HistoryThis section has been translated automatically.
DefinitionThis section has been translated automatically.
Common polygenetic skin disease with T-cell-mediated autoimmunesis, provoked by exogenous and endogenous stimuli, acute or chronic, occurring at all stages of life and affecting about 2% of the Central European population. Clinically, characteristic localized or generalized papules or plaques are found, emphasized on the extensor side, usually symmetrical, with varying degrees of consistency (palpation firm like leather), sharply demarcated, red or covered with white scales. Rarer are pustules or vesicles. Joint involvement of varying degrees is found in 30% of psoriatic patients. Due to pathophysiological and genetic similarities, psoriasis can be counted among the group of IMID (Immune-Mediated Inflammatory Diseases).
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ClassificationThis section has been translated automatically.
Clinical variants of psoriasis with partly very different courses are:
- Psoriasis plaque type:
- Psoriasis stationary plaque type(Psoriasis vulgaris chronic stationary plaque type).
- Psoriasis relapsing plaque type(psoriasis vulgaris chronic-active plaque type)
- Psoriasisguttata (acute, exanthematic psoriasis)
- Psoriasis inversa
- Pustular psoriasis (generalized type):
- Pustular psoriasis (localized type):
- Psoriasis arthropathica
- Special forms of psoriasis:
The individual clinical forms are defined on the one hand by their course (acute - chronic), on the other hand by the localization (psoriasis inversa, psoriasis palmo-plantaris) or by the appearance of pustules (psoriasis pustulosa) or by further organ manifestations (psoriasis arthropathica).
- mild psoriasis < 2%BSA (PASI < 5)
- moderate psoriasis 2-10% BSA(PASI 5-20)
- severe psoriasis: > 10%BSA (PASI >20)
Current classification (guideline)
Occurrence/EpidemiologyThis section has been translated automatically.
Prevalence of psoriasis in different countries:
- Germany: 1-2% (-3%) of the population. If one parent is affected, the prevalence is around 14%.
- Denmark: 2.9% of the population.
- Sweden: 2.3% of the population.
- USA: 2.2% of the population (several American studies have also described prevalences between 4.0-4.7%).
- China: 1.7% of the population.
- UK: 1.6% of the population.
- Sweden: 1.4% of the population.
- Norway: 1.4% of the population.
- Spain: 1.4% of the population.
- India: 0,7% of the population.
- Africa: 0.4-0.7% of the population.
- East Africa: 0.7% of the population.
Prevalences of 0.1-1.0% are given for children. In a larger collective (n= 293,181 children) the prevalence was 0.45% (Jacobi et al. 2016).
EtiopathogenesisThis section has been translated automatically.
I. Endogenous factors
Genetic factors: undisputedly, genetic disposition plays a crucial role. Genes associated with psoriasis have been identified on different chromosomes. Chromosomes (polygenetic inheritance). One genetic risk factor is PSORS1 (acronym for PSORiasis- S = susceptibility locus), a susceptibility locus within the major histocompatibility complex on chromosome locus 6p21.3. PSORS1 is the main predisposition factor for psoriasis in the early years of life (type I psoriasis). The susceptibility loci PSORS2 (gene locus: 17q24-q25) with associated genes for RUNX-1 and RAPTOR, PSORS3 (gene locus: 4q) PSORS4 (gene locus: 1cen-q21), PSORS5 (gene locus: 3q21), PSORS6 (gene locus: 19p), PSORS7 (gene locus: 1p), PSORS8 (gene locus: 4q31) have diverse other functions in psoriatic inflammation. Apparently, there exists a genetic network with a "variable disease-typical gene signature that can be activated by various factors". This gene network is influenced by inflammatory (Th1 and Th17 cells) cytokines (e.g. interferon gamma/TNF-α) in psoriasis (see also atopic eczema). Evidence suggests that a single nucleotide polymorphism (SNP+489 variant allele A) of the TNF-α gene predisposes significantly to psoriatic arthritis. This TNF-α gene polymorphism is also related to the severity of psoriasis or its response to etanercept.
HLA: associations with HLA-B13, HLA-Bw57, HLA-Cw6, HLA-B27, HLACw2, HLA-DR4 and HLA-DR7 have been described. Apparently, however, HLA-Cw*06:02 plays a special role (carriers of this allele are 10 times more frequently affected by psoriasis).
Antimicrobial peptides (AMP`s): apparently an overexpression of antimicrobial peptides, especially of cathelicidin, beta-defensin, and psoriasin plays an important role in the pathogenesis of psoriasis (compare also the low tendency to infections in psoriasis vulgaris!). It could be shown that the cathelicidin LL37 binds and complexes endogenous cytosolic DNA (these are detected in psoriatic keratinocytes!). The complexes may induce an interferon response with an inflammatory response (see inflammasome below).
II. exogenous factors
1. drugs: There is reasonable evidence that various drugs are capable of maintaining or inducing psoriasis vulgaris. These include:
- Beta-blockers (e.g. propanolol).
- Calcium channel blockers (e.g., diltiazem)
- Glucocorticoids (esp. after discontinuation or reduction of therapy)
- Antimalarials (e.g. chloroquine)
- NSAIDs (naprofen, diclofenac, indometacin)
- various antibiotics (e.g. macrolide antibiotics)
- In rare cases TNF-alpha blockers for inflammatory bowel disease (see case 2 below)
2. mechanical trauma
4. irritative local therapies
5. infections (e.g. streptococcal angina)
6. emotional stress
Keratinocytes/keratins: A proliferation stimulus occurs due to keratinocyte stimulating mediators (TNF alfa, IL-8, granulocyte macrophage colony-stimulating factor = GM-CSF). The cell cycle of keratinocytes is accelerated more than 8-fold. Cells of the basal cell layer need only 4 days to reach the str. corneum. 25% of keratinocytes (increased 3-fold) are in the proliferative S-cell cycle phase. Such proliferation-promoting mediators are also produced by keratinocytes themselves(interleukins - IL-1, IL-6, IL-8, IL-17A, interferon gamma, TNF, transforming growth factor alpha (TGF-alpha) and GM-CSF (see growth factors below). Furthermore, interleukins 17 and 22 are responsible for keratinocyte hyperplasia. These are produced by the Th17 cells. The structural proteins of keratinocytes are also altered (reduction of suprabasal keratins 1 and 10; neoexpression of keratins 6 and 16). The role of the cytokine"thymic stromal lymphopoietin" produced in psoriatic keratinocytes has not yet been definitively clarified.
Autoantigens: Various potential autoantigens, such as ADAMTS-like protein 5 expressed by melanocytes and the antimicrobial peptide LL37, are important for psoriatic inflammation. Both proteins are recognized by TH17 cells after binding to the protein HLA-C*06:02 (seeHLA system) and thus initiate psoriatic inflammation. Remarkably, there is a structural homology of keratin 17 with M-proteins of streptococci. In this respect, keratin 17 also presents itself as a potential autoantigen. Furthermore, heat shock proteins (HSP) seem to play an important role in the pathogenesis of psoriatic inflammation. For example, HSP 90 has been linked to affected cell survival and cytokine signaling in psoriatic patients.
Lymphocyte/homing signaling: probably at the beginning of the psoriatic inflammatory cascade are activated dendritic cells (DCs) and macrophages, which are stimulated to secrete pro-inflammatory cytokines such as IL-1, IL-6, IL-12, IL-23 and TNF-alpha. This activates interferon gamma producing CD4+ T lymphocytes . This process leads to the maturation of naïve T cells into Th17- cells and other inflammatory Th cell populations such as Th-1 lymphocytes (Th1 lymphocytes; no IL-4 production). Th-1 lymphocytes (as well as Th17 cells) play a central role in the pathogenesis of psoriasis (blockade of CD4 T lymphocytes by anti-CD4-AK leads to a clinical improvement of psoriasis, other lymphocyte-suppressive drugs such as ciclosporin, fumaric acid esters, as well as PUVA therapy, among others, also cause this effect). The activated T-lymphocytes receive an "address" through the expression of certain surface markers, which defines the place where they are needed. These so-called "homing" signals, mediated by cutaneous lymphocyte-associated antigens (CLA), enable the lymphocytes to infiltrate both compartments, epidermis and dermis. In psoriatic patients, inflammatory T cells have been shown to produce the receptor alpha-1-beta-1 integrin (VLA-1) directed against collagen IV (collagen of the basement membrane). This integrin is expressed on epidermal lymphocytes in lesional (not unaffected) skin. This suggests that epidermal T cells are central effectors in psoriasis. Blockade of VLA-1 significantly inhibits the migration of human VLA-1-expressing T cells.
Dendritic cells: Dendritic cells (DCs) are outposts of the immune system and provide links between the specific (acquired) and non-specific (innate) immune systems (see Immunity, innate/acquired). As so-called professional APs, they express both antigen-presenting HLA class II molecules and co-stimulatory molecules. Myeloid DCs are found in increased numbers in the psoriatic lesion. Under PUVA, lesional myeloid DCs decrease.
Chemokines: Infiltrating Th1 lymphocytes interact with various dermal and epidermal cell systems. A number of chemokines, chemokine receptors, integrins and adhesion molecules are involved (CCR5, CXCR3 receptors, E-selectin, LFA-1, ICAM-1, VLA-4, VCAM-1 and others). These promote adhesion of T lymphocytes and neutrophil granulocytes. Furthermore IL-8 and RANTES (see below chemokines), which induce the migration of certain T-lymphocytes.
Inflammatory mediators (see cytokines below): Numerous inflammatory mediators are detected in psoriatic inflammation: TNF-alpha, IL-8, IL-19. Peripheral mononuclear cells show increased titers of TNF-alpha, IL-1beta, IL-6, monocytes produce increased IL-1alpha, IL-1beta, IL-8. The detection of these proinflammatory mediators proves that psoriasis should be considered a systemic disease rather than just a local inflammation.
Endothelial cells: Angiogenesis factors (ESAF = Endothelial cell stimulating angiogenesis factor; Vascular endothelial growth factor = VEGF) are strongly increased in the psoriatic lesion and in serum. They cause vascular proliferation. ESAF is mainly produced by keratinocytes and fibroblasts, VEGF by keratinocytes. Activated dermal capillaries express adhesion molecules (ICAM-1, ELAM-1, VCAM-1) that allow CD4+ T lymphocytes to dock to the endothelium and penetrate through the vessel wall. The role of nitric oxide (NO) (INF-gamma is an inducer of NO) vasodilator is still unclear.
ManifestationThis section has been translated automatically.
- Occurrence is possible at any age. Predominantly occurring in the 2nd to 3rd decade of life (type I), more rarely in the 5th decade of life (type II). The prevalence in < 20-year-olds is 0.8%.
- No gender preference.
- 2/3 of psoriatics suffer from mild psoriasis, often not requiring treatment. About 80% have nail infections.
- A distinction is made between age of manifestation and association with HLA alleles:
- Type I psoriasis (manifestation maximum between the ages of 20 and 30; association with the alleles Cw6, B13, B57, DRB1). Association with streptococcal infections detectable.
- Type II psoriasis (manifestation maximum between the ages of 50 and 60; association with the HLA alleles Cw2, B27).
- HLA-Cw6-positive psoriatics have a 10-fold increased risk of disease with a preferred type of disease: Younger age of manifestation, often guttate psoriasis type, severe course of the disease.
- Associations with the HLA genes CW6, B13, B17, B27, DR7 are known for psoriasis arthropathica.
- Genetic studies show that type I and type II psoriasis are different diseases.
- The average duration of the disease in psoriatic patients is 21.8 years (1.0-66 years).
LocalizationThis section has been translated automatically.
Infestation pattern (MAPP study - 3,426 patients): elbows (46%), capillitium (45%), knees (31%), trunk (24%), face (15%), palms (12%), soles (11%), nails (11%), genital area (7%).
Joint symptoms in psoriasis patients with primary skin involvement: knee (45%), fingers (19%), hip (16%), spine (14%), ankle (11%), wrist (8%)
Clinical featuresThis section has been translated automatically.
The skin changes of psoriasis manifest themselves most frequently in the chronic stationary form with differently sized, inflammatory reddened, sharply delimited plaques covered by silvery scales (depending on the pre-treatment, these may be completely absent). This form of progression can occur in both type I psoriasis and type II psoriasis.
The acute exanthematic form of progression shows a strong eruption pressure and is preferentially found in type I psoriasis patients. Relapses are often triggered by infections with beta-hemolytic group A streptococci.
Due to the disease activity (relapse activity) and the resulting therapeutic consequences, it is useful to distinguish between:
- chronic stationary psoriasis vulgaris (chronically stable plaque psoriasis) and
- chronic active psoriasis vulgaris
Diagnostically important is the triggering of different "psoriasis phenomena" within the foci:
Other clinical variants of psoriasis are:
- chronic stationary plaque ps oriasis
- psoriasis anularis
- Psoriasis capillitii
- erythema anulare-like psoriasis
- Erythrodermia psoriatica (erythrodermic maximum form of psoriasis)
- Psoriasis follicularis
- Psoriasis guttata
- Psoriasis intertriginosa
- Psoriasis inversa
- Pustulosis palmaris et plantaris
- Psoriasis pustulosa palmaris et plantaris
- Psoriasis seborrhoides
- Psoriasis of the nails.
Oral mucosal changes are usually observed only in pustular psoriasis generalisata.
Joint and skeletal involvement (in about 30% of patients with psoriasis) see below.:
Arthritis psoriatic (psoriasiarthritis)
HistologyThis section has been translated automatically.
The non-pretreated psoriasis papel shows hyper- and vigorous parahyperkeratosis, acanthosis and papillomatosis in typical expression. Elongated narrow rete ridges, which may be bulbous at their lower end; apically bulbous papillary bodies, focal suprapapillary epidermal thinning with absent stratum granulosum; elongated dilated capillary loops; subcorneal or also intracorneal Munro microabscesses.
Diffusely distributed lymphocytic inflammatory infiltrates are found in the upper and middle dermis. Perivascular inflammatory infiltrates consisting of histiocytes, predominantly CD4-positive lymphocytes, and usually a few polymorphonuclear neutrophilic leukocytes are found in the upper and middle dermis sections; there is varying degrees of epidermotropy with only minor signs of spongiosis (DD. eczema reaction).
Differential diagnosisThis section has been translated automatically.
In the differential diagnosis of psoriasis, the predominant manifestation type plays the decisive role (see below). It is not difficult to diagnose psoriasis vulgaris untreated and in full clinical expression. It becomes more difficult with the clinical variants of the psoriasis family (see below pustular psoriasis, arthropathic psoriasis). Here, completely different clinical pictures will have to be taken into consideration in terms of differential diagnosis (differential diagnosis, see there). The differential diagnosis of psoriasis vulgaris is referred to depending on the subtype (see above).
Complication(s)This section has been translated automatically.
- Coronary heart disease: Recent evidence suggests that psoriasis is an independent risk factor for coronary heart disease. Only 40% of psoriatics are free of coronary artery calcifications compared with 72% of the control group of non-psoriatics. Moreover, among psoriatics, the proportion of severe calcifications and stenoses as well as of myocardial infarctions is much higher than in non-psoriatics. An analogous risk spectrum, which is reduced under therapy with TNF-alpha blockers, is also found in patients with rheumatoid arthritis.
- Obesity: Significantly increased BMI and increased abdominal and hip circumference in psoriatics.
- Psoriatic patients are more likely to meet criteria for metabolic syndrome (MetS) than the average population; furthermore, there is increased insulin resistance.
- Psoriatic patients are at increased risk for hypertension. The use of beta-receptor blockers appears to significantly increase the risk of new onset or exacerbation of psoriasis.
- Patients with psoriasis are more likely to develop enteritis regionalis (Crohn's disease).
- Celiac disease: In a larger collective, antibodies against a tissue transglutaminase could be detected in 4% of psoriatic patients (non-psoriatic control collective 0.4%). Gluten-free diet also leads to improvement of psoriasis.
- Alcohol and smoking are trigger factors for psoriasis.
- Possible secondary cause of Ig-A nephropathy (M.Berger)
General therapyThis section has been translated automatically.
Principles: Due to the expansion of the drug spectrum, increasingly potent local as well as systemic antipsoriatics have become available to medicine in recent years. The increasing understanding of cutaneous immunological processes opens up several possibilities for therapeutic intervention. A number of immunosuppressants and immunomodulators are available for this purpose, and others are in development. Based on their mode of action, they can be divided into 5 groups:
- Inhibitors of effector cytokines (especially TNF-alpha)
- Inhibitors of T-cell proliferation
- Inhibitors of T-cell activation
- Inhibitors of T-cell migration
- Modulators of the immune response
- Inhibitors of keratinocyte proliferation.
However, the system therapies are often associated with considerable side effects. Likewise, the treatment costs to be incurred for this must be taken into account, which range between 2,000-30,000 euros annually depending on the therapeutic agent. In this respect, systemic antipsoriatics should only be used after very careful indication. The therapy must be closely monitored by the attending physician. The physician must be closely familiar with the modalities of action and the side effect profile of the preparations. The duration of treatment must always be questioned.
Therapy combinations: Since clinical studies are almost exclusively evaluated as monotherapies, combination therapies (system therapy+system therapy, system therapy+external therapy; external therapy+external therapy, etc.) are a practical necessity.
Climatic therapy: Stays of several weeks in a sea or mountain climate are often very effective for a few weeks or months, but their effectiveness is limited in time after the end of the stay. Cures, e.g. at the North Sea or Baltic Sea as well as at the Dead Sea (German Medical Center (DMZ) at the Dead Sea in Ein Bokek, Israel or Dead Sea Spa Medical Center in Jordan) have proven to be effective.
Psoriasis and tonsillectomy: Opinions on the success of tonsillectomy are divided. Carriers of the allele HLA-Cw6 are 10 times more likely to be affected by psoriasis. Homocytogy for HLA-Cw6 is associated with a higher risk of disease. At the same time, these patients suffer more frequently from streptococcus-based pharyngitis. Obviously this special psoriasis clientele benefits from tonsillectomy.
Upgrade criteria: Not only the pure PASI and DLQI score determine the severity of psoriasis according to the European consensus, certain factors can lead to a particularly strong restriction of the quality of life and make a higher classification of the severity (from mild to moderate to severe) necessary and thus prefer a systemic therapy initiation. These so-called upgrade criteria are:
- Infestation of visible body regions,
- infestation of larger regions of the scalp,
- infestation of the genitalia,
- Infestation of the palms of the hands/soles of the feet..,
- Infestation of more than two fingernails,
- ...severe itching, prompting scratching..,
- Presence of single persistent plaques.
External therapyThis section has been translated automatically.
The classical external treatment methods are: dithranol, retinoids, salicylic acid, urea, glucocorticoids, vitamin D3 analogues, phototherapy (UV therapy), balneo-phototherapy, tacrolimus (strictest indication due to unclear long-term side effects! Off-label use!), Pimecrolimus (strictest indication due to unclear long-term side effects! Off-label use!).
- Calcipotriol: In 0.005% ointment base (e.g. Daivonex, Psorcutan) well suited for outpatient therapy. Caveat. Resorptive NW (hypercalcemia, nephrocalcinosis)! Limit daily amount to 10 g, weekly amount to 100 g. Treated skin area < 30% of the KO. Application 2 times/day, if necessary also under occlusion. Irritation in the facial area if necessary. Combination with glucocorticoids are possible (e.g. Daivobet®; this combination is also available as a spray foam - Enstilar®). Newer combination preparations Calcipotriol/Betamethasone: Wynzora®.
- Calcitriol: (Silkis 3 μg/g ointment). Due to the fit at the vitamin D3 receptor concentration of 0.0003% is sufficient. Limit daily amount to 30 g (weekly dose 210 g), treatable skin area 35% KO, use 2 times/day. Also in intertriginous skin areas and with caution on the face.
- Tacalcitol (Curatoderm): Application 1 time/day. Treatment of facial area and intertrigines if necessary is possible. In 0.0004% ointment base and emulsion for application 1 time/day, also suitable for sensitive areas. Approved for children over 12 years of age, maximum daily dose 10 g.
- Vitamin D3 analogues in rotation with dithranol (Psoradexan) have proved particularly effective. If necessary in combination with UVB irradiation.
- Tazarotene: (Zorac 0.05% and 0.1% gel) 1 time/day. Caution. Irritative effect! Allow preparation to absorb well, do not reapply cream.
- Inpatient treatment: Classic dithranol continuous therapy (see Table 1) with increasing concentrations (Psoradexan, Psoradexan mite/forte). The dithranol ointment (vaseline-based) has 2% salicylic acid added for preservation reasons. Treatment is basically 2 times/day. Start with 0.05% dithranol, increase depending on skin condition to 0.1%, 0.25%, 0.5%, 1%, 2% to max. 3% R076 R074. A rotation principle (see Table 2) with dithranol alternating with medium-strength glucocorticoids such as 0.1% betamethasone cream(e.g. Betagalen, R029 ) or 0.1% triamcinolone cream (e.g.e.g. Triamgalen, R259 ) or a 0.05% calcipotriol ointment (e.g. Daivonex ointment, Psorcutan ointment) or also tacalcitol (Curatoderm), see also Interval therapy, Tandem therapy. Supplementation with balneo-phototherapy: Before morning ointment therapy, brine bath in 1% NaCl solution with bath duration of 25-20 min. Initial dose 1/3 of the individual MED. Increase by the initial dose every 3 days.
- Therapy resistance: Individual psoriasis plaques (knees, elbows, sacral region) prove to be very therapy resistant. At these sites, application of Dithranol under occlusive film such as hydrocolloid films (e.g. Varihesive film) or simple household film, if necessary alternating with glucocorticoid ointments, for a duration of 2 hours, 2 times/day each.
- Outpatient treatment: Dithranol minute or short term therapy. Use of dithranol in washable ointment base R074. Alternatively, ready-to-use preparations in different concentrations are available for short-term therapy (e.g. Psoradexan mite/forte, Micanol).
- Contraindicated as sole therapeutic principle in extensive psoriasis (risk of systemic side effects due to absorption of the highly potent external glucocorticoids). In few, chronically stationary foci, initial therapy with glucocorticoid ointments/creams is acceptable. Combinations of glucocorticoid externals with salicylic acid have proven effective.
- Mometasone furoate (Ecural fat cream), betamethasone valerate (Betnesol, Betagalen, R029 ), 0.1% triamcinolone acetonide (Triamgalen, R260 ), amcinonide (Amciderm ointment/fat cream). Caution. Glucocorticoids are not antipsoriatics, they suppress inflammation for a few days!
Salicylic acid: this keratolytic and antiphlogistic agent is rightly used from the good and decades of clinical experience. The study documentation on this form of therapy is poor and will predictably not improve in the next decades. Nevertheless, the use of a 2-10% application form can be recommended without hesitation.
Calcineurin inhibitors: Topical treatment with calcineurin inhibitors is useful and successful for circumscribed foci. Success has also been described for tacrolimus and pimecrolimus in psoriasis inversa.
Coal tar: Low efficacy; lack of compliance due to the inherent odor of the tar preparations! Tar preparations can no longer be recommended today due to potential long-term side effects.
Radiation therapyThis section has been translated automatically.
SUP: Favorable effects can be achieved by selective ultraviolet phototherapy (SUP), using UVB rays with an emission maximum at 305 and 325 nm. Especially in combination with dithranol ointments and brine baths, this form of therapy has proven successful in the treatment of chronic stationary psoriasis. Disadvantage: High time expenditure, since usually approx. 30 applications are necessary to achieve a satisfactory result. UVB 311 nm narrow spectrum irradiation is preferable to conventional UVB broad spectrum therapy due to better or at least equal therapeutic efficacy and at the same time less erythema effect. It is recommended to apply 70% of the previously determined MED as the first therapeutic dose.
In moderate psoriasis, UVB irradiation, which can be localized with pinpoint accuracy, is preferable because of the significantly lower UV exposure, e.g. with B-Clear (high equipment purchase costs!).
Balneophototherapy: Several larger studies (evidence level Ib) prove a superiority of brine UVB therapy compared to UVB therapy alone.
Remark. In the implementation of this treatment method, the required brine concentrations between 4.5-12% prove to be practicable only to a limited extent!
In principle, phototherapies can be combined with system therapies. Experience is available for MTX. There are no recognizable contraindications for fumarates. For Ciclosporin A the combination is to be rejected because of the increased carcinogenicity. X-ray pre-irradiated skin areas should be covered during phototherapy.
Balneophotochemotherapy (see PUVA bath therapy below): Here, the external application of methoxsalene is via a full body bath, partial bath or shower application. Due to the higher active ingredient concentration of methoxypsalene on the skin surface, a reduction of the applied total UVA dose can be achieved in comparison to systemic PUVA therapy. Treatment scheme, see below. PUVA bath therapy.
Photodynamic therapy: It represents a therapy option, although the data situation cannot be assessed conclusively at present. Similarly, standardized instructions for use have not yet been established.
Internal therapyThis section has been translated automatically.
The indication for systemic therapy of psoriasis must be subject to particularly strict provisos.
- The classical external treatment methods should be sufficiently exhausted.
- Only if no acceptable skin condition can be achieved by the external therapy approaches, a system therapy should take place.
Thus, systemic therapies are reserved for the moderate and severe forms. Classification according to the following guidelines:
BSA <= 10 and BSA > 10
These include chronically active, refractory, extensive psoriasis vulgaris, psoriasis pustulosa, psoriatic erythroderma, all forms of psoriasis arthropathica that cannot be adequately treated monotherapeutically with nonsteroidal anti-inflammatory drugs, severe refractory psoriasis capitis, and psoriasis palmaris et plantaris.
Prerequisites for the system therapy of psoriasis:
- Psoriasis should be unmanageable or no longer manageable with available local therapeutic agents, resulting in long (more than two months per year) periods of disease with significant distress.
- The efficacy of the systemic therapeutic agent must be proven beyond doubt.
- The systemic therapeutic agent must act rapidly (within four weeks) and produce long-term, clinical freedom from symptoms.
- Even with long-term application (several months) of the drug, there must be no permanent, therapy-induced organ damage that is life-limiting or limits the individual's quality of life beyond that which is primarily disease-related.
- Possible acute side effects must be detectable by standard clinical examination techniques and laboratory parameters and manageable by simple means.
- Therapy must be feasible on an outpatient basis; therapeutic breadth should be such that follow-up appointments are not necessary more frequently than every four weeks.
- Drugs approved for psoriasis: acitretin, ciclosporin A, methotrexate, ustekinumab, adalimumab, infliximab, etanercept, brodalumab, apremilast, fumaric acid esters, glucocorticoids, PUVA therapy (systemic), bath PUVA therapy.
- Drugs approved for psoriatic arthritis: etanercept, infliximab, leflunomide, golimumab.
- Off-label use with known efficacy in psoriasis: mycophenolate mofetil, alefacept (approved in USA).
Therapeutics in detail:
- Fumaric acid esters (e.g. Skilarence®, Fumaderm®): Favorable benefit-risk ratio. Therapy suitable as long-term therapy. Regular laboratory value checks are required. The pharmacological effects of fumaric acid esters are not yet sufficiently known. Probable effects are an antiproliferative effect on lymphocytes and a selective immunomodulatory antipsoriatic effect on activated T lymphocytes. Particularly good effects by FAE are observed in chronic plaque psoriasis. However, localized or generalized exudative psoriasis forms such as pustular psoriasis generalisata or pustular psoriasis palmaris et plantaris also respond well to fumarates. Good effects are also observed in psoriasis capitis. Significant improvements of psoriatic nail involvement have been reported in several studies, 30-40% of cases are improved under therapy with FAE. Treatment starts in the 1st week of therapy with 1 tbl. Fumaderm initial, is increased by 1 tbl. in the 2nd week; then transition to 1 tbl. Fumaderm; further weekly increase by 1 tbl./day Fumaderm. Max. Dosage depending on clinical effect 6 tbl. Fumaderm/day. Maintenance dose is between 1 and 6 tbl. of Fumaderm. Side effects are primarily flush symptoms (1/2 hour to 6 hours after ingestion); flush symptoms persist for minutes to half an hour. With increasing duration of therapy, there is a marked decrease in flush symptoms. Gastrointestinal problems such as nausea, diarrhea, stomach cramps may occur. These symptoms also remit with therapy; mild to marked lymphopenias are regular side effects of therapy; eosinophilia is less common. Dose adjustment should be made in the presence of leukopenia, decrease in lymphocyte count < 500/µl, persistent eosinophilia > 25%, increase in creatinine > 30%, or massive tubular proteinuria. Combinations with other systemic antipsoriatics such as MTX or ciclosporin or retinoids are not currently recommended due to lack of experience. Laboratory testing with blood counts, monitoring of liver and kidney function, and urinalysis is required on a 4-weekly basis. Although teratogenicity has not been established, FAEs should not be given during pregnancy.
- Acitretin (Neotigason®): Vitamin A derivative used in Europe in psoriasis therapy as a systemic therapeutic. The best effects are found in pustular psoriasis or erythrodermic forms. Acitretin causes rapid loss of psoriatic scaling. Clinical freedom from manifestations is achieved in psoriasis vulgaris in nearly 25% of patients. Dosage: Initial 0.5-1.0 mg/kg bw; as a maintenance dose, 0.1 (max. 0.2) mg/kg bw should not be exceeded. Acitretin is characterized by high lipophilicity, resulting in accumulation of the drug in adipose tissue during long-term therapy. The very delayed release of acitretin after discontinuation of the preparation results in a half-life of 80-100 days. This has significant consequences with regard to the known teratogenicity of the preparation and considerably reduces the possibilities of using the preparation in women of childbearing age (contraception up to 2 years after discontinuation of the preparation). Acitretin can be used in combination with radiation therapies (ReSUP; RePUVA).
- Ciclosporin A: High response rate. Nephrotoxicity and possible carcinogenicity in long-term therapy are known NW. Ciclosporin A (Cy A) represents a rapidly effective systemic treatment strategy. Clinical success occurs within days to a few weeks. Ciclosporin is particularly effective in severe therapy-resistant psoriasis arthropathica. However, generalized plaque psoriasis, pustular forms and psoriatic erythroderma also respond to ciclosporin. Dosage: 2.5 - max. 7.5 mg/kg bw p.o. Regular laboratory controls, especially of blood, liver, and kidney status, are required.
- Glucocorticoids: Can be used only for a very short time in case of high relapsing activity of psoriasis. Glucocorticoids should be rejected as systemic long-term antipsoriatics. Their use generally leads to prompt clinical effects. In this respect, they can be used in a medium-high dosage (100-150 mg prednisolone) in highly exudative forms of psoriasis (e.g., in an acute episode of pustular psoriasis) in the short term (2-3 days). Regardless of the negative evaluation of systemic glucocorticoids, they are prescribed by internists and general practitioners most frequently of all systemic therapeutics (!).
Methotrexate (MTX): indication is especially psoriasis arthropathica. MTX has a proven clinical effect in moderate and severe psoriasis vulgaris. MTX is suitable for this indication according to the German and European S3 guidelines. MTX can also be used, if necessary, in combination with etanercept - adalimumab or fumarates in severe exudative forms of psoriasis such as Zumbusch-type pustular psoriasis. In the pustular forms of psoriasis, the MTX effect is explained by the proven inhibitory effect of MTX on the neutrophilic leukocytes of the psoriatic patient. Dosage: Test dose: To determine hematological hypersensitivity, initial application of 2.5 mg p.o. or i.m.; check blood count after 5-7 days; if neutroph. Leukocytes below normal value: discontinue therapy.
- Multiphasic therapy: Weekly oral application of 2.5-5.0 mg twice a week, 12 hours apart.
- Single-phase therapy: Weekly single oral application of 7.5-25 mg MTX.
Acute toxicity is rare (elderly with impaired renal function). In case of critical drop in leukocytes under an average methotrexate dose, immediate administration of leucovorin (3.0-6.0 mg folinic acid = 1 or 2 amps leucovorin i.v. or i.m.). Subsequently, administer the same dose again 4 times at 3-6 hourly intervals. On the other hand, long-term application causes liver damage in about 33% of patients. Liver fibrosis is observed in a maximum of 10% and liver cirrhosis in 5% of patients. Regular monitoring of blood, liver and kidney values (fortnightly) is necessary. Similarly, biannual sonographic liver examinations are recommended. If gastrointestinal side effects should occur, the intracutaneous form of application is recommended. A comparison of MTX and fumarates in severe plaque psoriasis (baseline PASI between 14 and 18) showed equivalence in the treatment groups.
- Apremilast (Otezla®), an oral thalidomide analogue (phosphodiesterase-4 inhibitor) developed for the indications spondylitis, psoriatic arthritis or psoriasis arthropathica, and psoriasis vulgaris by Celegene. In the phase III study (ESTEEM), patients with moderate to severe psoriasis were treated with 30mg 2x/day apremilast for 52 weeks. At week 16, 28.8% of those treated achieved a PASI-75 response (5.8% on placebo).
Etanercept (Enbrel®): Fusion protein (dimeric protein) of human tumor necrosis factor receptor and human IgG1 that specifically binds to TNF-α, biologically inactivating it and thus preventing the interaction of the molecule with its membrane receptor. The preparation Enbrel is approved for the treatment of plaque-type psoriasis vulgaris in children (from the age of 6) and adolescents as well as in adults. The effect of the preparation usually occurs after the first injection. Should not be prescribed during pregnancy and lactation (insufficient data). Dosage (Pat. > 5 y.): 2 times/week 25 mg s.c. Alternative: 2 times/week 50 mg s.c. for up to 12 weeks, then 2 times/week 25 mg s.c. Treatment until remission, for a maximum of 24 weeks in total. Discontinuation of therapy in patients who have not responded after 12 weeks. Intermittent therapy approaches do not lead to treatment resistance. Note: Approved for children > 5 years of age in severe juvenile plaque psoriasis. Combination of etanercept with retinoids has been described as successful. So has the combination with MTX. Note: an etanercept biosimilar (Erelzi®) is approved for rheumatologic and dermatologic indications (so in plaque psoriasis) and is equally effective and safe.
- Adalimumab (Humira®): The active ingredient neutralizes the biological functions of TNF-alpha by highly specific binding to the TNF-alpha molecules and inhibition of interaction with the cellular p55 and p75 TNF receptors. Secondary inhibition of IL-1 and IL-6 production and secretion, as well as leukocyte migration and expression of adhesion molecules. Combination with low-dose MTX is recommended to avoid formation of autoantibodies to adalimumab. Can also be used as monotherapy if MTX is intolerant. Dosage: adults/adolescents > 18 yrs: 40 mg s.c. 1 time/14 days. Recent studies indicate that not only arthritis but also skin symptoms can be improved by adalimumab. Adalimumab now has EU approval as first-line therapy.
- Infliximab (Remicade®): Chimeric monoclonal antibody (mouse-human) that interrupts the pro-inflammatory signal transduction chain by binding TNF-α. Approved for the treatment of rheumatoid arthritis and Crohn's disease, psoriasis vulgaris and psoriasis arthropathica. Dosage: 5 mg/kg bw i.v. over approximately 2 hours. Good, rapid results already after a single application with disease-free intervals of up to 3-4 months. In case of recurrence, a new treatment cycle should be performed within 14 weeks to minimize the risk of hypersensitivity reactions (sensitization to chimeric antibodies). Although described only in rare cases, emergency precautions (presence of a physician during application, epinephrine, corticosteroids, and antihistamines) should be taken to treat possible anaphylactoid incidents. Exclusion of active tuberculosis must be performed. TB screening with quantiferon TB gold test and chest X-ray (not older than 6 months) are recommended.
Interleukin-12 (IL-12) and -23 (IL-23) antibodies:
- Ustekinumab (Stelara®): Human monoclonal antibody directed against the p40 subunits of the cytokines interleukin-12 (IL-12) and -23 (IL-23). Moderates Th1 lymphocyte differentiation, as well as the IL-23/IL-17A axis of the TH17 immune response. Approved for the treatment of moderate-to-severe plaque psoriasis in adults who have had no or inadequate response to other basic therapies (e.g., MTX, ciclosporin A, fumarates, PUVA therapy) or who have contraindications or intolerances. Dosage: 45 mg s.c. at the start of therapy and after 4 weeks. Maintenance dose: 45 mg s.c. every 12 weeks. Compared to etanercept, ustekinumab shows the highest 5-year efficacy (Zweegers J et al. 2017).
- Brodalumab (Kyntheum® - Approval 09.2017 ): Recombinant, fully human, monoclonal immunoglobulin IgG2 antibody. The antibody binds with high affinity to human IL-17RA (interleukin-17 receptor), inhibiting the biological activities of the pro-inflammatory cytokines IL-17A, IL-17C, IL-17F, IL-17A / F heterodimer and IL-25, resulting in broad inhibition of psoriatic inflammation. Indication: Moderate to severe plaque psoriasis (psoriasis vulgaris). Approved in the EU directly for first-line therapy. Approved in the US under the name Siliq® as second-line therapy only.
- Secukinumab (Cosentyx®): the anti-Il-17A antibody Secukinumab (Cosentyx®), a monoclonal antibody introduced with the FEATURE and JUCTURE studies, each with convincing clinical results. Dosage: 150/300 mg s.c. every 4 weeks. Secukinumab was approved by the European Medicines Agency (EMA) in January 2015 for primary systemic therapy of moderate-to-severe plaque psoriasis in adult patients requiring systemic treatment. A 5-year control study demonstrated an unchanged high response rate to the drug. In 2016, the indication was expanded to include psoriatic arthritis and ankylosing spondylitis.
- Ixekizumab (Taltz® ) is another monoclonal antibody approved for psoriasis that binds with high affinity and specificity to the pro-inflammatory cytokine interleukin-17A (IL-17A) and neutralizes it. The substance is applied as a subcutaneous injection. The initial dose is 80 mg twice. Thereafter, ixekizumab is administered every two weeks.
- Guselkumab (Tremfya®), a monoclonal antibody that demonstrated superiority over adalimumab in moderate-to-severe psoriasis in the VOYAGE-1 study. Guselkumab has been available since November 2017 as first-line therapy in adult patients with moderate-to-severe plaque psoriasis. The human monoclonal antibody selectively targets the "master cytokine" interleukin-23 (IL-23). This cytokine plays an important role in the inflammatory process of psoriasis: The cytokine activates a specific subpopulation of T-cells, TH1 and TH17, which trigger TNF-α-mediated inflammation in psoriasis.
Tildrakizumab (Ilumetri®)is a humanized IgG1/k monoclonal antibody (produced in Chinese hamster ovary cells- CHO cells-) with anti-inflammatory and selective immunosuppressive activity. Tildrakizumab is used for the treatment of plaque psoriasis. The effects are based on the binding and inactivation of the cytokine interleukin-23 (IL-23).
Risankizumab (Skyrizi®): is a humanized IgG1/k monoclonal antibody (produced in Chinese hamster ovary cells -CHO cells-) with anti-inflammatory and selective immunosuppressive effects. Risankizumab is used for the treatment of plaque psoriasis. The effects are based on the binding and inactivation of the cytokine interleukin-23 (IL-23). The response to risankizumab was significantly better compared to ustekinumab. The co-primary endpoint, appearance-free or nearly appearance-free skin, was achieved by 84% and 88% of patients, respectively, after 16 -weeks of therapy.
Approved preparations for psoriatic arthritis:
- Etanercept (Enbrel®): Approval for juvenile idiopathic arthritis from 4 years of age.
- Infliximab (Remicade®): See above.
- Leflunomide (Arava®): The active metabolite inhibits, among other things, dihydroorate dehydrogenase, a key enzyme in pyrimidine and thus nucleic acid biosynthesis, including in the de novo synthesis of activated lymphocytes. Leflunomide prevents the de novo synthesis of pyrimidine and thus blocks the proliferation of activated lymphocytes. Thus, over time, there are not enough activated lymphocytes available to sustain the chronic inflammatory process. Results of clinical studies suggest that leflunomide shows good efficacy in patients with psoriatic arthritis and in seronegative spondyloarthritides. However, no larger, systematic studies are yet available on this topic. Dosage: Saturation of the level: 1 tbl. (100 mg) p.o. 1 time/day. From day 4: 1 tablet daily with only 20 (10) mg p.o. The reduced dose of 10 mg daily is recommended when intolerance occurs with the higher dose of 20 mg daily. However, lower efficacy also occurs in these cases. Clinical effect occurs on average after 14 days. About 75% of patients benefit after 1-2 months. Side effects include GI discomfort, headache, hepatotoxicity, and exanthema.
- Golimumab (Simponi®) 1 time/month 50 mg s.c. (same day of each month), in combination with the individually required dose of MTX, if necessary.
- Adalimumab (Humira®): See above.
Drugs not (or not yet) approved with known efficacy in psoriasis and/or psoriatic arthritis (off-label use):
- Alefacept (Amevive®): Immunosuppressive fusion protein (dimer) consisting of a CD2 extracellular binding site of leukocyte functional antigen 3 (LFA-3) and portions of IgG1. Effects: Inhibition of lymphocyte activation by specific binding to CD2 and inhibition of LFA-3/CD2 interaction. Indication: In moderate and severe forms of psoriasis vulgaris requiring systemic treatment. Dosage: 1 time/week 7.5 mg alefacept i.v. or 1 time/week 15 mg i.m. for 12 weeks. If necessary, repeat therapy cycle after a 12-week break in therapy. Contraindication: lymphocytopenia at planned start of therapy. Weekly monitoring of lymphocyte subpopulations, especially CD4 lymphocytes in differential blood counts!k
- Tacrolimus (Prograf®): Active substance from the group of immunomodulating macrolactams. Tacrolimus inhibits initial T-cell activation, differentiation and proliferation of cytotoxic T-cells and specifically the expression of E-selectin (adhesion molecule on endothelial cells). Indication: Severe forms of psoriasis vulgaris and osteoarthropathia psoriatica. Dosage: 0.1-0.2 mg/day/kg bw p.o. divided into 2 single doses. Ventricular wall and septum may thicken during immunosuppression with tacrolimus; therefore, regular echocardiographic examinations are required.
- Mycophenolate mofetil (CellCept®): Immunosuppressant, ester of mycophenolic acid. Antiproliferative effect on lymphocytes and immunosuppressive effect by inhibition of inosine monophosphate dehydrogenase. The effect on cytokine production is still unclear. Indication: In clinical trials for the treatment of severe courses of psoriasis vulgaris and psoriasis arthropathica. Dosage: Psoriasis: Initially 2 times/day 1 g p.o. for 3 weeks, then 2 times/day 0.5 g p.o. for 3 weeks. Psoriasis arthropathica: combination with low-dose acitretin (0.1-0.2 mg/kg bw/day) p.o..
Treatment of psoriasis vulgaris in childhood and adolescence (see below Psoriasis in childhood).
Progression/forecastThis section has been translated automatically.
Chronic recurrent course with varying lengths of non-appearance intervals.
NaturopathyThis section has been translated automatically.
Order therapy: avoidance of trigger mechanisms, especially friction, infections, stressors. Also some medications such as beta-blockers, which can lead to psoriasis flares, should be considered here.
Climatotherapy and hydrotherapy: brine baths, baths with dead sea salt that can also be carried out at home, showers with sea salt shower baths have also proven to be effective.In addition to natural tanning, UV therapy with short-wave UV-B rays.
Phytotherapeutic extracts of Mahonia aquifolium have proved to be effective, commercially available as a ready-to-use preparation: Rubisan ® cream or ointment (see below Mahoniae cortex and Mahoniae radix, see also Berberin). In a double-blind placebo-controlled study a significant improvement of psoriatic symptoms could be achieved. Especially in problem areas, such as the anal fold, this preparation is quite well tolerated (Bernstein S et al. 2006).
A smaller double-blind study proved the success of Olbanum indicum with local application (Togni S et al. 2014).
In the case of concomitant psoriatic arthritis, see under Arthritis psoriatic .
Betulin contained in the birch round, is also used for its anti-inflammatory, wound healing promoting differentiation, antibacterial, antiviral, antitumor, antioxidant and antipruritic effects. Commercial preparation: Imlan®
Diet/life habitsThis section has been translated automatically.
Patients with psoriasis experience a comparable impairment of the psychological and mental components of their health-related quality of life (HRQL = health-related quality of life) as patients with malignancies, arthritis, hypertension, heart disease, diabetes mellitus and depression.
The success of diets is not proven.
Note(s)This section has been translated automatically.
The average case costs (outpatients and inpatients) are defined for psoriatic patients by the severity of the case. They fluctuate between 6,700 Euro and 53,000 Euro/year. Inpatients incur costs of 2,300 to 32,000 euros, outpatients incur total costs of 204 to 770 euros. The indirect costs range between 1,300 and 8,200 euro per patient.
The term "psoriasis vulgaris" is used in different ways. It is often used synonymously for the most common form of psoriasis, the "plaque type".
Case report(s)This section has been translated automatically.
Psoriasis vulgaris and organ transplantation: The 32-year-old patient has been suffering from severe psoriasis vulgaris with generalized integumentary involvement since the age of 20. In 2006, due to Goodpasture's syndrome with pulmonary and renal involvement, an allogenic pancreas and kidney transplantation was performed. The following immunosuppressive therapy consisted permanently of prednisone 7.5 mg/day, tacrolimus 8.5 mg/day and mycophenolate mofetil 1.0 g/day.
- Psoriasis therapy: The psoriasis therapy before organ transplantation (OTX) included in the first years the usual topical therapy approaches with glucocorticoids, dithranol in different concentrations, bath-PUVA, UVB-irradiation. Later, due to insufficient response of the local therapy, systemic therapy with fumaric acid esters (FAE) in the usual dosages. The FAE had to be discontinued after a few weeks because of intolerable gastrointestinal problems. 2 years after OTX, a permanent and therapy-resistant significant worsening of the skin condition with a PASI of >25 occurred in spite of sufficiently performed topical therapies.
- New therapy approach: As no sufficient local therapy options were available, a therapy with Etanercept 2 x 25 mg/week was initiated. This resulted in a continuous improvement of the skin condition. After 10 months of etanercept therapy, the patient was largely free of symptoms. No relevant side effects of the therapy had to be observed under this therapy modality.
- Laboratory: The transplant functions were stable. A new tuberculosis screen(Quantiferon-Test; X-ray thorax) was performed without any problems.
- Comment: Psoriasis therapy in OTX is particularly challenging due to limited therapeutic options (e.g. phototherapy, side effect spectra of antipsoriatric drugs which may affect graft function), interaction of drugs and psoriatic activity (e.g. due to the varying administration of steroids).
- Biologics such as Eternacept (or Adalimumab) represent an effective and tolerable treatment option for OTX patients with severe psoriasis, as far as currently available limited experience allows.
LiteratureThis section has been translated automatically.
- Altmeyer P (2007) Dermatogical differential diagnosis. The path to clinical diagnosis. Springer Medizin Verlag, Heidelberg
- Bernstein S et al (2006) Treatment of mild to moderate psoriasis with Relieva, a Mahonia aquifolium extract- a double-blind, placebo-controlled study. Am.J.Ther 14: 121-126
- Celsus AC (50-60 AD) De medicina. Liber V, Caput XXVIII, De impetiginis speciebus.
- Elmets CA (2006) An animal model of psoriasis in mice deficient in epidermal Jun proteins. Arch Dermatol 142: 1499-1500
- Gordon KB et al.(2015) A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med 373:136-144.
- Gudjonsson JE et al.(2003) Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes. Br J Dermatol 148:233-235.
- Hebra von F (1854) Traité pratique des maladies de la peau. Paris, p. 479
- Henes JC et al (2014) High prevalence of psoriatic arthritis in dermatological patients with psoriasis: a cross-sectional study. Rheumatol Int 34:227-234.
- Jacobi A et al (2016) Psoriasis in childhood. Skin 16: 22-23
- Kibre P (1945) Hippocratic Writings in the Middle Ages. Bullettin of the History of Medicine XVIII: 371-412.
- Rapp SR et al (1999) Psoriasis causes as much disability as other major medical diseases. JAAD 42: 401-407
- Scarborough J (1988) Galen redivivus: an essay review. Journal of the History of Medicine and Allied Sciences 43: 313-321.
- Schäkel K et al (2016) Pathogenesis of psoriasis vulgaris. Dermatologist 67: 422-430
- Thorleifsdottir RH et al (2016) HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat
- infections and pronounced improvement after tonsillectomy: A prospective case series. J Am Acad Dermatol 75:889-896.
- Togni S et al. (2014) A cosmeceutical formulation based on boswellic acids for the treatment of erythematous eczema and psoriasis. Clin Cosmet Investig Dermatol 7:321-327.
- Willan R (1796-1808) Description and Treatment of Cutaneous Diseases. J. Johnson, London, vol. 1, pp. 152-188.
- Willan R (1808) Papulosquamous diseases. In: Willan R (Eds.) On cutaneous diseases (1st ed.) J. Johnson, London, vol. 1, p. 115.
- Zweegers J et al. (2017) Comparison of the 1- and 5-year effectiveness of adalimumab, etanercept and ustekinumab in patients with psoriasis in daily clinical practice: results fromthe prospective BioCAPTURE registry. Br J Dermatol 176:1001-1009.
- Majeed M et al (2014) Clinical evaluation of AKBBA in the management of psoriasis. Clinical Dermatology 2:17-24
Syed TA et al (1996) Management of psoriasis with Aloe vera extract in a hydrophilic cream: a placebo-controlled, double-blind study* Trop Med Int Health 4:505-509.
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