Psoriasis is a common skin disease characterized by thickened patches of red, inflamed skin, often covered by silvery scales. The disease usually appears between the ages of 10 and 30, tends to run in families, and affects both men and women. The exact cause of the disease is unknown, although one form (guttate psoriasis) may be caused by a streptococcal infection, such as tonsillitis.
Symptoms and Types
In psoriasis, new skin cells are made about ten times faster than normal. The excess cells accumulate, forming thickened patches covered with dead, flaking skin. Sometimes, there is also a painful swelling and stiffness of the joints. Psoriasis tends to recur in attacks, which may be triggered by factors such as emotional stress, skin damage, and physical illness. There are different forms of the disease, and the most common of which is discoid, or plaque, psoriasis, in which patches appear on the trunk, limbs, and scalp. Another type, guttate psoriasis, occurs most often in children, and consists of many small patches that develop over a wide area of skin. Pustular psoriasis is characterized by small pustules over part or all of the body.
In most cases of psoriasis, the condition can be improved with topical treatments, such as those containing corticosteroid drugs, coal tar, calcipotriol and other vitamin D analogues. Other treatments include dithranol ointment, PUVA, and drugs such as methotrexate. Psoriasis is usually a long-term condition.
Psoriasis in detail - technical article
Psoriasis is one of the most common and easily identifiable inflammatory skin diseases. In Western Europe the prevalence of psoriasis is estimated at 2%, but is higher in parts of Scandinavia, e.g. the Faroe Islands, where it reaches 5%. Worldwide, the disease is rare in Inuit, native American, Japanese, and Afro–Caribbean people, and has been estimated to affect just 0.3% of the general population in China. There is no evidence that the incidence of the disease is changing, by contrast with the year-on-year increase in atopic dermatitis. Overall, the sex incidence is equal, and the mean age of onset is 33 years, but 75% of cases occur before the age of 40 years. Disease starts earlier in females than males, indicating hormonal influences. Late-onset disease (type II), occurring after the age of 40 years, reaches a peak at onset between the ages of 55 and 65 years. There appears to be no association with either social class or diet.
Early-onset type I psoriasis is familial; one-third of patients have a first-degree relative with the disease. It is apparent that this form of psoriasis is genetically predetermined and polygenic. At least nine chromosomal psoriasis susceptibility loci have been identified. The most robust association is with chromosome 6p, probably involving MHC class I allele HLA Cw6, which contributes up to 50% of the risk in patients with psoriasis. No gene or gene product has thus far been definitively associated with psoriasis, but corneodesmosin, expressed solely in the upper layers of the epidermis, is a strong candidate. Type II psoriasis is not associated with HLA Cw6, and may be a separate disease.
Twin studies underscore the importance of an interaction between environment and genotype for the expression of psoriasis, and concordance is 72% in monozygotes. Environmental triggers in genetically susceptible individuals include: β-haemolytic streptococcal tonsillitis/pharyngitis; physical and psychological stress; HIV infection; drugs including β-blockers, nonsteroidal anti-inflammatories, lithium, and antimalarials; and alcohol.
The most common form of psoriasis, chronic plaque psoriasis or psoriasis vulgaris, accounts for 90% of cases. The characteristic features are well-circumscribed red plaques covered with silvery-white scales. These occur most commonly on the extensor aspects of the knees and elbows, the lower back, and the scalp, although any skin surface may be affected. Plaques are frequently strikingly symmetrical, varying in diameter from less than 1 cm to more than 10 cm. Individual plaques are dynamic, such that in active disease a plaque may clear from the centre to leave an annular or gyrate configuration that to the uninitiated could be misdiagnosed as tinea corporis.
Images below: plaque psoriasis on elbow and arm
Various phenotypes of psoriasis exist:
Named from the Latin guttata, meaning a droplet. This form classically occurs 2 to 3 weeks after streptococcal pharyngitis or tonsillitis, and is the most common presentation in childhood. Onset is acute, with a predominantly centripetal distribution of small (<1 cm diameter) papules. This form of psoriasis is frequently self limiting.
Total skin involvement by psoriasis is known as erythroderma, although this term is also used for any inflammatory skin disease affecting more than 90% of the skin’s surface area. Other diseases producing erythroderma include atopic dermatitis, lichen planus, drug eruptions, and cutaneous T-cell lymphoma. Erythroderma, particularly in older people, can lead to fluid loss, hypocalcaemia, impaired thermoregulation (both hypo- and hyperthermia), and high-output cardiac failure.
Generalized pustular psoriasis
Generalized pustular psoriasis, known also as Von Zumbusch’s disease, is described as an acute onset of painful red plaques of psoriasis studded with small sterile pustules. This form of psoriasis is usually indicative of unstable disease, particularly that precipitated by infection or acute withdrawal of either systemic glucocorticosteroids or, on occasion, high-potency topical corticosteroids, leading to a rebound pustular flare. The patient is systemically unwell, with pyrexia and influenza-like symptoms.
Flexural psoriasis (psoriasis inversa) pertains to a form that involves the groins, axillae, and inframammary regions. Psoriasis at these sites loses many of the characteristic clinical features, in that it is shiny, nonscaly, and bright red, but retains the characteristic clear demarcation between involved and uninvolved skin.
This form of psoriasis occurs in the seborrhoeic sites of the nasolabial folds, eyebrows, scalp, postauricular region, and presternum. At times it may be difficult to distinguish it from seborrhoeic dermatitis.
The scalp is often the first and sometimes the only site to be affected by psoriasis. Paradoxically, it may be the most difficult form of psoriasis to treat. The lesions vary from typical plaques to involvement of the entire scalp, with the encroachment of scales along the hair shafts, a process known as tinea amiantacea. Rarely do the lesions extend beyond the hairline. Alopecia may at times be a consequence.
The appearance of psoriasis at sites of recent trauma or pressure to the skin, such as under a tight waistband, is known as the isomorphic or Koebner phenomenon. Although not unique to psoriasis (it occurs also in lichen planus, viral warts, and vitiligo) it is a clinical marker of active, progressive psoriasis.
Approximately 50% of patients with psoriasis have characteristic clinical involvement of any one or up to all the finger and toe nails. The involvement of the skin of the fingers by psoriasis, and the presence of psoriatic arthritis, predispose to nail disease. The clinical features range from thimble-like pitting of the nail plate, to onycholysis (separation of the nail from the nail bed), oil spots (orange discolouration of the nail bed), and disabling nail dystrophy. Patients are frequently concerned about nail disease, and may request treatment for this aspect of psoriasis alone.
Chronic plaque psoriasis is associated with several comorbid conditions, which include:
Inflammatory bowel disease
Ten per cent of patients with inflammatory bowel disease, particularly Crohn’s disease, have concomitant psoriasis.
Now believed to be a condition separate from psoriasis, palmoplantar pustulosis has been reclassified as a comorbid condition. Yellow sterile painful pustules occur on the palms and soles, fading to brown scaled lesions. Up to 25% of patients have coexistent chronic plaque psoriasis. This is a disease of middle-aged women (female: male ratio 9:1), and more than 95% are current or previous smokers. There is an association with thyroid disease.
This seronegative inflammatory arthritis occurs in more than 25% of patients with psoriasis. Most cases present either concomitantly with or after the first signs of skin disease, but on occasion (<10%) the arthritis predates psoriasis. Five clinical phenotypes of psoriatic arthritis exist: asymmetrical distal interphalangeal arthritis (most commonly and classically), oligoarthritis, polyarthritis, spondylitis, and arthritis mutilans. A characteristic, perhaps pathognomonic, radiological feature is the presence of enthesitis—inflammation of a tendon sheath, particularly the Achilles. The immunogenetics of psoriatic arthritis are different from those of psoriasis, implying that the underlying pathogenic mechanisms are separate.
Emerging evidence suggests that patients with severe psoriasis have an increased incidence of the metabolic syndrome, particularly the components of diabetes mellitus, central obesity, hypertension, hyperlipidaemia, and coronary artery disease. There is also a threefold increased risk of myocardial infarction in young patients with severe disease. It is unknown whether these signs are a consequence of psoriasis per se or of chronic inflammation, as is the case with arthritis.
Psoriasis is associated with significant impairment of quality of life. Studies have shown that this is equivalent to or worse than for other chronic diseases, including chronic obstructive airways disease, diabetes mellitus, and ischaemic heart disease. There is a significant association with clinical anxiety, depression, and suicidal ideation. Worry about the chronicity of psoriasis produces resistance to therapy.
The classical histology of psoriasis comprises epidermal keratinocyte hyperproliferation and loss of markers of differentiation, e.g. keratins 1 and 10, loss of the granular cell layer, and parakeratosis of the stratum corneum. The epidermis also contains microabscesses (of Munro) and collections of neutrophils (micropustules of Kogoj). There is, at times, a significant inflammatory infiltrate comprising predominantly T lymphocytes, with localization of CD8+ T cells in the epidermis and CD4+ T cells in the dermis. Dilated blood vessels are prominent in the dermis.
Above: Histological section of psoriasis showing epidermal acanthosis, elongation of rete ridges, and inflammation
For many years it was believed that psoriasis was a disease primarily of keratinocytes, and that the inflammatory infiltrate was a secondary phenomenon. Current understanding of psoriasis is that it is an immune-mediated dermatosis, probably autoimmune in origin, although no autoantigen has been identified to date.
Components of the innate and adaptive immune responses play important roles in pathogenesis. CD8+ T cells within plaques are clonal, and most T cells are positive for cutaneous lymphocyte-associated antigen. It is believed that in the case of streptococcal pharyngitis there is stimulation and subsequent expansion of T cells, which cross-react with components of keratin in the epidermis. The central importance of T cells to the psoriatic process has been confirmed by the efficacy of T-cell targeted drugs including ciclosporin, an interleukin 2 (IL-2) diphtheria fusion toxin that is cytolytic for activated T cells, and biological therapies including efalizumab, a monoclonal antibody to CD11a. Natural killer and natural killer T cells also participate in the psoriatic process.
Plaques of psoriasis contain a predominance of Th1 cytokines, including interferon-γ, IL-2, and IL-12/23. By contrast, atopic dermatitis is primarily a Th2-cytokine-driven disease. This is confirmed by observations that atopic dermatitis is relatively rare in patients with psoriasis. Cytokines and chemokines of the innate immune response, including tumour necrosis factor-α (TNFα), are also present in plaques of psoriasis, and the demonstrated efficacy of biological agents targeted to TNFα has underscored the key role of this cytokine in the pathogenesis of psoriasis.
Keratinocytes are again the focus of researchers, in that the disruption of signalling in keratinocytes, either by abrogating activated protein 1 (AP-1) pathways such as jun-A, or up-regulating signal transducer and activator of transcription 3 (STAT3), will lead to cutaneous psoriasiform changes in the skin of transgenic mice. Angiogenesis is an underinvestigated area in psoriasis, but there is compelling evidence for significant vascular proliferation and angiogenesis in the dermis, and that this is associated with the overexpression of vascular endothelial growth factor produced by epidermal keratinocytes.
Research on the pathogenesis of psoriasis is hindered by the absence of an animal model for the disease—psoriasis occurs in no other animal but humans. The most reliable model for psoriasis is xenotransplantation, which involves transplantation of biopsies of uninvolved, clinically symptomless skin from patients with psoriasis onto the flanks of immunodeficient mice.
The management of psoriasis, as with any other chronic skin disease, involves a biopsychosocial approach and an understanding of the individual patient’s expectations of therapy. At present there is no cure. In the United Kingdom, 80% of patients with psoriasis can, with the use of topical agents, be treated adequately in primary care. Patients should be educated about psoriasis, e.g. it is not caused by diet, and is neither contagious nor neoplastic. An understanding of how psoriasis interferes with a patient’s daily activities, and the psychosocial disability associated with anxiety and depression, are key aspects of the consultation. Indeed, cognitive behavioural therapy is often a useful adjunctive management tool. Environmental triggers of psoriasis should be ascertained, such as underlying infection, including streptococcal pharyngitis/tonsillitis, and drug triggers. Up to 50% of patients with psoriasis may enter spontaneous remission for varying periods of time, but in most cases it is a persistent and lifelong disease.
In all cases the liberal use of emollients is important. Topical therapies are aimed at directly reducing the epidermal keratinocyte proliferation or the inflammatory mediators that drive the epidermal changes.
Vitamin D3 analogues
A major advance in the topical treatment of psoriasis in the past 20 years has been the introduction of vitamin D3 analogues. These include calcipotriol, calcitriol, and tacalcitol. All vitamin D3 analogues directly inhibit keratinocyte proliferation, but also switch intraplaque cytokines from a Th1 to a Th2 profile. Calcipotriol and calcitriol are applied twice daily, whereas tacalcitol is used once daily. Local side effects include the irritation of uninvolved skin, and if used over an extensive body surface area, a risk of hypercalcaemia. A recent innovation has been the combination of calcipotriol with betamethasone valerate in a once-daily preparation. This enhances efficacy and reduces irritation.
Worldwide, topical corticosteroids are still the predominant therapy for localized chronic plaque psoriasis. If used appropriately, they can be a valuable component of the armamentarium. Medium- and high-potency topical corticosteroids in ointment formulation are the most effective, but should be used for no more than 2 weeks on a continuous basis, and not on the face or in the flexures. Higher potency steroids carry an increased risk of rebound flare on withdrawal. To minimize complications various innovative regimens are employed, such as weekends-only usage, combination with nonsteroidal drugs such as calcipotriol (see above), and tapering to less potent topical steroids.
Tazarotene is the only topical vitamin A derivative available for the treatment of psoriasis. This is used once daily at night, the main limitation being a high incidence of local irritation. It is best used for recalcitrant plaques of psoriasis, particularly on the palms and soles.
The calcineurin inhibitor tacrolimus, although only approved for the treatment of atopic dermatitis, has an advantage over topical corticosteroids in that it does not produce skin atrophy. It is effective for the treatment of facial and flexural psoriasis.
Dithranol (formerly anthralin) has been one of the main topical treatments for psoriasis for many years. The mechanism of action is via an inhibitory effect on mitochondria. Dithranol is applied once daily, usually in a short-contact (30–60 min) outpatient regimen. Significant skin irritation, and staining of involved and uninvolved skin, clothing, and furniture nowadays limits dithranol to inpatient and day-treatment centre usage. The Ingram regimen is the combination of dithranol with ultraviolet B (UVB) phototherapy. With the advent of vitamin D3 analogues the use of dithranol has declined significantly over the past 20 years.
Coal tar has been a standby of treatment for psoriasis for over 100 years; the classical psoriasis treatment, the Goeckerman regimen, involves a combination of crude coal tar with UVB phototherapy. Dissatisfaction with the cosmetic aspects of crude coal tar, in addition to skin irritation and folliculitis, has reduced its use as a routine outpatient therapy, and it is mostly limited to day-treatment centre or inpatient management of psoriasis.
Broadband and narrowband UVB
Natural sunlight has been used for centuries for the treatment of psoriasis. The Dead Sea, because of its salinity and the abundant UV radiation, is a popular destination for psoriasis patients. The most effective wavelength of UV radiation for psoriasis is in the narrowband (311–313 nm) range. Narrowband UVB phototherapy is an effective treatment for psoriasis, and is superior to traditional broadband UVB phototherapy. UVB phototherapy is performed as an outpatient procedure following determination of the minimal erythema dose, based on an individual patient’s skin phototype. Twenty-five year follow-up studies have not demonstrated significant increases in melanoma or nonmelanoma skin cancers in patients receiving narrowband UVB phototherapy.
Psoralen UVA (PUVA) photochemotherapy is a combination of an ingested psoralen photosensitizer (8-methoxypsoralen or 5-methoxypsoralen), followed by exposure to UVA. This is one of the most effective treatments available for psoriasis. Apart from immediate side effects, which include nausea, headache, sunburn, and photosensitivity, there is a significant risk of premature skin ageing (photodamage) and nonmelanoma skin cancer, particularly in those who have received a cumulative dose of 1 000 mJ/m2 or 250 treatments. Side effects are reduced to some extent by bath PUVA, which involves immersion in a dilute aqueous solution of psoralen for 30 min before UVA exposure. PUVA patients should wear spectacles with plastic lenses, and avoid natural sun exposure on the day of treatment. Because of the complexities of treatment and significant skin cancer risk, the use of PUVA is declining.
Only a minority of psoriasis patients require therapy with systemic agents; most can be managed with topical therapies. However, some patients have disease that is too extensive, unstable, inflammatory, or recalcitrant for topical therapies, and thus phototherapy or systemic therapy is indicated.
Methotrexate is a folic acid antagonist that inhibits DNA synthesis and thus cell replication; it also has T-cell suppressive activities. Methotrexate is the gold standard systemic therapy. Very few trials of the efficacy of methotrexate have been performed. Approximately 60% of patients achieve at least a 75% improvement in clinical severity as measured by the psoriasis area severity index (PASI).
Methotrexate is prescribed orally (occasionally intramuscularly or subcutaneously) in a once-weekly dose following a 2.5 mg test dose. Dosages range from 7.5 to 22.25 mg per week, dependent on clinical response. Folic acid 1 to 5 mg daily is added to prevent stomatitis and anaemia, and to reduce gastrointestinal side effects. Psoriasis patients receiving methotrexate require careful monitoring; they appear to have an increased risk of hepatotoxicity compared with rheumatoid arthritis patients. Traditionally, hepatotoxicity from methotrexate was assessed by liver biopsy; however, serum assay of the amino propeptide of collagen III has been shown to be a reliable measure of hepatic fibrosis, thereby obviating the need for liver biopsy in most patients. The use of pharmacogenetics may optimize the use of methotrexate by identifying individuals susceptible to hepatotoxicity and bone marrow suppression, and those likely to achieve a clinical response.
Oral retinoids (vitamin A derivatives) have been used in the treatment of psoriasis for over 30 years. The original third-generation retinoid used for psoriasis, etretinate, has been superseded by its natural metabolite acitretin. Monotherapy with acitretin is normally commenced at a dose of 10 to 25 mg daily. Systemic retinoids are particularly effective for the treatment of the erythrodermic and pustular variants of psoriasis. As they are not immunosuppressive, retinoids have a role in the treatment of those psoriasis patients who are HIV infected or have cancer, particularly nonmelanoma skin cancer following PUVA.
Caution must be exercised when considering acitretin in women of childbearing potential, because of significant teratogenicity. Women should avoid pregnancy for up to 2 years (United Kingdom) or 3 years (United States of America) after completing acitretin treatment. Adverse psychiatric events, such as mood swings, depression, and suicidal ideation, have been reported as possible idiosyncratic reactions to the related retinoid isotretinoin. Retinoid toxicities are similar to those occurring with hypervitaminosis A, and can include mucocutaneous side effects including sticky skin, alopecia, and cheilitis. Osteoporosis, hyperlipidaemia, diffuse idiopathic skeletal hyperostosis syndrome, and pseudotumor cerebri may occur.
Combining acitretin with PUVA (Re-PUVA) significantly enhances the response to PUVA.
Ciclosporin is a highly effective, short-term therapy for moderate to severe psoriasis. It inhibits the activation of T cells as a consequence of blockade of cytoplasmic calcineurin phosphatase. Ciclosporin therapy is used for psoriasis at doses between 2.5 and 5 mg/kg per day, usually for no more than 12 weeks. Intermittent short-course therapies are recommended because of the association of long-term continuous ciclosporin therapy with nephrotoxicity and hypertension.
Unlike methotrexate or acitretin, ciclosporin is not teratogenic, thus it is the only systemic therapy that can be used in pregnancy. In those patients who have received significant PUVA there is an increased risk of nonmelanoma skin cancer. Patients may have other side effects, including hypertrichosis, gum hyperplasia, and paraesthesia. Long-term continuous therapy with ciclosporin is used on occasion at a daily dosage of 3 to 4 mg/kg, but regular monitoring of glomerular filtration rate is required. Ciclosporin has been used in combination with acitretin, low-dose methotrexate, and the newer biological agents.
Fumaric acid esters
A commercially available mixture of four fumaric acid esters (fumarates) has been used to treat psoriasis in Europe for around 50 years. They are hindered by a number of subjective side effects, mainly gastrointestinal in nature, including abdominal cramps, diarrhoea, nausea, and flushing.
Other systemic therapies
Less frequently used second-tier systemic agents include hydroxycarbamide, mycophenolate mofetil, sulfasalazine, azathioprine, and leflunomide. Few randomized controlled trials are available to confirm their effectiveness.
A major advance in the management of patients with moderate to severe psoriasis has been the introduction of biological agents. These are defined as recombinant molecules designed from the genetic sequence of existing living organisms, and are often similar or identical to proteins produced by humans. They include fusion proteins, recombinant proteins, and monoclonal antibodies, and have been in common use for diseases such as rheumatoid arthritis and Crohn’s disease. There are a number of biological agents used in the management of psoriasis; these can be divided into those that target T cells and those that block cytokines, TNFα and IL-12/IL-23.
T-cell targeted agents
Alefacept was the first biological agent specifically designed and approved for the treatment of psoriasis. It is a human leucocyte function-associated antigen 3 (LFA3)/IgG fusion protein that binds to CD2 on T cells, thereby inhibiting activation. Alefacept also produces apoptosis of memory effector CD45RO+ T cells. Delivered as a 12-week cycle of once-weekly intramuscular injections, approximately 20% of patients achieve a 75% reduction in PASI (PASI 75). Side effects are few, and monitoring involves the analysis of subsets of CD4+ and CD8+ T cells in peripheral blood. Some patients may go into long-term remission following a single cycle of therapy.
Etanercept is a human recombinant p75 TNF receptor/Fc fusion protein that binds TNF and is self-administered subcutaneously at doses from 25 to 50 mg twice weekly. At the lower dose 34% of patients achieve PASI 75 at 12 weeks, and at the higher dose 49% of patients achieve this level of improvement. In addition to its beneficial effects on psoriasis, etanercept, in common with other TNF antagonists, is an effective treatment for psoriatic arthritis.
Infliximab, a chimaeric monoclonal antibody, binds to and neutralizes the activity of TNFα. It is given as a 5 mg/kg intravenous infusion, with three loading infusions at 0, 2, and 6 weeks, and then subsequently at 8-week intervals. Infliximab is a highly effective, rapid-acting biological therapy in that more than 80% of patients achieve PASI 75 by 10 weeks. It can be used long term, and at 1 year 61% of patients maintain PASI 75 with a regular 8-week infusion. Infliximab is also effective for psoriatic arthritis.
Adalimumab, a fully human anti-TNFα monoclonal antibody, is self administered subcutaneously at a dose of 40 mg on alternate weeks. Twenty-four weeks of treatment with adalimumab significantly improves psoriasis, 54% of patients achieving PASI 75; psoriatic arthritis is improved also.
TNFa antagonist monitoring
Because of the role of TNFα in granuloma formation, infections such as tuberculosis, histoplasmosis, and deep fungal infections require careful monitoring with appropriate tuberculosis screening before starting therapy. Other reported serious adverse effects with TNF antagonists include demyelination, exacerbation of pre-existing cardiac failure, development of lupus, enhanced risk of soft-tissue infections, and the potential development of nonmelanoma skin cancer in patients who have received significant PUVA. Prospective pharmacovigilance under the auspices of national registries is of importance for ascertaining the true risk of biological therapies.
Ustekinumab, a fully human monoclonal antibody directed to the shared p40 subunit of IL-12 and IL-23 is self-administered subcutaneously at 0 and 4 weeks and 12 weekly thereafter at a dose of 45 mg or 90 mg. Twelve weeks of treatment significantly improves psoriasis, 70% of patients achieving PAS175, response is maintained with continuous therapy to 18 months.