathioprine is often used as well for its steroid-sparing effect. (From Lawrence CM, Cox NH. Physical Signs in Dermatology, 2nd edn. London: Mosby, 2002.)

Azathioprine

This is a widely used drug in dermatology. It has a slow onset of action, and is therefore mainly used as a steroid-sparing agent rather than as initial therapy. It is used in the following conditions.

Knowledge of the metabolism of azathioprine is of some importance. It is a prodrug of 6-mercaptopurine, which in turn is metabolized by three main pathways involving the enzymes thiopurine methyltransferase (TPMT), xanthine oxidase, and hypoxanthine guanine phosphoribosyl transferase. Activity of TPMT is genetically determined; individuals with low-activity TMPT are at very high risk of azathioprine toxicity, as a greater proportion of the dose is metabolized to form toxic 6-thioguanine nucleotides. Where possible, the activity of this enzyme should be measured before starting treatment so that appropriate doses can be determined. In any event, frequent blood monitoring is required during the first month of treatment.

The main adverse effects are as follows.

Methotrexate

This is an antimetabolite that interferes with folate metabolism. It is used in the following conditions.

    Treatment is usually commenced with a small test dose to identify patients with significant side effects, and is then increased with close monitoring of blood counts and liver function. It should not be used in patients with significant renal dysfunction or in patients with known liver disease or heavy alcohol intake. Liver biopsy is normally performed in the first few months as a baseline for assessment of the potential side effect of liver fibrosis (this period allows those with other side effects or with lack of benefit to avoid this investigation). Ongoing monitoring may include routine liver function tests, further liver biopsy (after a cumulative dose of 1–3g, depending on routine tests), and/or serial measurements of the amino terminal peptide of type III procollagen (PIIINP), a serum marker of fibrosis.

Side effects include the following.

Folate antagonists - antibiotics such as trimethoprim, sulfonamides (especially in combination as co-trimoxazole), and dapsone.

Non-steroidal antiinflammatory drugs - usually a mild effect, but avoid intermittent use due to unpredictability.

Others - ciclosporin, probenecid, phenytoin, phenothiazines, and tetracyclines.

Hydroxycarbamide (hydroxyurea)

The main dermatologic use of hydroxycarbamide is for psoriasis. It may cause myelosuppression, but this is usually gradual and readily reversible. The benefit seems to gradually wane in many patients over a period of years. Other side effects include macrocytosis (very common), liver or renal toxicity, gout, and flu-like symptoms. Notably, it has a number of potential dermatologic side effects, including photosensitivity, pigmentation, a dermatomyositis-like skin eruption, or, in long-term use for myeloproliferative disorders, leg ulceration.

Cyclophosphamide

This alkylating agent is not used widely in dermatology, but it is one of the first-line treatments for Wegener granulomatosis and is sometimes used in other vasculitides. It is also occasionally used in severe immunobullous diseases, such as refractory pemphigus, or in sight-threatening mucous membrane pemphigoid or linear IgA disease.

Gastrointestinal side effects, myelosuppression, and alopecia are anticipated at doses used for malignant disease; these effects are less prominent with the lower-dose oral therapy used in dermatology but may be troublesome with higher-dose pulsed intravenous treatment. The most important side effect that is novel to cyclophosphamide in this group of immunosuppressive treatments is bladder toxicity due to a metabolite called acrolein, leading to either a hemorrhagic cystitis or rarely bladder cancer. These risks are most significant with intravenous use as a cytotoxic. High fluid intake is recommended. To avoid long-term use, azathioprine is often substituted once disease control has been achieved.

Gold

This is not widely used in dermatology but may be useful in resistant cases of discoid lupus erythematosus or in immunobullous diseases such as pemphigus.

Leukopenia and proteinuria may occur and must be monitored; a rash due to gold is not uncommon.

Fumaric acid esters

These agents are used in treatment of psoriasis, most commonly in continental Europe but less often in the USA or the UK. Side effects include nausea, flushing, headache, lymphopenia, and increased hepatic transaminases.

PRACTICE POINTS

Sulfones

Dapsone is used in treatment of the following.

The main toxicity of dapsone relates to its effects on hematopoiesis. Agranulocytosis occurs rarely, but a dose-related hemolysis and methemoglobinemia occurs in all recipients; hemolysis occurs especially in patients with glucose-6-phosphate dehydrogenase deficiency, and this should be excluded in relevant populations prior to treatment. Headache is also common, probably due to methemoglobinemia. Weekly blood counts for a month, then fortnightly for a further month, monthly up to 3 months, then every 3–4 months are recommended: a reticulocyte count gives a guide to the degree of hemolysis (drop in hemoglobin of 2g/dL, and reticulocyte count up to about 5%, are usually acceptable). Vitamin E 800 IU daily may reduce hemolysis and headache; cimetidine also reduces methemoglobinemia.

Other side effects include a predominantly motor peripheral neuropathy, anorexia, and headache. Rash may occur, including toxic epidermal necrolysis; if severe rash occurs with eosinophilia (dapsone syndrome), then treatment should be stopped, as there is a risk of progression to hepatitis, psychosis, and even death.

Other sulfonamides such as sulfapyridine or sulfamethoxypyridazine are alternatives, especially for children, but are less readily available.

Potassium iodide

This is an old agent that may be useful in the following conditions.

Potassium iodide has an unpleasant taste, and treatment may be limited by gastrointestinal disturbance. It can cause various rashes, including iododerma, and may cause hypothyroidism.

Figure 4.14  Dermatitis herpetiformis: close-up examination showing scratched papules with some tiny, intact blisters. Often these are so itchy that the blisters are destroyed by scratching. There is usually a very rapid symptomatic response to dapsone.

Figure 4.15  Linear IgA disease. Dapsone is the usual treatment for this condition and was initially helpful in this patient. However, over time she developed severe scarring of the conjunctivae, causing blindness (see Fig. 16.53), and of the nails (as shown here). Unsuccessful treatments to arrest her disease included corticosteroids, several immunosuppressive drugs, and intravenous immunoglobulins. Interferon-alpha proved useful but had hematologic side effects that precluded ongoing treatment

Colchicine

Colchicine affects microtubule function and probably produces its antiinflammatory effects mainly by interfering with polymorphonuclear leukocyte function. It is mainly used in the treatment of gout (Fig.4.16), but in dermatology it has a potential role in a number of vasculitic and neutrophilic disorders. The main use is in different forms of cutaneous small-vessel vasculitis, in urticarial vasculitis (Fig.4.17), in Behçet disease (and other aphthous ulceration), occasionally in immunobullous diseases, and in rarities such as familial Mediterranean fever.

Figure 4.16 Large nodules of gout over the joints on the fingers. The deep location of these is apparent as the skin is stretched over them, with no textural changes and normal skin color. Individual tophi may be excised if required, and prophylactic treatment of the underlying metabolic disorder should be instituted with allopurinol (a rheumatologic drug that is not discussed here; it is rarely used by dermatologists but can be useful for cutaneous sarcoidosis). For painful joint exacerbations, analgesics and antiinflammatory drugs are typically used, but colchicine is often more effective.

Figure 4.17  Urticarial vasculitis: purpura within lesions of urticaria, which each last several days, is typical. Colchicine may be very useful therapy.

The main side effects when used at doses traditionally applied for gout are gastrointestinal disturbance and diarrhea, but these are unusual at the doses used for dermatoses (typically 0.5mg two or three times daily).

Antimalarials

Chloroquine, hydroxychloroquine, and mepacrine (Atabrine) are all used in a variety of disorders, such as the following.

Figure 4.18  Subacute cutaneous lupus erythematosus, a disorder that often has annular morphology and photosensitivity. Many patients with this condition have an excellent response to hydroxychloroquine, a drug that generally has a good safety profile if used at appropriate doses.

In most of these, the mechanism(s) of action are uncertain and probably multiple. Sarcoidosis is often relatively resistant by comparison with lupus erythematosus. In porphyria cutanea tarda, the drug (at lower dose than for the other inflammatory disorders listed) acts by binding porphyrins and enhancing excretion; this approach therefore does not work in patients with severe renal failure.

The main therapeutic issues with antimalarials for dermatologic indications are as follows.

Thalidomide

Thalidomide inhibits tumor necrosis factor (TNF) and various other cytokines, and decreases lymphocyte proliferation and neutrophil activity. It is not commonly used due to its potentially significant side effects, but it may be useful in the following.

Careful monitoring and application of precautions to avoid pregnancy are mandatory and reduce the usefulness of this agent.

Practice points

Interferons

Interferons are cytokines that have antimicrobialTest123 , antitumor, and antiinflammatory actions. They are administered by subcutaneous injection. The major uses in dermatology (although usually administered by oncologists) are for melanoma or cutaneous T-cell lymphoma. HIV-related Kaposi sarcoma may also be treated, and interferon-alpha is part of the regimen for hepatitis C infection (which may present to dermatologists as cryoglobulinemia). Other infections, such as warts, and proliferations, such as epithelial tumors or hemangiomas, have been treated; experience in inflammatory diseases such as lupus erythematosus or immunobullous disorders is mixed.

Monoclonal antibodies and cytokine inhibitors

A number of agents termed monoclonals or (immuno)biologicals are being introduced into dermatology, notably for the treatment of severe psoriasis and for some lymphomas, although they will undoubtedly have numerous applications in immunologic diseases (atopic dermatitis and alopecia areata) and in immunotherapy of tumors. These agents are manufactured to target key cytokines in the relevant disease, such as TNF in psoriasis or cell surface receptors (such as basiliximab for lymphomas).

The agents with which there is most experience to date in psoriasis are as follows.

Use of such agents is limited to treatment of chronic moderate or severe disease (generally, patients who might be considered for other systemic therapies or for photochemotherapy) due to high cost and some risks, for example risks of infection, especially reactivation of tuberculosis (discussed below). Most of these drugs are new, and there is therefore an uncertain risk of malignancy in the long term, as occurs with more commonly used immunosuppressive agents. None should be used in conjunction with immunosuppressive therapies or photochemotherapy. Antinuclear antibodies may occur in patients treated with TNF blockers, and rarely overt lupus erythematosus. All require monitoring of either CD4 + lymphocyte counts or platelet counts during therapy.

The main side effects that occur with this group of agents, most being applicable to several such drugs, include nausea, anaphylaxis or hypersensitivity reactions, fever, headache, blood dyscrasias (including thrombocytopenia and aplastic anemia), worsening of cardiac failure, and infection (especially reactivation of tuberculosis or development of septicemia, listeriosis, or varicella zoster). Some may cause injection site reactions: hypersensitivity reactions are a significant concern. Infliximab may also cause hepatitis, gastrointestinal bleeding, pneumonitis, arrhythmias, vasospasm, bleeding, rashes, and alopecia. Various anti-TNF drugs have been identified as possibly causing a demyelination disorder.

Many of the agents in use for systemic lymphomas have a potential role for cutaneous lymphomas as well, for example denileukin diftitox (which kills cells that express interleukin-2, e.g. in cutaneous T-cell lymphoma) and basiliximab (for B-cell lymphoma); again there are some potentially important side effects, such as vascular leak syndrome with denileukin diftitox.

Intravenous immunoglobulins

Aside from their original role in replacement therapy for hypogammaglobulinemias, intravenous immunoglobulins (IVIG; generally at higher doses than those used for replacement therapy) have an immunomodulatory role. They have been used with variable success in disorders such as the following.

This treatment is expensive and has a risk of transmitting infection, as it is derived from pooled donor blood. Side effects include the following.

Plasmapheresis

This is really a physical therapy but is pertinent here as it is (rarely) used in many of the diseases discussed as potentially responding to immunosuppressive therapy, such as immunobullous diseases, connective tissue disease, or vasculitis in which there are circulating antibodies or immune complexes that can potentially be decreased in titre by removal of plasma. Using a continuous circuit from the patient to the centrifuge machinery, blood is extracted and centrifuged, plasma removed, and fresh plasma replaced, before the blood is reinfused into the patient. It is relatively time consuming, and care must be taken to avoid hemodynamic instability or alteration of blood clotting.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.