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Dermatological pharmacology: systemic drugs
TREATMENTS
Dermatological pharmacology: systemic drugs
Key points C
Systemic treatment is used to manage acute and chronic severe skin disease
C
Systemic treatment needs careful monitoring for potential adverse effects
C
Systemic treatment needs to be titrated according to the clinical response
Sarah H Wakelin
Abstract Systemic treatment of skin disease is changing rapidly: we are at the dawn of a new era of targeted therapy that is emerging against the background of a clearer understanding of the molecular pathogenesis of common dermatoses and skin cancer. Biological agents and new oral therapies are being developed specifically against the underlying immune abnormalities in common inflammatory skin diseases, especially psoriasis. Biologics are now also indicated for urticaria and hidradenitis suppurativa, and treatment for atopic dermatitis is imminent. These drugs are restricted to severe disease, so conventional systemic therapy with immunosuppressants and anti-inflammatory drugs still plays a major role in the management of skin disease. The very poor prognosis of advanced melanoma has for the first time been improved by new immune and molecularly targeted therapy, although the optimum way of using these drugs remains to be decided.
prescribed by dermatologists. Newer anti-inflammatory targeted drugs include the phosphodiesterase 4 inhibitor apremilast, and oral janus kinase inhibitors are at an advanced stage of development. Biological drugs and targeted therapies are the latest addition to systemic therapy in dermatology. They are much more finely aimed at the underlying immunopathogenesis of individual diseases and offer the chance of more effective and safer treatment; long-term safety remains, however, unproven for most. These drugs are expensive and are therefore restricted to patients with severe skin disease. The psychosocial impact of skin disease is an important consideration, so measures such as the Dermatology Life Quality Index are used in deciding patient eligibility. To help patients share in treatment decisions, it is essential that the prescribing physician gives a clear and comprehensive explanation of the risks versus benefits of therapy. Careful documentation in the medical records provides evidence of informed consent to treatment in the event of subsequent litigation.
Keywords Anti-inflammatory; antimetabolite; azathioprine; biologics; ciclosporin; immunosuppressants; immunotherapies; methotrexate; retinoids; systemic
Introduction Immunosuppressants
Most patients with inflammatory skin diseases, in particular eczema and psoriasis, are managed with long-term or intermittent topical therapy that controls disease activity and symptoms. Phototherapy is a second-line option; if this is not effective or practical, the next step is systemic therapy with immunosuppressant/immunomodulating drugs (Table 1). These drugs are also used for rarer severe and life-threatening inflammatory rashes such as autoimmune blistering diseases, neutrophilic dermatoses, vasculitides and connective tissue disease; in many cases, this use is off-licence. Immunosuppressants have broad mechanisms of action and are usually effective in controlling inflammatory disease, but they require close and careful monitoring owing to potential toxicity. Systemic retinoids, corticosteroids and miscellaneous drugs such as antimalarials, dapsone and colchicine are also still widely
Several drugs that were originally developed to prevent organ transplant rejection are used in dermatology therapy. Azathioprine (AZA) is a synthetic purine analogue that interferes with DNA synthesis and inhibits cell proliferation in rapidly dividing cells, especially lymphocytes. It is licensed for the treatment of pemphigus, systemic lupus erythematous and dermatomyositis/polymyositis; it is also an effective monotherapy for severe atopic eczema in adults and children. AZA is also commonly used as a corticosteroid-sparing drug for the autoimmune blistering disease bullous pemphigoid. The onset of action in these diseases is slower than those of other immunosuppressants.
General treatment hierarchy for psoriasis and inflammatory skin disease Sarah H Wakelin BSc MBBS FRCP is a Consultant Dermatologist at St Mary’s Hospital, Imperial College Healthcare Trust, London, UK. She has a special interest in allergic and inflammatory skin diseases and dermatological therapy. She is the author of Your Guide to Eczema, the editor of the Handbook of Systemic Drug Treatment in Dermatology and a co-editor of A Colour Handbook of Dermatology. Competing interests: SW has done advisory work for Galderma and GSK.
MEDICINE --:-
First line
Second line
Third line
Fourth line
Topical drugs
Ultraviolet phototherapy
Traditional systemic drug
Biological therapy or new small molecule therapy
Table 1
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
TREATMENTS
AZA is a pro-drug and undergoes extensive metabolism (Figure 1). The major active metabolites are 6-thioguanine nucleotides (6TGN). Inactive metabolites are produced by two key enzymes: xanthine oxidase and thiopurine methyl transferase (TPMT). Activity of TPMT is genetically determined. Approximately 10% of the population has reduced TPMT activity, and 0.3% have very low or absent activity (Table 2). These patients are at high risk of bone marrow suppression and severe neutropenia. TPMT activity is routinely measured in dermatology patients before starting AZA; those with very low or absent concentrations should not be given AZA, and for the rest the drug dose is adjusted according to activity (Table 2).1 Careful monitoring is still needed as myelotoxicity can occur in patients with normal TPMT activity. Measurement of 6TGN can help in assessing adherence to treatment and dose optimization, but is not yet routine practice.
Thiopurine methyl transferase (TPMT) activity and azathioprine dosage
0.3 w10 w89
Contraindicated 1.0e1.5 2e3
Methotrexate (MTX) is a derivative of folic acid and an antimetabolite cytotoxic agent. When given once weekly at low dose (up to 25 mg), it has anti-inflammatory and complex immunomodulatory effects. It is licensed for severe psoriasis and is considered the gold standard systemic drug against which newer drugs and biologics are compared. Most patterns of psoriatic arthritis, but not spondyloarthropathy, respond to MTX. It is also an effective treatment for atopic dermatitis, cutaneous sarcoid, connective tissue disease and autoimmune bullous diseases.3 It can be given orally or by subcutaneous injection. Folic acid supplements are usually given to reduce gastrointestinal upset. Bone marrow toxicity is rare and has mainly been associated with renal impairment, dose errors or concomitant drug use, all of which are more common in older patients. MTX can cause drug-induced hepatitis and hepatic fibrosis, which can ultimately progress to cirrhosis. This risk may be greater in patients with pre-existing liver disease associated with obesity, alcohol or metabolic syndrome. Serial measurements of serum amino-terminal peptide of procollagen III (PIIINP) are now routinely made to monitor for MTX-induced hepatic fibrosis (Table 3) and have eliminated the need for routine liver biopsy. Measurement of hepatic ‘stiffness’ by transient elastography (FibroscanÒ) is helpful in detecting early fibrosis but is not yet widely available. Additional testing of a panel of serum markers (e.g. with FibrotestÒ) can improve accuracy.
AZA
6MP XO
6TU (inactive) TIMP
TPMT
6TGN (therapeutic activity)
Cyclophosphamide, a cytotoxic drug used in haematological and solid organ malignancy, is unlicensed in the UK for skin disease except advanced mycosis fungoides. It is used in rare instances at low doses with systemic corticosteroids to treat severe immunobullous disease (pemphigus and cicatricial pemphigoid) and for refractory primary cutaneous vasculitis.
6MeMP, 6-methylmercaptopurine; 6MeMPN, 6-methylmercaptopurine nucleotides; 6MP, 6-mercaptopurine; 6TGN, 6-thioguanine nucleotides; 6TU, 6-thiouric acid; AZA, azathioprine; TPMT, thiopurine methyl transferase (enzyme); XO, xanthine oxidase (enzyme).
Figure 1
MEDICINE --:-
Absent Intermediate Normal/high
Antimetabolites and cytotoxics
Metabolism of AZA (simplified)
6MeMPN
Daily maintenance dose (mg/kg)
common and opportunistic organisms. The drug is also a teratogen, with a distinct pattern of embryopathy,2 so treatment should be stopped at least 6 weeks before conception. Female partners of males taking mycophenolate mofetil should use an effective form of contraception during treatment and for 90 days after the last dose. Patients should be screened for HIV and hepatitis B virus infection before starting any of the above drugs, and frequent monitoring of routine bloods is required, especially at the start of therapy. Long-term immunosuppressant therapy increases the risk of skin cancer, so sun protection advice is important. The risk of lymphoma may also be increased.
Mycophenolate mofetil is widely used in transplant medicine but unlicensed in the UK for skin disease. It is used to treat severe immunobullous disease, connective tissue disease and vasculitides. Enteric-coated formulations have better gastrointestinal tolerability. There is an increased risk of infection with both
6MeMP (inactive)
Prevalence
Table 2
Ciclosporin is a calcineurin inhibitor with immunomodulatory effects on T cells. It is licensed for the treatment of severe atopic eczema and psoriasis. It is also used for pyoderma gangrenosum, severe urticaria and Behc‚et’s disease. Treatment is usually started at 2.5e3 mg/kg per day and escalated to 5 mg/kg per day if rapid disease control is needed. Blood pressure and renal tests (electrolytes, creatinine) should be checked every 2 weeks for the first 3 months and then at least 3-monthly thereafter. Adverse effects of hypertension and chronic nephrotoxicity limit the usefulness of ciclosporin as a long-term therapy, especially in older patients.
TPMT
TPMT range
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
TREATMENTS
Methotrexate (MTX) and non-invasive hepatic monitoring Investigation
Role
Routine liver function tests Serum amino-terminal peptide of procollagen III (PIIINP)
Detects MTX hepatitis. Unreliable/low sensitivity for hepatic fibrosis Routine investigation at baseline and 3-monthly. Sensitivity 77%, specificity 92% for detecting hepatic fibrosis. High negative predictive value of 97%. Concentrations also raised in growing children and bone disease Detects steatosis. Unable to detect hepatic fibrosis until advanced cirrhosis with gross anatomical change Sensitive and specific for fibrosis in other liver disease. Combination with serum biomarkers of fibrosis may improve accuracy. Not routinely available
Routine ultrasonography Transient elastography (FibroscanÒ)
Table 3
Other traditional anti-inflammatory drugs used in dermatology include: dapsone e for neutrophilic disorders including dermatitis herpetiformis, Sweet’s syndrome, and linear IgA bullous disease hydroxychloroquine e for cutaneous lupus and photosensitive skin disorders colchicine e for neutrophilic disorders and Behc‚et’s disease thalidomide e which has complex immunomodulatory effects including suppression of TNF-a; in the UK it is used off-label to treat erythema nodosum leprosum and recalcitrant inflammatory skin disease such as lupus erythematosus, Behc‚et’s disease, nodular prurigo and actinic prurigo. There are strict controls on prescription and dispensing owing to its notorious teratogenicity. Newer analogues have been developed for use in oncology, but these remain extremely expensive and largely untested in dermatology.
Anti-inflammatory drugs Oral glucocorticosteroids are still widely used in dermatology to treat severe inflammatory and allergic skin diseases including eczema, acute urticaria, angioedema, immunobullous diseases, vasculitis, neutrophilic dermatosis (pyoderma gangrenosum, Sweet’s syndrome), connective tissue diseases and severe cutaneous adverse drug reactions. There are numerous, well-established long-term risks, including osteoporosis and fractures, adrenal suppression, weight gain, hyperglycaemia and dyslipidaemia, cataracts, glaucoma, psychiatric disturbance, gastrointestinal and dermatological effects. Use of 5 mg/day or more of prednisolone (or equivalent) is associated with significant reductions in bone mineral density and an increase in fracture risk within 3e6 months of starting treatment. Intervention to prevent osteoporosis, such as lifestyle measures, should start as soon as corticosteroids are prescribed, and bisphosphonate therapy should be considered for individuals at high risk. Apremilast is the first oral phosphodiesterase-4 inhibitor to be licensed for the treatment of psoriasis and psoriatic arthritis. It acts upstream in the inflammatory cascade to raise intracellular concentrations of the messenger molecule cyclic adenosine monophosphate. This leads to reduced concentrations of inducible nitric oxide synthetase, tumour necrosis factor-a (TNF-a) and interleukin (IL)-23, and increased IL-10. These changes reverse the inflammatory pathophysiology in psoriatic skin and joints. Adverse effect such as diarrhoea, nausea and vomiting, upper respiratory tract infection and headache are common. As the drug is also less effective than biologics (see below), it is currently recommended for use in patients who do not respond to or cannot take conventional systemic therapy.
Retinoids Retinoids are vitamin A derivatives with wide-ranging effects on cell growth and differentiation, and on the innate immune system. Three oral retinoids are commonly used in dermatology: acitretin e for severe psoriasis, Darier’s disease and congenital ichthyosis alitretinoin e for severe chronic hand eczema unresponsive to potent topical corticosteroids isotretinoin e for severe, scarring or recalcitrant acne. All oral retinoids can cause drug-induced hepatitis and adverse metabolic effects, particularly hypertriglyceridaemia. They are also powerful teratogens, so there are stringent recommendations for their use in female patients of childbearing age. Acitretin is rarely given to this group owing to the very long half-life of its metabolite etretinate. Female patients taking alitretinoin and isotretinoin should follow a pregnancy prevention plan that includes use of highly effective contraception and monthly pregnancy tests (Table 4). Oral isotretinoin is a very effective treatment for severe acne and has long-lasting benefit. It causes a profound inhibition of sebum production that leads to minor adverse effects of dry lips, mucosal surfaces and skin. Mood change, in particular depression and rarely suicide, has been reported in patients taking
Fumaric acid esters are commonly used in the treatment of psoriasis in Germany but are unlicensed in other countries. Their effects include shifting T lymphocyte profiles towards a T helper cell type 2 phenotype and reducing keratinocyte proliferation. The active ingredient, dimethyl fumarate, is licensed as a treatment for multiple sclerosis and is effective, but is currently unlicensed in the UK for psoriasis. Flushing and gastrointestinal upset are common adverse effects. Rare cases of progressive multifocal leucoencephalopathy (PML) have been reported and may be related to drug-induced lymphopenia.
MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
TREATMENTS
Pregnancy prevention programme with isotretinoin and alitretinoin (required for all female patients of reproductive age) C C C C C
Careful counselling with written information on the risk of retinoid birth deformities Ensure effective contraception if sexually active (ideally two methods) Start contraception 1 month before treatment; continue during treatment and for at least 1 month after treatment Start treatment on the second day of menses Negative pregnancy test before starting treatment and repeated testing at monthly intervals
Table 4
which have been developed primarily as treatment for psoriasis rather than other inflammatory diseases. These drugs are more effective than conventional systemic therapy and have raised the goals of psoriasis treatment, with complete or almost complete disease clearance a possibility for some patients. Cost remains a major barrier to prescribing, even with the availability of biosimilars, and long-term safety data are lacking for newer drugs. The anti-TNF drug adalimumab is now also licensed for hidradenitis suppurativa, a painful, disabling acne-like chronic inflammatory disease of the large flexures that has a profound effect on quality of life. The anti-IgE antibody omalizumab, originally licensed for asthma, is now also licensed for treatment of severe urticaria that has not responded to an increased dosage of second-generation antihistamines. Dupilumab (unlicensed drug), a long-awaited anti-IL-4/IL-13 drug for atopic dermatitis, is due to be marketed shortly. Other biologics used in dermatology include the anti-CD20 monoclonal antibody rituximab for severe immunobullous disease, and the IL-1 receptor antagonist anakinra, given in Schnitzler’s syndrome, a rare autoinflammatory disease with urticaria. Adverse effects of biologics include injection site reactions, infusion reactions and allergy, infection (especially reactivation of tuberculosis with anti-TNF drugs), demyelination and autoimmune syndromes.
isotretinoin; however, it is difficult to be certain of causation as acne itself is associated with these psychological effects. Nevertheless, it is advised that patients should be specifically asked at each visit about mood change. Alitretinoin is the only oral drug specifically licensed for severe hand eczema and is recommended as a second-line treatment in patients who do not respond to topical corticosteroids.4 It appears to be most effective for hyperkeratotic disease variants and can lead to complete disease clearance over a 6-month course of treatment, with improved quality of life. Acitretin is less effective than other traditional treatments (ciclosporin, MTX) for systemic psoriasis, but it lacks immunosuppressive effects. Therefore it is useful for patients with a history of skin malignancy, severe sun damage or internal malignancy.
Biologics Biological drugs are changing the face of dermatology therapy. They are complex protein molecules targeting specific target points in inflammatory or neoplastic processes. They are broadly classified as (Table 5): monoclonal antibodies fusion proteins recombinant human cytokines and growth factors. Treatment of psoriasis has led this field, first with infliximab and other anti-TNF drugs, which have broad anti-inflammatory effects, and then with biological agents acting downstream against IL-12/IL-23. The latest development is IL-17 inhibitors,
Treatment for advanced skin cancer Advanced melanoma has a very poor prognosis, with fast progression and low survival rates. Until recently, there was no specific treatment that improved overall survival. This has changed with the advent of new molecular therapy that significantly prolongs overall survival, including ipilimumab, nivolumab, pembrolizumab, vemurafenib, dabrafenib and trametinib. In advanced melanoma, these act in the following ways: Immunotherapies e ‘immune checkpoint inhibitors’ are designed to boost the immune response to tumours. These include monoclonal antibodies against the cytotoxic T lymphocyte antigen 4 (CTLA4) (ipilimumab) and antiprogrammed cell death protein 1 (PD1) (nivolumab, pembrolizumab). Combination therapy seems superior to monotherapy.5 Targeted drugs against BRAF kinase V600 mutations (vemurafenib, dabrafenib), which occur in about 50% of advanced melanomas, are used in combination with MEK inhibitors (trametinib) to delay the development of resistance. More studies are needed to determine the optimal duration, sequencing and combinations of these agents to further improve survival.
Biological drugs for inflammatory skin disease Monoclonal antibodies C Anti-TNF-a: infliximab, adalimumab C (Anti-LFA1: efalizumab e now withdrawn) C Anti IL-12/IL-23: ustekinumab C Anti-IL-17: secukinumab, ixekizumab C Anti-CD20: rituximab C Anti-IgE: omalizumab C Anti-IL4/IL-13: dupilumab e approval pending Fusion antibody proteins C TNF-a inhibitor: etanercept C (LFA3 inhibitor: alefacept e now withdrawn) Recombinant human cytokines and growth factors C Interferons a and g C IL-1 receptor antagonist IL, interleukin; LFA, lymphocyte function-associated antigen; TNF, tumour necrosis factor.
Table 5
MEDICINE --:-
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
TREATMENTS
Basal cell carcinoma is the most common form of skin cancer, and surgery is curative in most patients. However, a minority of patients develop inoperable or metastatic disease. Vismodegib is a novel hedgehog signalling pathway inhibitor that is effective in these cases and has been shown to shrink and sometimes clear tumours. A
4 Diepgen TL, Andersen KE, Chosidow O, et al. Guidelines for diagnosis, prevention and treatment of hand eczema. J Deutsch Dermatol Ges 2015; 13: e1e22. 5 Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol 2017 Mar; 43: 604e11.
KEY REFERENCES 1 Megitt SJ, Anstey AC, Mustapha MF, Reynolds NJ, Wakelin S. British Association of Dermatologists’ guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol 2011; 165: 711e34. 2 Perez-Aytes A, Marin-Reina P, Boso V, et al. Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet 2017; 60: 16e21. 3 Warren RB, Weatherhead SC, Smith CH, et al. British Association of Dermatologists guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol 2016; 175: 23e44.
FURTHER READING Goodfield MJD, Cox NH, Bowser A, et al. Advice on the safe introduction and continued use of isotretinoin in acne in the UK 2010. Br J Dermatol 2010; 162: 1172e9. Simpson EL, Beiber T, Guttman- Yasslay E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016; 375: 2335e48. Wakelin SH, Maiback HI, Archer CB, eds. Handbook of systemic drug treatment in dermatology. 2nd edn. Boca Raton, FL: CRC Press, Taylor and Francis Group, 2015; 22487e742. Wong DJ, Ribas A. Targeted therapy for melanoma. Cancer Treat Res 2016; 167: 251e62.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
Investigations Routine haematology and biochemistry normal
A 56-year-old man presented with worsening chronic plaque psoriasis that had failed to respond to topical treatment and ultraviolet B phototherapy. He also had psoriatic arthritis and hypertension.
What is the most appropriate additional investigation before commencing treatment? A. Dual-energy X-ray absorptiometry scan B. Erythrocyte thiopurine methyltransferase concentration C. Erythrocyte 6-thioguanine nucleotide concentration D. Serum procollagen III amino-terminal peptide concentration E. Xanthine oxidase genotyping
Investigations Routine haematology and biochemistry negative Estimated glomerular rate 50 ml/minute (>60) HIV serology negative Hepatitis serology negative
Question 3 Which is the most appropriate drug treatment option? A. Azathioprine B. Ciclosporin C. Dupilumab D. High-dose and then tapering oral corticosteroids E. Methotrexate
A 33-year-old pastry chef presented with a 6-month history of widespread hand eczema that had failed to respond to emollients and a 2-month course of potent topical corticosteroids. Patch testing showed no evidence of contact allergies. He had taken sick leave, and his quality of life was severely affected (Dermatology Quality of Life Index score 15). Which treatment should be considered management? A. 1% hydrocortisone cream B. Increasing doses of oral antihistamines C. Oral alitretinoin D. Oral isotretinoin E. Subcutaneous omalizumab
Question 2 A 75-year-old woman presented with a widespread blistering rash. Histology and immunofluorescence confirmed features of bullous pemphigoid. After a month’s treatment with tapering oral prednisolone, a decision was made to start azathioprine as a corticosteroid-sparing drug.
MEDICINE --:-
5
for
further
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
Dermatological pharmacology: systemic drugs
Key points C
Systemic treatment is used to manage acute and chronic severe skin disease
C
Systemic treatment needs careful monitoring for potential adverse effects
C
Systemic treatment needs to be titrated according to the clinical response
Sarah H Wakelin
Abstract Systemic treatment of skin disease is changing rapidly: we are at the dawn of a new era of targeted therapy that is emerging against the background of a clearer understanding of the molecular pathogenesis of common dermatoses and skin cancer. Biological agents and new oral therapies are being developed specifically against the underlying immune abnormalities in common inflammatory skin diseases, especially psoriasis. Biologics are now also indicated for urticaria and hidradenitis suppurativa, and treatment for atopic dermatitis is imminent. These drugs are restricted to severe disease, so conventional systemic therapy with immunosuppressants and anti-inflammatory drugs still plays a major role in the management of skin disease. The very poor prognosis of advanced melanoma has for the first time been improved by new immune and molecularly targeted therapy, although the optimum way of using these drugs remains to be decided.
prescribed by dermatologists. Newer anti-inflammatory targeted drugs include the phosphodiesterase 4 inhibitor apremilast, and oral janus kinase inhibitors are at an advanced stage of development. Biological drugs and targeted therapies are the latest addition to systemic therapy in dermatology. They are much more finely aimed at the underlying immunopathogenesis of individual diseases and offer the chance of more effective and safer treatment; long-term safety remains, however, unproven for most. These drugs are expensive and are therefore restricted to patients with severe skin disease. The psychosocial impact of skin disease is an important consideration, so measures such as the Dermatology Life Quality Index are used in deciding patient eligibility. To help patients share in treatment decisions, it is essential that the prescribing physician gives a clear and comprehensive explanation of the risks versus benefits of therapy. Careful documentation in the medical records provides evidence of informed consent to treatment in the event of subsequent litigation.
Keywords Anti-inflammatory; antimetabolite; azathioprine; biologics; ciclosporin; immunosuppressants; immunotherapies; methotrexate; retinoids; systemic
Introduction Immunosuppressants
Most patients with inflammatory skin diseases, in particular eczema and psoriasis, are managed with long-term or intermittent topical therapy that controls disease activity and symptoms. Phototherapy is a second-line option; if this is not effective or practical, the next step is systemic therapy with immunosuppressant/immunomodulating drugs (Table 1). These drugs are also used for rarer severe and life-threatening inflammatory rashes such as autoimmune blistering diseases, neutrophilic dermatoses, vasculitides and connective tissue disease; in many cases, this use is off-licence. Immunosuppressants have broad mechanisms of action and are usually effective in controlling inflammatory disease, but they require close and careful monitoring owing to potential toxicity. Systemic retinoids, corticosteroids and miscellaneous drugs such as antimalarials, dapsone and colchicine are also still widely
Several drugs that were originally developed to prevent organ transplant rejection are used in dermatology therapy. Azathioprine (AZA) is a synthetic purine analogue that interferes with DNA synthesis and inhibits cell proliferation in rapidly dividing cells, especially lymphocytes. It is licensed for the treatment of pemphigus, systemic lupus erythematous and dermatomyositis/polymyositis; it is also an effective monotherapy for severe atopic eczema in adults and children. AZA is also commonly used as a corticosteroid-sparing drug for the autoimmune blistering disease bullous pemphigoid. The onset of action in these diseases is slower than those of other immunosuppressants.
General treatment hierarchy for psoriasis and inflammatory skin disease Sarah H Wakelin BSc MBBS FRCP is a Consultant Dermatologist at St Mary’s Hospital, Imperial College Healthcare Trust, London, UK. She has a special interest in allergic and inflammatory skin diseases and dermatological therapy. She is the author of Your Guide to Eczema, the editor of the Handbook of Systemic Drug Treatment in Dermatology and a co-editor of A Colour Handbook of Dermatology. Competing interests: SW has done advisory work for Galderma and GSK.
MEDICINE --:-
First line
Second line
Third line
Fourth line
Topical drugs
Ultraviolet phototherapy
Traditional systemic drug
Biological therapy or new small molecule therapy
Table 1
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
TREATMENTS
AZA is a pro-drug and undergoes extensive metabolism (Figure 1). The major active metabolites are 6-thioguanine nucleotides (6TGN). Inactive metabolites are produced by two key enzymes: xanthine oxidase and thiopurine methyl transferase (TPMT). Activity of TPMT is genetically determined. Approximately 10% of the population has reduced TPMT activity, and 0.3% have very low or absent activity (Table 2). These patients are at high risk of bone marrow suppression and severe neutropenia. TPMT activity is routinely measured in dermatology patients before starting AZA; those with very low or absent concentrations should not be given AZA, and for the rest the drug dose is adjusted according to activity (Table 2).1 Careful monitoring is still needed as myelotoxicity can occur in patients with normal TPMT activity. Measurement of 6TGN can help in assessing adherence to treatment and dose optimization, but is not yet routine practice.
Thiopurine methyl transferase (TPMT) activity and azathioprine dosage
0.3 w10 w89
Contraindicated 1.0e1.5 2e3
Methotrexate (MTX) is a derivative of folic acid and an antimetabolite cytotoxic agent. When given once weekly at low dose (up to 25 mg), it has anti-inflammatory and complex immunomodulatory effects. It is licensed for severe psoriasis and is considered the gold standard systemic drug against which newer drugs and biologics are compared. Most patterns of psoriatic arthritis, but not spondyloarthropathy, respond to MTX. It is also an effective treatment for atopic dermatitis, cutaneous sarcoid, connective tissue disease and autoimmune bullous diseases.3 It can be given orally or by subcutaneous injection. Folic acid supplements are usually given to reduce gastrointestinal upset. Bone marrow toxicity is rare and has mainly been associated with renal impairment, dose errors or concomitant drug use, all of which are more common in older patients. MTX can cause drug-induced hepatitis and hepatic fibrosis, which can ultimately progress to cirrhosis. This risk may be greater in patients with pre-existing liver disease associated with obesity, alcohol or metabolic syndrome. Serial measurements of serum amino-terminal peptide of procollagen III (PIIINP) are now routinely made to monitor for MTX-induced hepatic fibrosis (Table 3) and have eliminated the need for routine liver biopsy. Measurement of hepatic ‘stiffness’ by transient elastography (FibroscanÒ) is helpful in detecting early fibrosis but is not yet widely available. Additional testing of a panel of serum markers (e.g. with FibrotestÒ) can improve accuracy.
AZA
6MP XO
6TU (inactive) TIMP
TPMT
6TGN (therapeutic activity)
Cyclophosphamide, a cytotoxic drug used in haematological and solid organ malignancy, is unlicensed in the UK for skin disease except advanced mycosis fungoides. It is used in rare instances at low doses with systemic corticosteroids to treat severe immunobullous disease (pemphigus and cicatricial pemphigoid) and for refractory primary cutaneous vasculitis.
6MeMP, 6-methylmercaptopurine; 6MeMPN, 6-methylmercaptopurine nucleotides; 6MP, 6-mercaptopurine; 6TGN, 6-thioguanine nucleotides; 6TU, 6-thiouric acid; AZA, azathioprine; TPMT, thiopurine methyl transferase (enzyme); XO, xanthine oxidase (enzyme).
Figure 1
MEDICINE --:-
Absent Intermediate Normal/high
Antimetabolites and cytotoxics
Metabolism of AZA (simplified)
6MeMPN
Daily maintenance dose (mg/kg)
common and opportunistic organisms. The drug is also a teratogen, with a distinct pattern of embryopathy,2 so treatment should be stopped at least 6 weeks before conception. Female partners of males taking mycophenolate mofetil should use an effective form of contraception during treatment and for 90 days after the last dose. Patients should be screened for HIV and hepatitis B virus infection before starting any of the above drugs, and frequent monitoring of routine bloods is required, especially at the start of therapy. Long-term immunosuppressant therapy increases the risk of skin cancer, so sun protection advice is important. The risk of lymphoma may also be increased.
Mycophenolate mofetil is widely used in transplant medicine but unlicensed in the UK for skin disease. It is used to treat severe immunobullous disease, connective tissue disease and vasculitides. Enteric-coated formulations have better gastrointestinal tolerability. There is an increased risk of infection with both
6MeMP (inactive)
Prevalence
Table 2
Ciclosporin is a calcineurin inhibitor with immunomodulatory effects on T cells. It is licensed for the treatment of severe atopic eczema and psoriasis. It is also used for pyoderma gangrenosum, severe urticaria and Behc‚et’s disease. Treatment is usually started at 2.5e3 mg/kg per day and escalated to 5 mg/kg per day if rapid disease control is needed. Blood pressure and renal tests (electrolytes, creatinine) should be checked every 2 weeks for the first 3 months and then at least 3-monthly thereafter. Adverse effects of hypertension and chronic nephrotoxicity limit the usefulness of ciclosporin as a long-term therapy, especially in older patients.
TPMT
TPMT range
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006
TREATMENTS
Methotrexate (MTX) and non-invasive hepatic monitoring Investigation
Role
Routine liver function tests Serum amino-terminal peptide of procollagen III (PIIINP)
Detects MTX hepatitis. Unreliable/low sensitivity for hepatic fibrosis Routine investigation at baseline and 3-monthly. Sensitivity 77%, specificity 92% for detecting hepatic fibrosis. High negative predictive value of 97%. Concentrations also raised in growing children and bone disease Detects steatosis. Unable to detect hepatic fibrosis until advanced cirrhosis with gross anatomical change Sensitive and specific for fibrosis in other liver disease. Combination with serum biomarkers of fibrosis may improve accuracy. Not routinely available
Routine ultrasonography Transient elastography (FibroscanÒ)
Table 3
Other traditional anti-inflammatory drugs used in dermatology include: dapsone e for neutrophilic disorders including dermatitis herpetiformis, Sweet’s syndrome, and linear IgA bullous disease hydroxychloroquine e for cutaneous lupus and photosensitive skin disorders colchicine e for neutrophilic disorders and Behc‚et’s disease thalidomide e which has complex immunomodulatory effects including suppression of TNF-a; in the UK it is used off-label to treat erythema nodosum leprosum and recalcitrant inflammatory skin disease such as lupus erythematosus, Behc‚et’s disease, nodular prurigo and actinic prurigo. There are strict controls on prescription and dispensing owing to its notorious teratogenicity. Newer analogues have been developed for use in oncology, but these remain extremely expensive and largely untested in dermatology.
Anti-inflammatory drugs Oral glucocorticosteroids are still widely used in dermatology to treat severe inflammatory and allergic skin diseases including eczema, acute urticaria, angioedema, immunobullous diseases, vasculitis, neutrophilic dermatosis (pyoderma gangrenosum, Sweet’s syndrome), connective tissue diseases and severe cutaneous adverse drug reactions. There are numerous, well-established long-term risks, including osteoporosis and fractures, adrenal suppression, weight gain, hyperglycaemia and dyslipidaemia, cataracts, glaucoma, psychiatric disturbance, gastrointestinal and dermatological effects. Use of 5 mg/day or more of prednisolone (or equivalent) is associated with significant reductions in bone mineral density and an increase in fracture risk within 3e6 months of starting treatment. Intervention to prevent osteoporosis, such as lifestyle measures, should start as soon as corticosteroids are prescribed, and bisphosphonate therapy should be considered for individuals at high risk. Apremilast is the first oral phosphodiesterase-4 inhibitor to be licensed for the treatment of psoriasis and psoriatic arthritis. It acts upstream in the inflammatory cascade to raise intracellular concentrations of the messenger molecule cyclic adenosine monophosphate. This leads to reduced concentrations of inducible nitric oxide synthetase, tumour necrosis factor-a (TNF-a) and interleukin (IL)-23, and increased IL-10. These changes reverse the inflammatory pathophysiology in psoriatic skin and joints. Adverse effect such as diarrhoea, nausea and vomiting, upper respiratory tract infection and headache are common. As the drug is also less effective than biologics (see below), it is currently recommended for use in patients who do not respond to or cannot take conventional systemic therapy.
Retinoids Retinoids are vitamin A derivatives with wide-ranging effects on cell growth and differentiation, and on the innate immune system. Three oral retinoids are commonly used in dermatology: acitretin e for severe psoriasis, Darier’s disease and congenital ichthyosis alitretinoin e for severe chronic hand eczema unresponsive to potent topical corticosteroids isotretinoin e for severe, scarring or recalcitrant acne. All oral retinoids can cause drug-induced hepatitis and adverse metabolic effects, particularly hypertriglyceridaemia. They are also powerful teratogens, so there are stringent recommendations for their use in female patients of childbearing age. Acitretin is rarely given to this group owing to the very long half-life of its metabolite etretinate. Female patients taking alitretinoin and isotretinoin should follow a pregnancy prevention plan that includes use of highly effective contraception and monthly pregnancy tests (Table 4). Oral isotretinoin is a very effective treatment for severe acne and has long-lasting benefit. It causes a profound inhibition of sebum production that leads to minor adverse effects of dry lips, mucosal surfaces and skin. Mood change, in particular depression and rarely suicide, has been reported in patients taking
Fumaric acid esters are commonly used in the treatment of psoriasis in Germany but are unlicensed in other countries. Their effects include shifting T lymphocyte profiles towards a T helper cell type 2 phenotype and reducing keratinocyte proliferation. The active ingredient, dimethyl fumarate, is licensed as a treatment for multiple sclerosis and is effective, but is currently unlicensed in the UK for psoriasis. Flushing and gastrointestinal upset are common adverse effects. Rare cases of progressive multifocal leucoencephalopathy (PML) have been reported and may be related to drug-induced lymphopenia.
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TREATMENTS
Pregnancy prevention programme with isotretinoin and alitretinoin (required for all female patients of reproductive age) C C C C C
Careful counselling with written information on the risk of retinoid birth deformities Ensure effective contraception if sexually active (ideally two methods) Start contraception 1 month before treatment; continue during treatment and for at least 1 month after treatment Start treatment on the second day of menses Negative pregnancy test before starting treatment and repeated testing at monthly intervals
Table 4
which have been developed primarily as treatment for psoriasis rather than other inflammatory diseases. These drugs are more effective than conventional systemic therapy and have raised the goals of psoriasis treatment, with complete or almost complete disease clearance a possibility for some patients. Cost remains a major barrier to prescribing, even with the availability of biosimilars, and long-term safety data are lacking for newer drugs. The anti-TNF drug adalimumab is now also licensed for hidradenitis suppurativa, a painful, disabling acne-like chronic inflammatory disease of the large flexures that has a profound effect on quality of life. The anti-IgE antibody omalizumab, originally licensed for asthma, is now also licensed for treatment of severe urticaria that has not responded to an increased dosage of second-generation antihistamines. Dupilumab (unlicensed drug), a long-awaited anti-IL-4/IL-13 drug for atopic dermatitis, is due to be marketed shortly. Other biologics used in dermatology include the anti-CD20 monoclonal antibody rituximab for severe immunobullous disease, and the IL-1 receptor antagonist anakinra, given in Schnitzler’s syndrome, a rare autoinflammatory disease with urticaria. Adverse effects of biologics include injection site reactions, infusion reactions and allergy, infection (especially reactivation of tuberculosis with anti-TNF drugs), demyelination and autoimmune syndromes.
isotretinoin; however, it is difficult to be certain of causation as acne itself is associated with these psychological effects. Nevertheless, it is advised that patients should be specifically asked at each visit about mood change. Alitretinoin is the only oral drug specifically licensed for severe hand eczema and is recommended as a second-line treatment in patients who do not respond to topical corticosteroids.4 It appears to be most effective for hyperkeratotic disease variants and can lead to complete disease clearance over a 6-month course of treatment, with improved quality of life. Acitretin is less effective than other traditional treatments (ciclosporin, MTX) for systemic psoriasis, but it lacks immunosuppressive effects. Therefore it is useful for patients with a history of skin malignancy, severe sun damage or internal malignancy.
Biologics Biological drugs are changing the face of dermatology therapy. They are complex protein molecules targeting specific target points in inflammatory or neoplastic processes. They are broadly classified as (Table 5): monoclonal antibodies fusion proteins recombinant human cytokines and growth factors. Treatment of psoriasis has led this field, first with infliximab and other anti-TNF drugs, which have broad anti-inflammatory effects, and then with biological agents acting downstream against IL-12/IL-23. The latest development is IL-17 inhibitors,
Treatment for advanced skin cancer Advanced melanoma has a very poor prognosis, with fast progression and low survival rates. Until recently, there was no specific treatment that improved overall survival. This has changed with the advent of new molecular therapy that significantly prolongs overall survival, including ipilimumab, nivolumab, pembrolizumab, vemurafenib, dabrafenib and trametinib. In advanced melanoma, these act in the following ways: Immunotherapies e ‘immune checkpoint inhibitors’ are designed to boost the immune response to tumours. These include monoclonal antibodies against the cytotoxic T lymphocyte antigen 4 (CTLA4) (ipilimumab) and antiprogrammed cell death protein 1 (PD1) (nivolumab, pembrolizumab). Combination therapy seems superior to monotherapy.5 Targeted drugs against BRAF kinase V600 mutations (vemurafenib, dabrafenib), which occur in about 50% of advanced melanomas, are used in combination with MEK inhibitors (trametinib) to delay the development of resistance. More studies are needed to determine the optimal duration, sequencing and combinations of these agents to further improve survival.
Biological drugs for inflammatory skin disease Monoclonal antibodies C Anti-TNF-a: infliximab, adalimumab C (Anti-LFA1: efalizumab e now withdrawn) C Anti IL-12/IL-23: ustekinumab C Anti-IL-17: secukinumab, ixekizumab C Anti-CD20: rituximab C Anti-IgE: omalizumab C Anti-IL4/IL-13: dupilumab e approval pending Fusion antibody proteins C TNF-a inhibitor: etanercept C (LFA3 inhibitor: alefacept e now withdrawn) Recombinant human cytokines and growth factors C Interferons a and g C IL-1 receptor antagonist IL, interleukin; LFA, lymphocyte function-associated antigen; TNF, tumour necrosis factor.
Table 5
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TREATMENTS
Basal cell carcinoma is the most common form of skin cancer, and surgery is curative in most patients. However, a minority of patients develop inoperable or metastatic disease. Vismodegib is a novel hedgehog signalling pathway inhibitor that is effective in these cases and has been shown to shrink and sometimes clear tumours. A
4 Diepgen TL, Andersen KE, Chosidow O, et al. Guidelines for diagnosis, prevention and treatment of hand eczema. J Deutsch Dermatol Ges 2015; 13: e1e22. 5 Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol 2017 Mar; 43: 604e11.
KEY REFERENCES 1 Megitt SJ, Anstey AC, Mustapha MF, Reynolds NJ, Wakelin S. British Association of Dermatologists’ guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol 2011; 165: 711e34. 2 Perez-Aytes A, Marin-Reina P, Boso V, et al. Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet 2017; 60: 16e21. 3 Warren RB, Weatherhead SC, Smith CH, et al. British Association of Dermatologists guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol 2016; 175: 23e44.
FURTHER READING Goodfield MJD, Cox NH, Bowser A, et al. Advice on the safe introduction and continued use of isotretinoin in acne in the UK 2010. Br J Dermatol 2010; 162: 1172e9. Simpson EL, Beiber T, Guttman- Yasslay E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016; 375: 2335e48. Wakelin SH, Maiback HI, Archer CB, eds. Handbook of systemic drug treatment in dermatology. 2nd edn. Boca Raton, FL: CRC Press, Taylor and Francis Group, 2015; 22487e742. Wong DJ, Ribas A. Targeted therapy for melanoma. Cancer Treat Res 2016; 167: 251e62.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
Investigations Routine haematology and biochemistry normal
A 56-year-old man presented with worsening chronic plaque psoriasis that had failed to respond to topical treatment and ultraviolet B phototherapy. He also had psoriatic arthritis and hypertension.
What is the most appropriate additional investigation before commencing treatment? A. Dual-energy X-ray absorptiometry scan B. Erythrocyte thiopurine methyltransferase concentration C. Erythrocyte 6-thioguanine nucleotide concentration D. Serum procollagen III amino-terminal peptide concentration E. Xanthine oxidase genotyping
Investigations Routine haematology and biochemistry negative Estimated glomerular rate 50 ml/minute (>60) HIV serology negative Hepatitis serology negative
Question 3 Which is the most appropriate drug treatment option? A. Azathioprine B. Ciclosporin C. Dupilumab D. High-dose and then tapering oral corticosteroids E. Methotrexate
A 33-year-old pastry chef presented with a 6-month history of widespread hand eczema that had failed to respond to emollients and a 2-month course of potent topical corticosteroids. Patch testing showed no evidence of contact allergies. He had taken sick leave, and his quality of life was severely affected (Dermatology Quality of Life Index score 15). Which treatment should be considered management? A. 1% hydrocortisone cream B. Increasing doses of oral antihistamines C. Oral alitretinoin D. Oral isotretinoin E. Subcutaneous omalizumab
Question 2 A 75-year-old woman presented with a widespread blistering rash. Histology and immunofluorescence confirmed features of bullous pemphigoid. After a month’s treatment with tapering oral prednisolone, a decision was made to start azathioprine as a corticosteroid-sparing drug.
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Please cite this article in press as: Wakelin SH, Dermatological pharmacology: systemic drugs, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.03.006