Pemphigus Vulgaris With Thromboembolism: A Case Report and Literature Review

Authors:
Relindis N. Awah, MD; Pamela N. Chavero; Wei-Chun J. Hsu; Matthew Dacso, MD; and Jennifer McCracken, MD

Citation:
Awah RN, Chavero PN, Hsu WCJ, Dacso M, McCracken J. Pemphigus vulgaris with thromboembolism: a case report and literature review. Consultant. 2017;57(7):399-403.

ABSTRACT: Pemphigus vulgaris (PV) is a rare and potentially fatal autoimmune blistering disease. PV can be associated with an increased risk of thrombosis, with studies demonstrating a clear association between pemphigoid disease and an increased risk of venous thromboembolism (VTE). The etiology of VTE in PV is unknown but is likely multifactorial. The presence of high titers of autoantibodies against desmogleins and treatment with high-dose corticosteroids in acute pemphigus flares are thought to be associated with an increased risk of VTE. We describe the case of a man with severe, intractable mucocutaneous PV covering more 60% of his total body surface area, on a high-dose corticosteroid regimen, who developed extensive deep vein thrombosis (DVT) and bilateral pulmonary embolisms (PEs) despite adequate systemic DVT/PE prophylaxis, and who subsequently required therapeutic anticoagulation.

KEYWORDS: Pemphigus vulgaris, venous thromboembolism, deep vein thrombosis, pulmonary embolism, corticosteroids, immunosuppressive agents

Pemphigus vulgaris (PV) is a rare and potentially fatal autoimmune blistering disease with an incidence of 0.1 to 0.5 per 100,000 people per year.¹ PV, like other autoimmune conditions, can be associated with an increased risk of thrombosis; record-linkage studies of national government databases have shown a clear association between pemphigoid disease and an increased risk of venous thromboembolism (VTE).² The etiology of VTE in pemphigus is unknown but is likely multifactorial. In addition, the presence of high titers of autoantibodies against desmogleins (DSGs) and treatment with high-dose corticosteroids in acute pemphigus flares are thought to be associated with increased risk of VTE.

PV is characterized by suprabasal and intraepidermal blisters and skin erosions. The acantholysis seen in PV is mediated by immunoglobulin G (IgG) antibodies against DSG3 and DSG1. DSGs are calcium-binding transmembrane glycoproteins (desmosomal cadherins) that bind and stabilize keratinocytes. DSG3 is primarily located in the suprabasal layer associated with both the mucosal and skin layers, and DSG1 is found in the intraepidermal layer in the superficial epithelium. The phenotype of PV depends on the presence of autoantibodies against DSG1, DSG3, or both.

Because DSG1 can compensate for the loss of DSG3 in the skin but not the mucosa, patients with autoantibodies only against DSG3 present with a mucosal-dominant PV. Similarly, patients with only autoantibodies against DSG1 present with pemphigus foliaceus (PF), a related and less severe pemphigoid disease limited to superficial blistering without mucosal involvement. The presence of autoantibodies against both DSG1 and DSG3 produces mucocutaneous PV, since the dysfunction of both precludes the ability for one to compensate for the other; this finding differentiates PV from other members of the pemphigus group. Furthermore, the blisters in PV have the characteristic Nikolsky sign, a finding characterized by exfoliation of the outermost layer of the skin with slight rubbing, also seen in patients with Staphylococcus aureus scalded skin syndrome.

The conventional treatment of PV involves the use of high-dose corticosteroids in addition to immunosuppressive agents such as mycophenolate, methotrexate, azathioprine, and intravenous immunoglobulin (IVIG). The response to systemic glucocorticoids is rapid and is the first-line treatment for initial therapy; in addition, mycophenolate, methotrexate, and azathioprine are often used in conjunction with corticosteroids.^3,4 The use of these adjunct agents varies by clinician; some clinicians prescribe nonsteroidal adjunct agents at the start of corticosteroid therapy, while others use these agents to control flares caused by corticosteroid taper, or if the response to steroid therapy is insufficient. In addition, patients with refractory PV have been shown to benefit from rituximab and IVIG in addition to corticosteroids.⁵ Furthermore, there have been documented cases of increased thromboembolic events in patients with PV that may complicate management.

This article describes a case of recurrent extensive deep vein thrombosis (DVT) and pulmonary embolism (PE) despite adequate anticoagulation in a patient with intractable PV on high-dose corticosteroids.

Case Presentation

A 39-year-old man with no significant past medical history was admitted with severe, widespread, painful, flaccid blisters covering more than 60% of his total body surface area. The blisters initially had started on his torso but subsequently had spread to his mouth and distal extremities.

Physical examination findings were notable for markedly elevated blood pressure, as well as desquamated, honeycombed lesions involving the torso, face, back, and all proximal and distal extremities (Figure 1), with positive Nikolsky sign. Oral examination revealed multiple flaccid blisters and buccal mucosal erosions bilaterally. There was 2+ pitting lower-extremity edema bilaterally up to the mid tibia. The right lower extremity was tender to palpation, and its diameter was approximately 2 cm larger than the left lower extremity.

Figure 1. Photograph of the patient on hospital day 3. Extensive epithelial skin erosion and desquamation from previous flaccid blistering was observed on physical examination prior to initiation of treatment.

Histologic results of a shave biopsy specimen of the lesion showed superficial epidermal and subcorneal acantholysis with intraepidermal neutrophils (Figure 2). The histologic differential was re-epithelialized PV, PF, bullous impetigo, or possibly staphylococcal scalded skin syndrome. Results of immunofluorescence testing were remarkable for strong intradermal staining for pemphigus antigens (Figure 3). Other diagnostic studies revealed significantly elevated epithelial cell surface IgG and DSG1 and DSG3 antibody titers (Table).

Figure 2. Histology results from a shave biopsy specimen showed extensive subcorneal and intraepidermal acantholysis.

Figure 3. Immunofluorescence test results showed strong intraepidermal staining for DSG3 and DSG1, shown in green.

Results of duplex ultrasonography of the bilateral lower extremities were remarkable for extensive right lower extremity proximal and distal DVTs. Two weeks into his hospitalization, the patient developed worsening hypoxia. Computed tomography of the thorax showed bilateral segmental and subsegmental pulmonary artery embolisms.

Upon presentation, the patient was started on antibiotics (doxycycline) for infection prophylaxis due to the extensive skin breakdown. He also required high-dose oral corticosteroids, which were dosed at 1 mg/kg/d. He was started on oral anticoagulation, and an inferior vena cava filter was placed after he developed acute PE.

Given the patient’s poor clinical response to higher doses of oral corticosteroids and multiple adverse medical outcomes from prolonged corticosteroid use, the decision was made to start rituximab and IVIG infusion.

Since then, the patient has had marked improvement on rituximab and IVIG. His peripheral IgG4 levels are steadily improving. He continues to require corticosteroids at lower doses (Figure 4).

Figure 4. Graphical representation of the patient's clinical course in response to treatment with corticosteroids, rituximab, and IVIG.

NEXT: Discussion, Management of PV

Discussion

Our guideline for the decision to use rituximab came from the study by Ahmed et al⁵ on 11 patients with severe refractory PV who had previously failed conventional therapy, including corticosteroids and immunosuppressive agents. Given the multiple extensive thromboembolic events that the patient experienced while on adequate DVT prophylaxis with subcutaneous heparin, and his subsequent development of worsening recurrent bilateral PEs, we wanted to investigate the potential roles of high-dose corticosteroids and cadherins in inducing thrombosis.

The Role of Cadherins

Vascular endothelium is a barrier that isolates platelets from the underlying subendothelial connective tissue matrix. Damage to the endothelium as a result of mechanical or functional trauma exposes the underlying charged surfaces to coagulation factor XII, the main initiator of the intrinsic coagulation pathway. In addition, disruption of hemodynamic flow, associated with agitated low shear stress, also activates endothelial cells. This process is associated with an increased proliferation of endothelial cells, higher permeability, and discontinuity in vascular endothelial cadherin (VE-cadherin) and connexin-43 distribution.^6,7

The expression of VE-cadherin has been shown to be indispensable for proper vascular development. Targeted disruption of VE-cadherin in transgenic mouse models (VEC^–/–, VEC^δC/δC) has been shown to impair the remodeling and maturation of endothelial cells in embryonic vessels, causing abnormal endothelial apoptosis after 8 days of gestation and lethality after 9.5 days of gestation.⁸ VE-cadherin is essential for endothelial survival signaling, and it prevents the disassembly of blood vessels.^8,9 Leukocyte extravasation is known to involve the disruption of VE-cadherin, which coordinates the inflammatory cascade and prothrombotic mechanisms such as thrombomodulin and protein C pathways.¹⁰

Furthermore, VE-cadherin interacts with fibrin to control vascular endothelial permeability and the extravasation of important blood components including leukocytes and platelets,^11,12 suggesting that like cadherin-6, which is a closely related member of the cadherin family,¹³ VE-cadherin may exert effects on platelet aggregation and thrombus formation.

Recent studies suggest that differential VE-cadherin expression may directly affect platelet function. The results of a comparative study evaluating the effectiveness of recently developed drug-eluting stent technologies have suggested that platinum chromium stents, which induce higher VE-cadherin expression, may lead to reduced platelet activation and thrombus accumulation compared with polyvinylidene fluoride-co-hexafluoropropene–coated stents, as measured by neointimal area and residual fibrin around the struts of the stent at 30 days.¹⁴

These finding suggest that disruption of VE-cadherins, possibly through endogenous autoantibodies against cadherins, may result in dysregulation of prothrombotic pathways that are normally tightly regulated in the healthy endothelium. Notably, E-cadherin antibodies are the second most frequent antibody present in patients with pemphigoid disease; patients with mucosal PV and mucocutaneous PV both demonstrate levels of anti-E-cadherin antibodies that are significantly higher than healthy controls by enzyme-linked immunosorbent assay (ELISA), with a moderate correlation between levels of anti-E-cadherin and DSG1 autoantibodies.¹⁵ In addition, mucocutaneous PV is considerably more strongly associated with anti-E-cadherin reactivity than mucosal PV, and immunoadsorption and competitive ELISA show that most anti-E-cadherin antibodies cross-react with DSG1.¹⁶

In addition to cadherin, other autoantibodies have been found in patients with PV. A significant proportion of patients with PV present with immunoglobulin M (IgM) or IgG anticardiolipin antibodies, as well as antiphosphatidylserine-prothrombin complex.¹⁷ More so, nonclassical antiphospholipid autoantibodies, including antiphosphatidylserine-β-2-glycoprotein-I and antiprothrombin complex have been found to be significantly enriched in patients with PV and bullous pemphigoid compared with normal control subjects.¹⁸ The relevance of these antibodies to VTE in pemphigus remains an open question; however, record-linkage studies of national government databases have shown a clear association between pemphigoid disease and risk of VTE² that deserves further study.

Management of PV

First-line treatment of PV consists of systemic corticosteroids, often with high doses and prolonged duration of treatment.⁴ The rarity of the condition has limited the availability of studies exploring the efficacy of the standard therapy in comparison with newer and possibly safer choices.

Several studies have depicted an increase in mortality in patients with PV secondary to the numerous adverse effects associated with systemic steroid use.¹⁹ The adverse effects associated with systemic glucocorticoid use are multisystemic, involving the musculoskeletal system (osteoporosis, avascular necrosis, myopathy), the endocrine/metabolic system (dyslipidemia, hyperglycemia), the cardiovascular system (arrhythmias, hypertension, premature atherosclerotic disease), the gastrointestinal tract (gastritis, peptic ulcer disease, pancreatitis), and the central nervous system (behavioral and cognitive changes), among others. Additionally, systemic glucocorticoid use has been linked with an increased risk of VTE, especially with cumulative doses and in relation to average dose.²⁰

Normal hemostasis exists when there is equilibrium between procoagulation and anticoagulation factors. Hypercoagulability results from a shift toward thrombogenicity resulting from either increased coagulation potential or decreased antithrombotic capability.

The association of autoimmune blistering diseases, such as PV and bullous pemphigus, with increased levels of antiphospholipid antibodies and subsequent alteration in hemostasis has been previously studied, with polarizing results. A report by Echigo et al¹⁷ in 2007 found increased levels of anticardiolipin antibodies and a significant increase of VTE events in patients with PV, PF, bullous pemphigoid, and systemic lupus erythematosus compared with control subjects. Coagulation profiles of blistering conditions associated with VTE events have also been studied. In 2009, Marzano et al²¹ reported a difference in blood coagulation activation between bullous pemphigoid and PV, attributing the difference to the type of inflammatory infiltrates associated with each condition. Coagulation activity in bullous pemphigoid was associated with the tissue factor pathway, with significantly higher plasma prothrombin and D-dimer compared with normal subjects. The coagulation effects were related to the expression of tissue factor in eosinophils, the predominant inflammatory infiltrate in bullous pemphigoid. In contrast, normal serum prothrombin and D-dimer levels in patients with PV were attributed to the lack of eosinophils in inflammatory infiltrate, which consists mostly of T lymphocytes.

The overall effect of autoimmune and inflammatory diseases on blood hemostasis must take into consideration the possible effects of treatment, especially systemic use of glucocorticoids. In vitro studies have depicted glucocorticoids’ procoagulation effect secondary to increased formation of von Willebrand factor and plasminogen-activator inhibitor. In vivo studies have not been successful in identifying a parallel link, since it is difficult to isolate the effect on coagulation resulting from glucocorticoids and the condition necessitating their use.

The controversial effect of glucocorticoid use on procoagulant, anticoagulant, and fibrinolytic factors was analyzed in a systematic review.²² Only one high-quality controlled trial studied the effect of glucocorticoid therapy on coagulation as an isolated parameter. The study found increased levels of factor VII, factor VIII, and factor XI following glucocorticoid therapy compared with controls.

A cumulative report found increased levels of plasminogen activator inhibitor-1 and decreased levels of von Willebrand factor in patients treated with systemic glucocorticoids, although no association with dose was reported. A decrease in fibrinogen levels in patients treated with glucocorticoids was also reported and was attributed to their anti-inflammatory effect on acute-phase reactants. The review concluded that glucocorticoids may not necessarily enhance the already associated prothrombotic effect of inflammatory conditions. In addition, only one study reported an increase in thromboembolic events in patients treated with glucocorticoids. It is worth noting that the variability of factors in each study contributed to an array of conclusions, and more research is needed to further explore each association.²²

Future Directions

In this patient population, future studies could investigate the potential benefit of using antiplatelet therapy in addition to anticoagulation to prevent thromboembolic events. In addition, other studies could investigate the benefits of empiric therapeutic anticoagulation during severe flares of PV. Should we reconsider the use of IVIG in patients with acute pemphigus flares, who have venous or arterial thrombosis, even though IVIG in combination with rituximab has been shown to be very beneficial in inducing remission in patients with refractory PV? These topics arising from the complicated, stormy course that our patient experienced while receiving care for his PV deserve further study to improve outcomes and guide management strategies for VTEs in future patients.

Although the link between high-dose corticosteroid management in patients with PV and the development of thromboembolic events is still tenuous, emerging evidence suggests that cadherins and cell surface receptors, alone or in multiple combinations, do disrupt the Virchow triad and may disrupt the delicate procoagulation/anticoagulation pathway, leading to systemic hypercoagulability.

We document a case of PV complicated by systemic VTE managed initially by systemic corticosteroids, the first-line therapy for PV; the initiation of rituximab and IVIG later in the patient’s course, which led to significant clinical improvement, along with the urgent initiation of heparin anticoagulation markedly improved the patient’s course. It is possible that in addition to its effects on the production of antidesmoglein antibodies, rituximab and IVIG may have had an ancillary role in reversing this patient’s procoagulation factors through the suppression of anticadherin and antiphospholipid antibodies, although more studies need to be performed to justify this conclusion. However, PV is such a rare disease that we acknowledge the difficulty of obtaining well-designed, case-controlled studies to further investigate contributing factors. 

Relindis N. Awah, MD, is a physician in the Department of Internal Medicine Residency Program at the University of Texas Medical Branch (UTMB) in Galveston, Texas.

Pamela N. Chavero is a student at the UTMB School of Medicine in Galveston, Texas.

Wei-Chun J. Hsu is in the Department of Pharmacology and Toxicology at UTMB and a student in the Biochemistry and Molecular Biology Graduate Program and in the MD/PhD Combined Degree Program at the UTMB Graduate School of Biomedical Sciences in Galveston, Texas.

Matthew Dacso, MD, is an associate professor in the Department of Internal Medicine, Division of General Medicine, at UTMB in Galveston, Texas.

Jennifer McCracken, MD, is an assistant professor in the Department of Internal Medicine, Division of Allergy and Immunology, at UTMB in Galveston, Texas.

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