Narrow‐band ultraviolet B phototherapy versus broad‐band ultraviolet B or psoralen‐ultraviolet A photochemotherapy for psoriasis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of narrow‐band ultraviolet B phototherapy versus broad‐band ultraviolet B or psoralen‐ultraviolet A photochemotherapy for psoriasis.
Background
Please note that unfamiliar terms may be listed in Table 1 ('Glossary of terms used') found in the Additional tables section of this protocol.
| Medical term | Explanation |
| Apoptosis | A process of programmed cell death by which cells undergo an ordered sequence of events which lead to the death of the cell. This occurs during growth and development of the organism as a part of normal cell aging or as a response to cellular injury |
| Collagenase | An enzyme which breaks the peptide bonds in collagen |
| Cytokines | Small protein molecules that are secreted by cells of the nervous system or the immune system. They are used in intercellular communication |
| Defective maturation of epidermal keratinocytes | Incomplete formation of keratin (the horny material in nails) due to rapid growth of cells in the epidermal layer of the skin |
| Dilatation of dermal capillaries | Dilation of small blood vessels in the skin |
| Erythrodermic psoriasis | A subtype of psoriasis that affects all body sites |
| Erythrogenic response | Redness of the skin caused by light exposure |
| Extensor aspects | An anatomical term ‐ when a joint bends, the parts of the skin on the opposite side of the joint are called the extensor aspects |
| Hyperkeratosis | Thickening of the stratum corneum (outermost layer of the skin) usually associated with an abnormality of the keratin and an increase of the granular layer of the skin |
| Hyperplasia | An increase in the number of cells |
| Hyperproliferation | An abnormally high rate of proliferation of cells by rapid division |
| Pustular | Lesions containing purulent materials |
| Photosensitiser | Chemical treatments that are used to sensitise the skin and enhance the effect of light treatments |
Description of the condition
Description and epidemiology
Psoriasis is a common, chronic inflammatory skin disease, with an estimated global prevalence ranging from 0.5% to 4.6% (Lebwohl 2003). The typical lesions of psoriasis include well‐demarcated red patches, with variable degrees of silvery thickening, and surface scale, particularly on the scalp; extensor aspects (backs of the elbows, fronts of the knees) of the limbs; and the trunk. Psoriatic arthritis, pustular psoriasis (a subtype of psoriasis with lesions containing purulent materials), or erythrodermic psoriasis (a subtype of psoriasis that affects all body sites) may also be present. Among the various subtypes, psoriasis vulgaris is the most common form and accounts for more than 80% of psoriasis cases (Lebwohl 2003). The characteristic pathological changes of psoriasis present with hyperkeratosis (thickening of the stratum corneum, which is usually associated with an abnormality of the keratin and an increase of the granular layer), hyperplasia (increase in the number of cells) of the epidermis, inflammatory cell infiltration into the dermis and epidermis, and dilatation of dermal capillaries (dilated small blood vessels in the dermis). The diagnosis of psoriasis is mainly based on clinical features, and pathological changes are usually helpful to distinguish psoriasis from other diseases with a similar appearance.
Cause
The exact cause of psoriasis remains unclear. However, psoriasis appears to be a disorder of immune function (specifically involving the T‐set of lymphocytes), which causes an accelerated rate of cell‐turnover in the epidermal layer of the skin (Griffiths 1996). People seem to have a strong genetic predisposition to develop the condition. Certain medications (such as lithium, beta blockers, antimalarial drugs, and nonsteroidal anti‐inflammatory drugs) and infections are thought to be possible triggers.
Impact
Although psoriasis is rarely life‐threatening, the effect on a person's quality of life can be profound, with a damaging effect on their self‐esteem, due to the long‐term nature of the disease, the persistent itching or pain of the skin, and the stigmatising effect of a disfiguring condition. It also seems to be associated with a significantly increased risk of cardiovascular disease (Gelfand 2006) and a variety of malignant diseases (Boffetta 2001; Gelfand 2003; Hannuksela‐Svahn 2000).
Description of the intervention
Management of psoriasis should depend upon a number of factors: These include the severity of the disease, associated diseases (comorbidities), education about the chronic nature of the disease, and realistic expectations about the effect of treatments, as well as the use of medication. Complete clearance of psoriasis may be unrealistic, so the main aim of treatment is to reduce disease activity with minimal side‐effects.
Interventions include topical therapy, ultraviolet light (phototherapy), systemic agents, and biological treatments. Those mildly affected can generally be treated adequately with topical medication, but 10% to 20% of those with moderate‐to‐severe psoriasis often depend upon phototherapy, systemic treatment, or combination therapy to achieve and sustain disease remission (Jensen 2010).
Phototherapy is a mainstay in the treatment of psoriasis. The most commonly used types of phototherapy are photochemotherapy using psoralen UVA (PUVA), and ultraviolet B (UVB) therapy.
PUVA therapy is administered by the use of a photosensitiser prior to exposure to the phototherapy. The photosensitiser, psoralen, is administered orally; in bath water; or as a cream before exposure to long wavelength (320 to 400 nm) UVA radiation. PUVA therapy has been proven to be effective for most forms of psoriasis and induces complete or partial remission in 79% to 90% of those with psoriasis (Lauharanta 1997; Morison 1998). Unfortunately, there is a clear relationship between cumulative PUVA exposure and an increased risk of skin cancer and premature ageing of the skin. Therefore, the British Association of Dermatologists' guidelines on biological interventions for psoriasis recommend that PUVA should be limited to 150 lifetime treatments, to decrease the risk of skin cancer (Smith 2009).
UVB (spectrum light 290 to 320 nm) has been used to treat psoriasis for at least 90 years (Anderson 1984). Phototherapy with broadband UVB (BB‐UVB) can result in the successful clearance of psoriasis within six weeks (Boer 1980).
Narrow‐band UVB (NB‐UVB) phototherapy was developed in the 1980s. It is emitted through Philips TL01 lamps and consists of a subset of the UVB spectrum between 311 and 313 nm. A study conducted by Parrish and Jaenicke demonstrated that the peak action spectrum for clinical antipsoriatic efficacy was between 308 and 312 nm (Fischer 1976; Parrish 1981). In this way, NB‐UVB can theoretically achieve an optimal response while minimising the erythrogenic (redness of the skin) response to non‐therapeutic wavelengths.
Although each type of phototherapy has been proven to be effective for psoriasis, treatment with UVB is much easier to perform and seems to have lower side‐effects, especially considering the carcinogenic potential of PUVA (De Gruijl 1996; Young 1995).
How the intervention might work
It has been found that UV exposure can affect cell signalling, favour development of T‐helper 2 (Th2) immune responses, and reduce both the number and function of antigen‐presenting Langerhans cells (Zanolli 2000).
UVA was successfully used in the treatment of psoriasis, based on its ability to reduce mast cells and induce type I collagenase activity. Psoralen is used as a photosensitiser in PUVA therapy. Once psoralen is activated by UVA, it crosslinks DNA strands, preventing replication of keratinocytes and inducing the death of activated T‐cells in the skin (Coven 1999). The significant effects of PUVA may be due to its immunosuppressive properties. The immunosuppressive mechanisms of PUVA mainly involve the following: decreasing the antigen‐presenting capacity of epidermal Langerhans cells and the numbers and functional activity of T‐helper cells and mRNA encoding for proinflammatory cytokines IL‐6, IL‐8, and TNF‐A. They may also involve inhibition of cell proliferation, reduction of the percentage of CD3+ peripheral T lymphocytes producing IFN‐gamma and IL‐2, and induction of an anergy (failure of response) of type 1 activity in peripheral lymphocytes (Aubin 1998; Ashworth 1989; Borroni 1991; Kozenitzky 1992; Neuner 1994).
The exact mechanism of action of UVB is not fully understood. The proposed mechanism may cause apoptosis (cell death) of lymphocytes and epidermal cells, and immunosuppressive and anti‐inflammatory effects (Aufiero 2006). It has been demonstrated that the peak action spectrum for clinical efficacy is between 308 and 312 nm, while the maximal erythrogenic response occurs around 297 nm (Fischer 1976; Parrish 1981). With NB‐UVB, as the peak spectrum is at 311 nm, significant antipsoriatic efficacy can be achieved with a limited erythrogenic response.
Why it is important to do this review
There have been many studies, of variable methodological quality, comparing the efficacy of different types of phototherapy: Some indicated that PUVA is more effective than BB‐UVB radiation (Brenner 1983; Boer 1984; Honigsmann 1977; Morison 1995); others demonstrated that NB‐UVB provided faster clearing of psoriasis, less burning reactions, and longer periods of remission than BB‐UVB phototherapy (Coven 1997; Green 1988; Storbeck 1993). Recently, while some authors have claimed that NB‐UVB therapy had similar efficacy with PUVA (Markham 2003), different results have been found by other authors (Dawe 2003; Gordon 1999; Tahir 2004).
No systematic review has been conducted to summarise the evidence for the effects of NB‐UVB phototherapy compared to BB‐UVB or PUVA photochemotherapy for psoriasis. Therefore, we aim to assess and, if possible, combine results from randomised controlled trials (RCTs) to provide reliable information that will assist clinicians and decision‐makers in the management of psoriasis.
Objectives
To assess the effects of narrow‐band ultraviolet B phototherapy versus broad‐band ultraviolet B or psoralen‐ultraviolet A photochemotherapy for psoriasis.
Methods
Criteria for considering studies for this review
Types of studies
We will include any RCTs involving NB‐UVB phototherapy versus BB‐UVB or PUVA photochemotherapy for psoriasis. Quasi‐randomised trials will be excluded.
Types of participants
We will include any individual with a diagnosis of psoriasis vulgaris, regardless of age, race, gender, or the severity of their lesions.
Types of interventions
Any NB‐UVB phototherapy compared with BB‐UVB or PUVA photochemotherapy, either as a single or combination therapy. In particular, the following comparisons will be conducted, if possible:
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NB‐UVB vs PUVA
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NB‐UVB combined with methotrexate vs PUVA combined with methotrexate
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NB‐UVB combined with retinoids vs PUVA combined with retinoids
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NB‐UVB vs BB‐UVB
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NB‐UVB combined with methotrexate vs BB‐UVB combined with methotrexate
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NB‐UVB combined with retinoids vs BB‐UVB combined with retinoids
Types of outcome measures
Primary outcomes
1) Participant‐rated global improvement.
2) Percentage of participants reaching PASI 75.
3) Withdrawal due to side‐effects.
Based on the timing of outcome measures, the primary outcomes will be classified into three categories: short‐term (up to four weeks), medium‐term (four weeks to six months), and long‐term (more than six months).
Secondary outcomes
1) The Physician's Global Evaluation score.
2) Dermatology Life Quality Index (DLQI).
3) Number of treatments to complete clearance.
4) Percentage of participants who achieved complete clearance in the clinician's opinion.
Search methods for identification of studies
We aim to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
We will search the following databases for relevant trials:
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the Cochrane Skin Group Specialised Register;
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the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane library;
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MEDLINE (from 1948);
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EMBASE (from 1974);
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CNKI (China National Knowledge Infrastructure, from 1974); and
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CBM (Chinese Biomedical Database, from 1978).
We have devised a draft search strategy for randomised controlled trials (RCTs) for MEDLINE (OVID), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.
Searching other resources
Ongoing Trials databases
We will search the following ongoing trials registers:
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The metaRegister of Controlled Trials (www.controlled‐trials.com).
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The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
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The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
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Chinese Clinical Trial Registry (www.chictr.org).
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The World Health Organization International Clinical Trials Registry platform (www.who.int/ trialsearch).
Reference lists
The references of all included trials and relevant systematic reviews or meta‐analyses will be scanned to identify other relevant trials.
Conference proceedings
Abstracts from the following dermatological conference proceedings will be scanned for further RCTs:
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World Congress of Dermatology (from 1980).
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International Congress of Dermatology (from 1980).
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European Academy of Dermatology and Venereology (from 1980).
Unpublished literature
We will obtain unpublished trials and grey literature through correspondence with authors.
Adverse effects
Data on adverse effects in the included studies will be analysed in the review. In addition, any other data from clinical trials, including non‐RCTs and adverse drug reaction reports, will be summarised qualitatively. For this purpose, we will run a search in MEDLINE for non‐RCTs to look for potential side‐effects, using the Cochrane Skin Group's standard adverse effects search strategy and the intervention terms.
Language
There will be no language restrictions. Translations will be sought where necessary.
Data collection and analysis
Selection of studies
Two of us (XMC and YC) will independently scan the titles and abstracts of all articles identified from the searches according to our inclusion and exclusion criteria. For all initially selected articles, we will obtain the full text, and two of us (XMC and MY) will independently assess them to see whether they are eligible for inclusion.
We will list the studies we exclude and the reasons for their exclusion in the review. We will resolve any discrepancies by discussion with MZ, who will act as an arbitrator.
Data extraction and management
Two of us (XMC and MY) will extract the data from the included studies separately. We will compare our results, and any differences will be resolved by discussion within the review team or by consultation with MZ. We will document the process of resolving discrepancies within our review. We will amend the extraction form recommended by the Cochrane Skin Group to summarise the trials, and we will address the following information:
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general information (authors, title, source, year of publication, language of publication, trial numbers);
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trial characteristics (design; manner of recruitment; inclusion and exclusion criteria; duration of intervention period; reason for, and number of, dropouts and withdrawals);
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participants (baseline characteristics of participants in all groups, such as gender, age, psoriasis severity, and baseline health‐related quality of life (HRQoL) scores);
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interventions (any intervention in both study and control groups); and
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outcomes (specific outcomes reported, assessment instrument used, adverse events).
We will contact trial authors for more information where necessary. One of us (YC) will check and enter the data into Review Manager (Revman). Another author (MY) will double‐check the data.
We will extract the data of adverse events from non‐RCTs separately.
We will not be blinded to the names of trial authors, journals, or institutions during the process of data extraction.
Assessment of risk of bias in included studies
The methodological quality of the included studies will be assessed by two authors (XMC and YC) independently. We will settle any discrepancies by discussion with the review team or by consultation with MZ, our arbitrator. The Cochrane Collaboration's tool for assessing risk of bias, which forms part of the 'Characteristics of included studies' tables (Higgins 2011), will be used, and we will address the following issues:
(a) was there adequate sequence generation?;
(b) was allocation adequately concealed?;
(c) was knowledge of the allocated interventions adequately prevented during the study?;
(d) were incomplete outcome data adequately addressed?;
(e) are reports of the study free of suggestion of selective outcome reporting?; and
(f) was the study apparently free of other problems that could put it at a risk of bias?
Our judgements for each item and the reasons for our judgements will be documented in the 'Risk of bias' table for each included study within the review.
Where necessary, we will attempt to contact trial authors for more information.
Measures of treatment effect
According to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will define measures of treatment effects as follows.
Dichotomous data
We will present dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI) for individual trials. We will discuss the main outcomes of each study and, if possible, pool feasible data. If the results are significant, we will calculate the number needed to treat (NNT).
Continuous data
For continuous variables, such as the score of life quality index, we will use the mean difference and 95% CI, unless different scales are used in the trials, in which case we will use a standardised mean difference (SMD) and 95% CI to summarise the data.
Ordinal data
We will measure the types of adverse events data as ordinal data, which will be reported qualitatively.
Unit of analysis issues
Simple parallel RCTs
The unit of analysis will be individual participants.
Cluster RCTs
If cluster RCTs are identified, we will try to re‐analyse these trials by calculating the effective sample sizes according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). And, if possible, we will calculate an estimate of the intra‐cluster coefficient (ICC), using external estimates obtained from similar trials. Data from cluster RCTs will not be pooled with those from parallel RCTs.
Cross‐over RCTs
If cross‐over RCTs are identified, only data from the first period will be extracted and analysed (Higgins 2011). Data from cross‐over RCTs will not be pooled with those from parallel RCTs.
Multiple intervention groups within a trial
If there are multiple intervention groups within a trial, we will make pair‐wise comparisons of one intervention versus another, or one intervention versus no intervention or placebo. We will split the number of participants in the control (or placebo) group to avoid participants being counted twice in the pooled analyses. Data from these studies will be analysed separately.
Multiple body parts receiving the same intervention
In some trials, the participants are randomised, but multiple body parts receive the same treatment, and a separate outcome judgement is made for each body part. The number of body parts is used as the denominator in the analysis. In such cases, it is similar to the situation in cluster trials, except that individuals are the "clusters" (Higgins 2011). Therefore, if such trials are identified, we will try to re‐analyse the data from these trials using the methods mentioned above. Data from these studies will be analysed separately.
Multiple body parts receiving different interventions
In some other trials, participants are randomised and multiple body parts receive different treatment, which may be similar to the situation in cross‐over trials. However, if possible, all relevant data from these trials will be extracted and analysed. Data from these studies will be analysed separately.
Dealing with missing data
First, we will try to contact the trial authors to get more information where necessary. If this does not succeed, we will consider participants with missing outcomes as treatment failures for dichotomous outcomes. In the case of participant dropout, we will conduct an intention‐to‐treat analysis.
For continuous outcomes we will only extract and analyse the available data. In addition, we will explore the impact of missing data on the treatment effect by using sensitivity analyses. The whole process of dealing with the missing data, and it's potential impact on the results of the review, will be stated in the Discussion section of our review.
Assessment of heterogeneity
We will evaluate the level of clinical heterogeneity by comparing the differences between the trials in the administration of therapy, the type of comparators used, and the characteristics of the study population. If an appropriate level of clinical homogeneity exists, the level of statistical heterogeneity will be analysed using the Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and the I² statistic. I² statistic values of 25%, 50%, and 75% correspond to low, medium, and high levels of heterogeneity (Higgins 2011). If heterogeneity exists, we will try to probe reasons for it and advise caution in the interpretation of our results.
Assessment of reporting biases
If we identify sufficient RCTs, we will use funnel plots to test for publication bias (Higgins 2011).
Data synthesis
We will pool data using the random‐effects model, unless there are less than three trials ‐ in which case, we will use the fixed‐effect model. If substantial heterogeneity is identified, we will report the results qualitatively.
Subgroup analysis and investigation of heterogeneity
If possible, we will conduct subgroup analyses to explore possible sources of heterogeneity due to participants, interventions, or study quality. Heterogeneity among participants may be related to their age or the severity of their psoriasis. Heterogeneity in treatments may be related to the dose or duration of therapy.
Sensitivity analysis
If possible, we will perform the following sensitivity analyses.
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To assess the effect of including trials with a high or unclear risk of bias (as defined above), we will exclude such trials in the sensitivity analysis.
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To assess the effect of missing data, we will exclude trials with high levels of missing data (> 20%) in the sensitivity analysis.
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To assess the effect of cross‐over trials, we will exclude such trials in the sensitivity analysis.
| Medical term | Explanation |
| Apoptosis | A process of programmed cell death by which cells undergo an ordered sequence of events which lead to the death of the cell. This occurs during growth and development of the organism as a part of normal cell aging or as a response to cellular injury |
| Collagenase | An enzyme which breaks the peptide bonds in collagen |
| Cytokines | Small protein molecules that are secreted by cells of the nervous system or the immune system. They are used in intercellular communication |
| Defective maturation of epidermal keratinocytes | Incomplete formation of keratin (the horny material in nails) due to rapid growth of cells in the epidermal layer of the skin |
| Dilatation of dermal capillaries | Dilation of small blood vessels in the skin |
| Erythrodermic psoriasis | A subtype of psoriasis that affects all body sites |
| Erythrogenic response | Redness of the skin caused by light exposure |
| Extensor aspects | An anatomical term ‐ when a joint bends, the parts of the skin on the opposite side of the joint are called the extensor aspects |
| Hyperkeratosis | Thickening of the stratum corneum (outermost layer of the skin) usually associated with an abnormality of the keratin and an increase of the granular layer of the skin |
| Hyperplasia | An increase in the number of cells |
| Hyperproliferation | An abnormally high rate of proliferation of cells by rapid division |
| Pustular | Lesions containing purulent materials |
| Photosensitiser | Chemical treatments that are used to sensitise the skin and enhance the effect of light treatments |
