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REVIEW ARTICLE
Year : 2023 | Volume
: 41
| Issue : 2 | Page : 67-77
Pemphigus scoring systems and their validation studies – A review of the literature
Darby Boucher1, Anna Wilson2, Dedee F Murrell2
1 Faculty of Medicine, University of NSW, Sydney, NSW, Australia
2 Faculty of Medicine, University of NSW; Department of Dermatology, St. George Hospital, Sydney, NSW, Australia
Correspondence Address:
Prof. Dedee F Murrell
Department of Dermatology, St. George Hospital, Gray St, Kogarah, Sydney NSW 2217
Australia
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ds.DS-D-22-00150
Pemphigus is a rare autoimmune blistering disease that affects the skin and mucous membranes. Despite recent advances in treatment, pemphigus is associated with high patient mortality and has a significantly negative impact on patients' quality of life and mental health. Validated scoring systems to accurately measure pemphigus severity are vital for the monitoring of disease activity, evaluation of treatment efficacy and trialing, comparison and introduction of new treatments. This article reviews the existing scoring systems for pemphigus and their validation studies and proposes a future area of research regarding global assessments for simplistic scoring of pemphigus severity.
Keywords: Bullous, outcome measure, pemphigus, reliability, scoring system, validation
Pemphigus is a rare autoimmune blistering disease (AIBD) that affects the skin and mucous membranes.[1] Despite recent advances in treatment, the patient mortality remains over two times higher than the general population.[2] Pemphigus has a profound negative effect on patients' quality of life and mental health.[3] There is an international shortage of multi-center controlled trials to assess and introduce new treatments that could significantly improve patients' disease and quality of life. This can be attributed to the lack of standardized and validated outcome measures to accurately compare new and conventional therapies.[4] This review aims to evaluate the existing scoring systems for pemphigus severity and discuss the rationale for Investigator Global Assessments (IGAs) as simplistic tools for assessing pemphigus severity.
PemphigusOverview
Pemphigus is a group of rare chronic AIBDs characterized by immunoglobulin G (IgG)-mediated acantholysis, resulting in blister and erosion formation in the skin and mucous membranes. Acantholysis refers to the loss of adhesion between keratinocytes and is due to autoantibodies against cell adhesion molecules found in desmosomes, such as desmoglein 1 and desmoglein 3.[1] This process affects stratified squamous epithelium, which is found in the epidermis of the skin and mucosa such as the conjunctiva, nose, mouth, and genitals. Patients with pemphigus may develop cutaneous flaccid bullae and pustules, and painful erosions in the mucosa or epidermis, as shown in [Figure 1].[5]
Figure 1: Clinical manifestations of pemphigus. (a) flaccid purulent bullae on the trunk; (b) erosions, erythema and crusting on the scalp; (c) erosions on the upper gingiva and hard palate; (d) erosions, crusting and post-inflammatory hyperpigmentation on the back.The patients have provided informed consent for the publication of their photographs in [Figure 1].
Types of pemphigus
There are four main types of pemphigus, including pemphigus vulgaris (PV), pemphigus foliaceus (PF), paraneoplastic pemphigus (PNP), and IgA pemphigus [Table 1]. Pemphigus types vary in terms of their clinical, histological, and immunological features. PV is the most common type of pemphigus and causes blisters and erosions in the mucous membranes and skin, including the oral mucosa, flexural areas, upper and lower limbs, trunk, face, and scalp. There are three subtypes of PV, which include mucocutaneous, mucosal-dominant, and cutaneous only. Mucocutaneous PV is attributed to the presence of autoantibodies against both desmoglein 1 and desmoglein 3 (i.e. anti-dsg1 and anti-dsg3). Mucosal-dominant PV is due to anti-dsg3 antibodies only, and cutaneous PV is due to anti-dsg1 antibodies and pathogenically weak anti-dsg3 antibodies. PF is a less common and less severe type of pemphigus that affects the skin only, owing to the presence of anti-dsg1 autoantibodies. PNP occurs in association with neoplastic diseases, such as non-Hodgkin's lymphoma or chronic lymphocytic leukemia. It variably affects the skin and mucosa, with severe stomatitis being a consistent clinical finding. Patients with PNP may have autoantibodies against dsg-1 and dsg-3, or plakin proteins such as envoplakin and periplakin. IgA pemphigus is a very rare form of pemphigus that manifests as a cutaneous vesicopustular disease with no mucosal involvement. The autoantibodies against cell-adhesion molecules are of the IgA subtype, rather than IgG.[6] All forms of pemphigus have a profoundly negative impact on patients' quality of life and mental health, with rates of moderate-to-severe anxiety and depression reported in 50% and 45% of patients, respectively.[3]
Epidemiology
Pemphigus is a rare disease and incidence rates vary considerably based on geography and ethnicity. PV has particularly high incidence rates in Jewish, Indian, South-Eastern Europe, and Middle Eastern populations.[7] Annual incidence rates have been reported to range from 0.8/100,000 in Finland, to 1.61/100,000 in the Israeli Jewish population.[8],[9] The age of onset of PV is typically between 50 and 60 years and it preferentially affects women.[10] PF has the highest rates of incidence in South America and North Africa, where an endemic form of the disease exists in young adults.[11] PF affects men and women equally.[10] Limited data exist on the epidemiology of IgA pemphigus and PNP due to their rarity.[7],[12]
Etiology
The etiology of pemphigus is not well understood, but current theories suggest that it is due to genetic predisposition and an environmental trigger. Certain alleles have been suggested to have a correlation with PV, such as HLA-DRB1 * 0402 and the STI8 gene, which are prevalent in Jewish populations.[1],[13] Hypothesized environmental triggers include drugs such as penicillamine and angiotensin-converting enzyme inhibitors, viruses such as herpes simplex virus, psychological stress, and diet.[1]
Treatment
Before the introduction of corticosteroids in the 1950s, 1-year mortality rates among pemphigus patients were 75%.[7] The introduction of immunosuppressants such as mycophenolate mofetil and azathioprine for the treatment of pemphigus further reduced mortality rates from 30% to <5%.[7],[14] However, the overall mortality rate for pemphigus patients remains 2.4 times greater than the general population, mostly due to adverse effects associated with long-term use of high-dose corticosteroids and other immunosuppressants.[2],[15] Adverse effects due to long-term corticosteroid use have been well documented, including osteoporosis, cataracts, hyperlipidemia, hyperglycemia, hypertension, and infection.[16],[17] Rituximab, an anti-CD20 monoclonal antibody, was first used for severe pemphigus in Italy in 2004 and has been used off-label in Australia following the 2017 Ritux 3 randomized clinical trial.[18] A meta-analysis found that rituximab achieved complete remission in 76% of pemphigus patients.[19] However, severe adverse events have been associated with rituximab therapy, such as hepatitis, leukoencephalopathy, and cardiac arrhythmias.[17] Other second- and third-line therapies available for pemphigus include cyclophosphamide, intravenous immunoglobulin (IVIG), plasmapheresis, immunoadsorption, dapsone, methotrexate, and cyclosporine. Many of these drugs, such as cyclophosphamide and methotrexate, are associated with frequent adverse events. Others such as IVIG and plasmapheresis are highly effective and safe, however, are associated with high costs and barriers to access. Potential future therapies have been suggested for the treatment of pemphigus, such as T-cell immunotherapy, chimeric antigen receptor therapy, and B-cell activating factor inhibitors.[17] However, the current research in these areas is limited.
Scoring Systems for PemphigusIn 2006 a systematic review identified that there was a shortage of sufficiently powered and high-quality clinical trials evaluating treatments for pemphigus.[20] This was mostly attributed to the absence of a universally accepted outcome measure of pemphigus severity to compare therapeutic outcomes, with the review finding 116 different scoring systems for the severity of pemphigus. This finding prompted the development and validation of new scoring systems for pemphigus severity, namely the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and the Pemphigus Disease Area Index (PDAI), as well as the Autoimmune Bullous Disease Quality of Life Questionnaire for quality of life evaluation in patients with AIBD (including pemphigus).[21],[22],[23] Validated scoring systems for disease severity and comorbidities are pivotal for the trialing, evaluation, and comparison of new and conventional treatments for pemphigus.
Validation of scoring systems
The validation of an outcome measure involves assessment based on quality domains as set out by the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) group in 2010. Validation of outcome measures is important because the use of unvalidated tools may lead to unreliable and biased results that lead to incorrect conclusions.[24] For example, a systematic review of outcome measures for schizophrenia found that randomized controlled trials with unvalidated scoring systems were more likely to find that a treatment was superior to a control.[25] Validated scoring systems increase cost-effectiveness through the elimination of ineffective treatments, and allow for uniform comparison of results of clinical trials.[26] The quality domains identified by the COSMIN group include reliability, validity, responsiveness, and interpretability. Each domain and its subsections are summarized in [Table 2].
Search StrategyA literature search was conducted across two databases (PubMed and Embase) using the search terms “pemphigus,” “outcome measure,” “scoring system,” “valid*” and “reliab*.” The process of article retrieval is shown in [Figure 2].[29] Further studies were also identified through citation searching. The search allowed for the identification of scoring systems for pemphigus disease severity and their validation studies to be analyzed, discussed [Table 3] and [Table 4].
Figure 2: Diagram of a literature search for pemphigus outcome measure publications. Created using Prisma Flowchart.[29] Search terms: (((pemphigus) AND ((scoring system) OR (outcome measure)) AND ((valid*) OR (reliab*))). Scoring Systems for Pemphigus The most frequently used scoring systems in practice are the ABSIS and the PDAI.[38] Other less commonly used instruments include the Pemphigus Area and Activity Score (PAAS), Harman's scoring system, and the PV Activity Score (PVAS).
Pemphigus Area and Activity Score
The PAAS was developed in 1998 as one of the first scoring systems for pemphigus.[30] It has a score range between 0 and 15 with components relating to number of new lesions, extension of blisters, and Nikolsky's sign. Nikolsky's sign is elicited when lateral pressure is applied to the edge of a blister, causing further separation of the epidermis and extension of the blister.[43] Elicitation of this sign is variable depending on the expertise of the clinician, and impractical to be conducted routinely in both practice and clinical trials. The PAAS also requires a large change in affected body surface area (BSA) to change the severity score, thus it is rarely used as a scoring system due to its imprecision.[37],[38],[41]
Harman's score
Harman's scoring system is a simplistic scoring system developed in 2001 with oral and cutaneous components, as well as autoantibody titers.[31] Autoantibodies against dsg-1 and dsg-3 as a measure of disease severity are controversial, with some studies showing correlations and some concluding that autoantibody titers are not an accurate representation of disease course. Anti-dsg1 and anti-dsg3 persist in the blood despite the clinical improvement, and non-pathogenic Dsg-3 antibodies are often present.[36],[38] Like the PAAS, Harman's scoring system is insensitive to small BSA changes and therefore is not an optimal scoring tool.[4],[41]
Autoimmune Bullous Skin Disorder Intensity Score
The ABSIS was developed in 2007 in Germany as a generic tool to measure the severity of AIBDs, including pemphigus.[21] It has a possible score between 0-206 with components relating to location and quality of lesions, BSA affected, and discomfort during eating/drinking. An advantage of the ABSIS is that it assesses both objective and subjective aspects of disease severity, which may not otherwise be appreciated by clinicians.[38],[42] A disadvantage of the ABSIS is that it combines disease activity and damage components, and uses a weighting factor based on lesion type which can greatly amplify differences between scorers.[40],[42] It also uses the “rule of 9s” to calculate BSA, which is consistently overestimated by scorers and has been proven inaccurate.[33],[38],[44] Furthermore, the ABSIS only has a component for oral mucosa, when ocular, nasal, genital, and anal mucosa can also be involved.[32]
Pemphigus Disease Area Index
The PDAI was developed in 2006 and published in 2008 after validation by the International Pemphigus Definitions Group (IDPG) to assess pemphigus disease extent, with a possible score between 0-263 and activity and damage components relating to skin, scalp, and mucous membranes.[22] It is particularly sensitive to small numbers of lesions and is precise as it does not require BSA calculation, instead examining individual anatomical sites.[4],[34],[39],[40],[41] The initial validation study showed that the PDAI was superior to the ABSIS in terms of reliability and validity in assessing disease severity in pemphigus patients with mild-to-moderate disease.[22] Fifteen patients with mild disease were scored by five assessors in a one-day face-to-face exercise. Intra-rater reliability was assessed by having assessors rescore patients two hours later – unknowingly-to minimize recall bias. Bastuji-Garin and Sbidian[27] identified limitations of the study's methodology, proposing that the two-hour time gap was not sufficient to prevent recall bias. Furthermore, the mild nature of the sample's disease severity limited the proposed validity of the PDAI for pemphigus patients with more severe disease. As such, further studies were conducted to validate the PDAI and ABSIS for patients with a wider range of disease severity. Rahbar et al.[33] concluded that the PDAI was the superior outcome measure in terms of inter-rater reliability and convergent validity with the PVAS. An advantage of this study was its large sample size, more heterogeneous study population in terms of disease severity, and its independence from the IDPG who devised the PDAI, eliminating the risk of bias.[33] An international multi-center study to validate the PDAI and ABSIS was later conducted, demonstrating that both the PDAI and ABSIS had excellent reliability and validity for assessing pemphigus of all severities.[35] The risk of selection bias was eliminated through the recruitment of consecutive patients from secondary and tertiary centers, and the sample size was ample with 116 patients recruited.
Pemphigus Vulgaris Activity Score
The PVAS is a PV-specific scoring system for disease severity, developed and validated in 2013 in Iran, where pemphigus is relatively common. It has a possible score between 0-18 with 11 points for cutaneous involvement and 7 points for mucosal involvement.[32] It was noted that the assessors involved in the validation of the PDAI felt that both the PDAI and ABSIS would be too difficult to incorporate into routine practice due to their complexity and time taken to complete (4.7 and 3.9 minutes, respectively).[22],[35] Thus an advantage of the PVAS is its superior feasibility, completed in a mean time of 3.1 minutes in its validation study.[32] However, a significant limitation of the validation of the PVAS was that only one expert scored each patient using the PVAS, meaning that inter-rater reliability for the PVAS could not be calculated. Furthermore, the PVAS takes into account Nikolsky's sign, which is impractical as aforementioned.[4]
The advantages and disadvantages of each scoring system are summarised in [Table 5].
An important consideration when measuring pemphigus severity is which scoring tool to use for different types of pemphigus. PV tends to affect the upper body including the head and neck more than PF, especially in milder cases.[32],[33] The PDAI places a greater emphasis on the head and neck compared to the ABSIS, with 50 points allocated for scalp, ears, nose, neck, and rest of the face. Rahbar et al. found that the PDAI had markedly higher convergent validity with anti-dsg1 levels compared to the ABSIS, suggesting that the ABSIS was not an optimal tool for measuring the severity of PF.[33] As such, the PDAI may be a more suitable scoring tool for both PV and PF.
Global AssessmentsThe US Food and Drug Administration (FDA) is the authority by which drugs are regulated and new drugs are reviewed and approved. As part of the drug-approval process, the FDA must review data gathered during human clinical trials to assess the efficacy of a drug. Despite the excellent reliability and validity of disease-specific scoring systems such as the PDAI and ABSIS, the FDA often prefers the primary endpoint of a clinical trial to be a global assessment for drug applications.[45] Global assessments are generic instruments used to give an overview of overall disease severity, usually on an ordinal scale.[46] The most well-known global assessment is the IGA, which is typically a 5-point scale from 0 to 4, with 0 = Clear/No Disease, 1 = Almost Clear, 2 = Mild, 3 = Moderate and 4 = Severe. IGAs have been developed and validated for a variety of dermatological diseases, including acne vulgaris, atopic dermatitis, and psoriasis.[46],[47],[48] In clinical trials for psoriasis, the FDA typically requests that the responder analyses either achievement of an IGA score of 0/1 (clear or almost clear), or at least a 2-point reduction in disease severity from baseline, or both.[46] The FDA's preference for global assessments is likely because a simplistic ordinal score, such as 2 = Mild, is more clinically meaningful to patients in comparison to a PDAI of 7, for example.[45] Another advantage of IGAs is that they are simple and can be used by non-experts. Disadvantages of IGAs include their subjectivity and potential for inconsistency and manipulation by scorers. The FDA accepts created IGA scores before validation but not well-validated scores such as PDAI and ABSIS, unlike the European Medicines Agency. As such, there is a delay in trials as it takes time to correctly validate IGAs. To date, an IGA has not yet been validated for pemphigus. A validated IGA for pemphigus would require mucosal and cutaneous components due to the variability in lesion locations of types of pemphigus. The development of IGAs for pemphigus would facilitate the approval of pemphigus clinical trials and allow for efficient comparison of therapeutic outcomes between trials.
ConclusionScoring systems are important for measuring and monitoring the severity of pemphigus and responses to treatment. Scoring systems must be validated using appropriate methodologies for thte evaluation of reliability and validity. An optimal scoring tool for pemphigus would assess all possible lesion locations – cutaneous and mucosal, score both activity and damage, be sensitive to small numbers of lesions, be applicable for use in different types of pemphigus, and be quick and easy to use. The PDAI and ABSIS are the most valid and reliable tools for assessing pemphigus severity, though the FDA prefers simplistic scores such as IGAs. Further research is needed to evaluate whether IGAs could be valid and reliable measures of pemphigus severity in clinical trials.
Data availability statement
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Acknowledgment
The ILP/Honours program of UNSW for D.B. to work with D.F.M.
Financial support and sponsorship
Nil.
Conflicts of interest
Prof. Dedee F. Murrell has been a co-author/senior author of many of the outcome studies and reviews referenced in this article.Prof. Dedee F. Murrell, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.References
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