University of Groningen
Pemphigoid diseases: Insights in the nonbullous variant and disease management
Lamberts, Aniek
DOI:
10.33612/diss.132159641
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Publication date: 2020
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Lamberts, A. (2020). Pemphigoid diseases: Insights in the nonbullous variant and disease management. University of Groningen. https://doi.org/10.33612/diss.132159641
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CHAPTER 12
Summary
Aniek Lamberts
Center for Blistering diseases, Department of Dermatology University Medical Center Groningen, University of Groningen Groningen the Netherlands
This thesis presents studies that are focused on pemphigoid diseases. Pemphigoid diseases are autoantibody mediated bullous diseases that may affect the skin and/or mucous membranes. We further introduce the clinical presentation, diagnostics, and management of different pemphigoid variants in chapter 1. The thesis is divided into two parts. Part 1 of the thesis consists of studies performed to characterize the pemphigoid variant named nonbullous pemphigoid (NBP). Part 2 presents studies that focus on the management of pemphigoid diseases.
PART 1 – Nonbullous pemphigoid: diseases characteristics and immunological
aspects.
Bullous pemphigoid (BP) is the most prevalent pemphigoid subtype, and typically presents with severe pruritus and tense blisters mainly located on the skin. Interestingly, a less known phenotypic variant of BP clinically lacks blisters, a disease termed NBP. NBP is understudied, as only few case reports and small case series exist in literature. Therefore, patients with NBP often have a long diagnostic delay. Diagnostic and immunological findings can be similar to BP, and it is
unknown which underlying mechanism prevents blisters to form in NBP. The aim of part 1 of this thesis was to study the disease characteristics of NBP, and to learn more about its underlying immunological disease mechanism.
Pemphigoid-specific autoantibodies in healthy individuals
In chapter 2 we first assessed the prevalence of pemphigoid-specific IgG
autoantibodies in sera of dermatology patients with a nonbullous skin disorder. A diagnosis of pemphigoid was excluded based on skin biopsy with negative direct immunofluorescence microscopy. We found single serological test positivity in 14%. Interestingly, single test positivity was related to a significant higher median age. In chapter 6 we also found circulating pemphigoid-specific IgE autoantibodies in 28% of elderly controls with pruritus. The relevance of these IgG and IgE serum autoantibodies against BP180 and BP230 in ‘healthy’ elderly persons is unknown. It was hypothesized that ELISA positivity might rely on nonspecific binding, or that the immune response could be related to a phenomenon termed ‘epitope spreading’. Moreover, autoantibody formation could be related to a decrease in functional regulatory T cells, due to aging of the immune system.
mandatory for the diagnosis of pemphigoid. Based on their findings and proposed diagnostic criteria, ten patients in chapter 2 received a delayed diagnosis of NBP. Disease characteristics of nonbullous pemphigoid
Clinical findings
In chapter 3 we systematically reviewed the literature on NBP and identified 132 published cases. Overall, patients had long diagnostic delays (mean 23 months), and presented with heterogeneous skin manifestations. Erythematous urticarial plaques (52%), and papules and nodules (21%) were most commonly reported. Reported histopathologic findings were mainly nonspecific. Blister formation during follow-up was observed in 10% of the patients only. In chapter 4 we described the disease characteristics of our cohort of 68 NBP patients. Again, long diagnostic delays (mean 29 months) were observed. Skin examination most frequently showed papules and nodules (31%). Pruritus on primary nondiseased, noninflamed skin was found in 22%. In line with chapter 3, we observed that blisters occurred in the minority of patients (17%) during follow-up. Interestingly, low dose methotrexate showed high remission rates (43%) of long duration (mean 95 weeks). The all-cause mortality rate was high, as 36% of the patients died after a mean follow-up time of 2 years. The standardized mortality ratio was higher (8.6) compared to previous reports on BP, but should be interpreted with caution because of our low sample size. Both chapter 3 and chapter 4 plead for more awareness amongst clinicians for NBP as cause of pruritus in elderly patients. Moreover, our data indicates that NBP has no mild disease course, and shows a frequent necessity for systemic treatment.
Prevalence of nonbullous pemphigoid
In chapter 5 we assessed the prevalence of pemphigoid in the assumed high-risk population of nursing home residents. An extra blood sample for serologic diagnostic pemphigoid tests was taken of 125 nursing home residents during a routine venous punction. Seven nursing home residents were diagnosed with pemphigoid (3 bullous, 4 nonbullous). The overall pemphigoid prevalence in nursing home residents was 6%, which is substantially higher than the prevalence in the general population (0.3% in persons aged ≥ 85 years). All four NBP cases were newly diagnosed, and had inappropriately treated pruritic symptoms. Our
findings illustrate that NBP can be a cause of pruritus in nursing home residents, and merits more attention from nursing home physicians.
Immunological aspects of nonbullous pemphigoid
In chapter 6 we investigated the presence of IgE autoantibodies in serum and skin of NBP and BP patients, using ELISA and immunofluorescent staining. The
percentage of positive anti-BP180 and anti-BP230 IgE ELISAs did not differ significantly between both pemphigoid phenotypes. In the skin of NBP and BP patients, we mainly detected IgE bound to the surface of cells in the dermis (71% and 86%). Only two skin samples (7%; 1 NBP, 1 BP) showed linear IgE along the basement membrane zone. Based on our findings we concluded that IgE might play a role in the pathogenesis of both NBP and BP, but is presumably not centrally involved in blister formation.
In chapter 7 we aimed to learn more about the disease pathogenesis of NBP and BP by assessing the gene expression profile of lesional skin of NBP and BP patients, using the nanoString technology. Six of ten BP patients showed high expression of complement activation related genes, while a low expression was found in four BP, and all 12 NBP skin samples. A dual high expression of Th1 and Th2 related genes was seen in all BP skin samples, while only the minority of NBP samples showed elevated Th1 or Th2 related gene expression. Moreover, several genes were significantly higher expressed in BP compared to NBP skin, including genes encoding for chemoattractants IL-8 and CCL3, epidermal growth factors HBEGF and AREG, transcription factors CREM and FOSL1, receptors ILR1RL1 and GPR65, the gene encoding for COX2, and the proteinase ADAMTS4. These
activated genes may be relevant in blister formation, however, further studies are needed to validate this genetic data.
In chapter 11, discussion and future perspectives, we further elaborated on several other immunological aspects that could have a role in the disease
pathogenesis of NBP. This includes antigen- and epitope recognition, complement activation, IgG subclass profile, and the activation of eosinophilic granulocytes.
PART 2 – Management of pemphigoid diseases
Part 2 of this thesis presents studies concerning the management of pemphigoid diseases. In general, the treatment of pemphigoid diseases consists of
are not always successful in achieving disease control, and may have serious side effects, especially in the vulnerable elderly population that often has multiple comorbidities. Hence, the ongoing search for drugs for pemphigoid diseases with a high effectiveness and a better safety profile.
In chapter 8 we performed an international survey study to explore unmet needs in pemphigoid diseases from the perspective of patients, clinicians, and researchers. In total, 107 participants were included, of which most were patients (66%). All three interest groups expressed a high need for improvement and widening of therapeutic options for pemphigoid diseases. Moreover, patients with pemphigoid diseases strongly carried out the need for more disease awareness amongst clinicians, to prevent long diagnostic delays, and misdiagnosis.
In chapter 9 we investigated the effectiveness and safety of rituximab infusions in 28 patients with recalcitrant pemphigoid diseases in a retrospective case series. Overall, remission was achieved in 57% of the patients. Mucous membrane pemphigoid patients responded best (remission in 64%), followed by BP patients (63%). Patients with epidermolysis bullosa acquisita showed lower remission rates (40%), and one patient with linear IgA disease showed no response. Overall, two-third of the pemphigoid patients that achieved remission eventually relapsed, and repeated rituximab infusions again led to remission in 86%. Moreover, our data implied that 1000 mg rituximab on day 0 and 15 was more effective than 500 mg, although this difference was not statistically significant. Also, we observed a poor response on rituximab in IgA-dominant pemphigoid cases, suggesting that clinicians should rather prescribe an alternative therapy in such patients. In chapter 10 we assessed the prevalence of pneumocystis pneumonia (PCP) in patients with autoimmune blistering diseases without routine PCP prophylaxis in a multicenter retrospective patient chart study. Data of 801 patients with
autoimmune blistering diseases showed an incidence of PCP of 0.1%. This incidence was below the previously determined threshold of 3.5% to justify PCP prophylaxis, and we therefore concluded that routine PCP prophylaxis is not warranted in all patients with autoimmune blistering diseases. Future research should study individual patient characteristics, and the level of immunosuppression
in patients that developed a PCP, to provide more guidance in which patients do benefit of PCP prophylaxis.
In chapter 11, discussion and future perspectives, we shortly discussed several novel therapies that are currently being researched. These drugs include anti-complement therapies, IgE blockage, eosinophilic granulocyte targeting drugs (anti-IL-5 and anti-eotaxin-1), and phosphodiesterase 4 inhibitors.
