 |
Dermatologic Emergencies CME Part IV: Vesiculobullous diseases, connective tissue and rheumatological disorders
Department of Dermatology, Basildon University Hospital NHS Foundation Trust, UK
Citation tools:
Copyright information
© Our Dermatology Online 2022. No commercial re-use. See rights and permissions. Published by Our Dermatology Online.
ABSTRACT
This section reviews the emergency presentations of autoimmune blistering diseases, connective tissue and rheumatological disorders as well as common pitfalls associated with their diagnosis and management.
Key words: Vesiculobullous diseases; Systemic lupus; Dermatomyositis; Systemic sclerosis
Vesiculobullous diseases are characterized by skin separation at various levels on histopathology. Autoimmune blistering diseases (AIBDs) are among the most common dermatologic emergencies, and they can have a dramatic clinical presentation with substantial morbidity and mortality. Connective tissue and rheumatological diseases can occasionally present as emergencies due to the disease process, internal organ damage, infection, and adverse effects of therapeutic agents.
PEMPHIGUS
Pemphigus is a group of autoimmune diseases affecting stratified squamous epithelia, such as the skin and mucous membranes, in which acantholysis (the loss of cell adhesion) causes blisters and erosions [1]. Before the advent of immunosuppressive therapy, pemphigus was associated with high mortality and morbidity rates. Although pemphigus remains a possible dermatologic emergency with substantial morbidity, mortality rates have decreased due to the new therapeutic modalities [2,3].
Pemphigus vulgaris (PV) is the most frequent and severe form of pemphigus resulting from circulating autoantibodies against intercellular desmogleins (Dsg) 1 and 3 [4,5]. It is characterized by painful oral erosions with widespread flaccid skin blisters that break easily, resulting in extensive denuded skin and erosions [6,7]. Previously the disease was invariably fatal due to loss of body fluids and secondary bacterial infections; however, the outlook has dramatically changed since the introduction of immunosuppressives [8-10].
Pemphigus foliaceus (PF) results from circulating autoantibodies directed solely against Dsg1, leading to more superficial and fragile blisters with predominant erosions and scale-crust of a corn-flake like appearance [11,12]. PF predominantly affects the seborrheic areas without mucosal involvement [13]. Compared to PV, PF has a better prognosis except for occasional acute cases that can progress into exfoliative erythroderma [14,15].
Paraneoplastic pemphigus (PNP) is a fatal autoimmune blistering disease in patients with underlying neoplasms [16]. Castleman disease is the most commonly associated neoplasm in children, while in adults; it is frequently associated with non-Hodgkin lymphoma, chronic lymphocytic leukemia, thymoma, and Castleman’s disease [17]. The disease is characterized by severe, recalcitrant oral stomatitis with polymorphous skin eruptions resembling lichen planus, erythema multiform, pemphigus vulgaris, or bullous pemphigoid. PNP has a poor prognosis with a 75% to 90% mortality rate [18-20]. The leading causes of death include underlying malignancy and respiratory failure (bronchiolitis obliterans) [21,22].
BULLOUS PEMPHIGOID
Bullous pemphigoid (BP) is the most common immunobullous disease in Western Europe that more commonly affects the elderly and is characterized by subepidermal blistering. Bullae are generated when autoantibodies attack two main hemidesmosomal antigens, BP230 (BPAg1) and BP180 (BPAg2, collagen XVII) [23-25].
It is characterized by tense vesicles and bullae on apparently normal or erythematous skin. Bullae and/or erosions may be present in the oral and genital mucosa [26]. In the early stages, typical blistering lesions may be completely absent, and the patient may present with pruritus alone or associated with erythema and/or urticated plaques. Hence, bullous pemphigoid should be considered in all elderly patients with chronic pruritic skin eruptions [27,28].
BP has less aggressive course than pemphigus vulgaris. Complications in untreated patients may result from secondary bacterial infection, dehydration, electrolyte imbalance, and septicemia [29,30].
The exact diagnosis of autoimmune bullous disease (AIBD) is vital for prognosis and appropriate treatment decisions (Fig. 1). Clinical suspicion can be confirmed by freshly formed blisters (less than 48 h old) sampling and histopathological examination. Direct immunofluorescence (IF) microscopy of non-bullous perilesional skin (within 1 cm of the blister) is still the diagnostic gold standard in most cases. The circulating antibodies against specific autoantigens can be identified using indirect IF microscopy of organ substrates, enzyme-linked immunosorbent assay (ELISA), and newer techniques such as immunoblotting and immunoprecipitation. Patients with PNP should be screened for underlying neoplasms, and pulmonary function tests (PFTs) are essential for the diagnosis of bronchiolitis obliterans, a rare and serious complication of PNP [31-34]
 |
Figure 1: Autoimmune blistering diseases (AIBDs) Diagnostic approach to patients with immunobullous disease [41-43] *Applying lateral pressure with the index finger leading to shearing force to disrupt the intercellular adhesion (Nikolsky’s sign). ICS= intercellular spaces, BMZ= basement membrane zone, BP= bullous pemphigoid, IgA p= IgA pemphigus, PV= pemphigus vulgaris, PF= pemphigus foliaceus, PNP= paraneoplastic pemphigus, MMP= mucous membrane pemphigoid, Gep= gestational pemphigoid, DH= dermatitis herpetiformis, LIBD= linear IgA bullous dermatosis. |
Treatment
Systemic corticosteroids alone or with adjuvant immunosuppressants such as azathioprine and mycophenolate mofetil are the cornerstones of PV treatment [35]. For refractory cases, rituximab and/or intravenous immunoglobulin (IVIG) may be used as monotherapy or adjunctive treatment. Recent studies have shown promising results of rituximab (an anti-CD20 monoclonal biological agent) in the treatment of AIBD [36,37]. Good wound and oral lesion care is essential to prevent secondary infection. It is vital to identify and treat underlying neoplasms in patients with PNP. BP treatment aims to control symptoms with minimal adverse effects where possible. Both systemic and topical steroids remain the most widely used first-line treatments depending on the disease severity. Both PV and BP can be treated with the same immunosuppressive and immunomodulatory steroid-sparing agents [38].
|
Pitfalls in the diagnosis and management of AIBDs [39,40]
|
|
Practical pearls An itchy eczematous, urticarial or prurigo-like rash affecting the distal extremities of elderly patients should raises the possibility of the non-bullous stage of BP. This non-specific rash can precede the classical blisters or be the only manifestation of the disease |
CONNECTIVE TISSUE AND RHEUMATOLOGICAL DISORDERS
Systemic lupus erythematosus (SLE)
Patients with SLE should be evaluated for internal organ involvement. It is not uncommon for patients with SLE to present with acute life-threatening complications that require emergency management. The patient with undiagnosed SLE may initially present to the emergency department with variable symptoms; hence, the physician should be alert to the broad-spectrum features of SLE [44] (Table 1).
 |
Table 1: The most common SLE complications that could be encountered at ER. |
SLE is usually diagnosed on clinical grounds in the presence of characteristic serological abnormalities [50].
Treatment
A multidisciplinary approach is essential for the effective management of acute emergencies associated with SLE. The management plan is guided by the severity and risk of significant organ dysfunction. Unless contraindicated, hydroxychloroquine is recommended for all patients with SLE. High-dose intravenous steroids alone or in combination with other immunomodulatory agents are often required in acute, organ-threatening complications after exclusion of infection [52]. In RCT, belimumab a B lymphocyte stimulator (BLyS) inhibitor was associated with a significant reduction in severe SLE flare-up [53]. In the reported cases of Acute Syndrome of Apoptotic Pan-Epidermolysis (ASAP syndrome), corticosteroids, intravenous immunoglobulin and wound care are considered the cornerstones of treatment [54].
|
Pitfalls in the diagnosis of SLE [51]
|
|
Practical pearls A high suspicion index is vital to consider the possibility of SLE in patients with multi-systemic clinical presentation. |
DERMATOMYOSITIS (DM)
Dermatomyositis may present with a constellation of systemic features caused by internal visceral involvement including, the lung, heart and gastrointestinal tract. The major adverse prognostic factors in patients with DM are underlying malignancy, lung and cardiac complications, and infections [55] (Table 2).
 |
Table 2: Major causes of morbidity and mortality in patients with DM. |
|
Practical pearls
|
When a DM diagnosis is confirmed, patients need to undergo further workup to identify systemic complications, especially interstitial lung disease and screening for potential underlying malignancies.
Treatment
The treatment of DM involves a multidisciplinary approach. Corticosteroids are the main component of treatment, either alone or with other immunosuppressive drugs. A few studies have suggested that rituximab and intravenous immunoglobulin (IVIG) are alternative therapeutic options for the treatment of steroid-refractory progressive ILD [62-65].
SYSTEMIC SCLEROSIS (SSC)
Fibrosis and degenerative SSc changes may involve other internal organs, such as the lung, kidney, heart and gastrointestinal tract. The most common visceral complication is esophageal dysfunction, while lung involvement is the leading cause of morbidity and mortality in patients with SSc (Table 3).
 |
Table 3: Systemic Sclerosis life-threatening complications which may require admission to ICU. |
The diagnosis of SSc-related ILD is primarily based on the clinical presentation and can be confirmed with high resolution computed tomography (HRCT) and pulmonary function testing. Scleroderma renal crisis (SRC) can be diagnosed based on the characteristic clinical findings and impaired renal function tests. The gold standard test for pulmonary arterial hypertension test is right heart catheterization, which shows elevated pulmonary artery pressure. Annual electrocardiograms and echocardiograms are recommended for the screening of cardiac complications [70].
Treatment
ACE inhibitors are the first-line agents for the treatment of scleroderma renal crisis, while renal replacement therapy is required for end-stage renal failure. Both mycophenolate mofetil and cyclophosphamide have shown potential clinical efficacy for SSc-ILD in randomized clinical trials [71]. Treatment of PAH includes the use of vasoactive agents such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclin analogs and riociguat, a guanylate cyclase stimulant [72].
|
Practical pearls
|
REFERENCES
1. Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, Amagai M. Pemphigus Nat Rev Dis Primers. 2017;3:1-8.
2. Bystryn JC, Rudolph JL. Pemphigus. Lancet. 2005;366:61-73.
3. Chams-Davatchi C, Valikhani M, Daneshpazhooh M, Esmaili N, Balighi K, Hallaji Z, et al. Pemphigus:analysis of 1209 cases. Int J Dermatol. 2005;44:470-6.
4. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol. 1999;40:167-70.
5. Harman KE, Seed PT, Gratian MJ, Bhogal BS, Challacombe SJ, Black MM. The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels. Br J Dermatol. 2001;144:775-80.
6. Scully C, Challacombe SJ. Pemphigus vulgaris:update on etiopathogenesis, oral manifestations, and management. Crit Rev Oral Biol Med. 2002;13:397-408.
7. Scully C, Mignogna M. Oral mucosal disease:pemphigus. Br J Oral Maxillofac Surg. 2008;46:272-7.
8. Porro AM, Seque CA, Ferreira MC. Pemphigus vulgaris. An Bras Dermatol. 2019;94:264-78.
9. Saha M, Bhogal B, Black MM, Cooper D, Vaughan RW, Groves RW. Prognostic factors in pemphigus vulgaris and pemphigus foliaceus. Br J Dermatol. 2014;170:116-22.
10. Baican A, Chiorean R, Leucuta DC, Baican C, Danescu S, Ciuce D, et al. Prediction of survival for patients with pemphigus vulgaris and pemphigus foliaceus:a retrospective cohort study. Orphanet J Rare Dis. 2015;10:1-4.
11. Stanley JR, Koulu L, Thivolet C. Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies. J Clin Invest. 1984;74:313-20.
12. James KA, Culton DA, Diaz LA. Diagnosis and clinical features of pemphigus foliaceus. Dermatol clin. 2011;29:405-12.
13. Shirakata Y, Amagai M, Hanakawa Y, Nishikawa T, Hashimoto K. Lack of mucosal involvement in pemphigus foliaceus may be due to low expression of desmoglein 1. J Invest Dermatol. 1998;110:76-8.
14. Kridin K, Zelber-Sagi S, Bergman R. Pemphigus vulgaris and pemphigus foliaceus:differences in epidemiology and mortality. Acta Derm Venereol. 2017;97:1095-9.
15. Zaraa I, Mokni M, Hsairi M, Boubaker S, Sellami M, Zitouni M, et al. Pemphigus vulgaris and pemphigus foliaceus: similar prognosis?. Int J Dermatol. 2007;46:923-6.
16. Anhalt GJ. Paraneoplastic pemphigus. J Investig Dermatol Symp Proc. 2004;9:29-33.
17. Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol. 2007;34:503-11.
18. Anhalt GJ, Kim S, Stanley JR, Korman NJ, Jabs DA, Kory M, et al. Paraneoplastic pemphigus:an autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. 1990;323:1729-35.
19. Yong AA, Tey HL. Paraneoplastic pemphigus. Australas J Dermatol. 2013;54:241-50.
20. Wieczorek M, Czernik A. Paraneoplastic pemphigus:a short review. Clin Cosmet Investig Dermatol. 2016;9:291-5.
21. Nousari HC, Deterding R, Wojtczack H, Aho S, Uitto J, Hashimoto T, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. 1999;340:1406-10.
22. Leger S, Picard D, Ingen-Housz-Oro S, Arnault JP, Aubin F, Carsuzaa F, et al. Prognostic factors of paraneoplastic pemphigus. Arch Dermatol. 2012;148:1165-72.
23. Schiavo AL, Ruocco E, Brancaccio G, Caccavale S, Ruocco V, Wolf R. Bullous pemphigoid:etiology, pathogenesis, and inducing factors:facts and controversies. Clin Dermatol. 2013;31:391-9.
24. Genovese G, Di Zenzo G, Cozzani E, Berti E, Cugno M, Marzano AV. New insights into the pathogenesis of bullous pemphigoid:2019 update. Front Immunol. 2019;10:1506.
25. Ujiie H, Nishie W, Shimizu H. Pathogenesis of bullous pemphigoid. Dermatol Clin. 2011;29:439-46.
26. Miyamoto D, Santi CG, Aoki V, Maruta CW. Bullous pemphigoid. An Bras Dermatol. 2019;94:133-46.
27. Bernard P, Antonicelli F. Bullous pemphigoid:a review of its diagnosis, associations and treatment. Am J Clin Dermatol. 2017;18:513-28.
28. Bac IS, Horváth ON, Ruzicka T, Sardy M. Bullous pemphigoid. Autoimmun Rev. 2017;16:445-55.
29. Phoon YW, Fook-Chong SM, Koh HY, Thirumoorthy T, Pang SM, Lee HY. Infectious complications in bullous pemphigoid:an analysis of risk factors. J Am Acad Dermatol. 2015;72:834-9.
30. Teixeira VB, Cabral R, Brites MM, Vieira R, Figueiredo A. Bullous pemphigoid and comorbidities:a case-control study in Portuguese patients. An Bras Dermatol. 2014;89:274-8.
31. Van Beek N, Zillikens D, Schmidt E. Diagnosis of autoimmune bullous diseases. J Dtsch Dermatol Ges. 2018;16:1077-91
32. Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med. 2007;11:462-81.
33. van Beek N, Dähnrich C, Johannsen N, Lemcke S, Goletz S, Hübner F, et al. Prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases. J Am Acad Dermatol. 2017;76:889-94.
34. Zillikens D. Diagnosis of autoimmune bullous skin diseases Clin Lab. 2008;54:491-503.
35. Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, et al. British Association of Dermatologists’guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017;177:1170-201.
36. Schmidt E. Rituximab as first-line treatment of pemphigus. Lancet. 2017;389:1956-8.
37. Huang A, Madan RK, Levitt J. Future therapies for pemphigus vulgaris:rituximab and beyond. J Am Acad Dermatol. 2016;74:746-53.
38. chmidt E, Sticherling M, Sárdy M, Eming R, Goebeler M, Hertl M, et al. S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid:2019 update. J Dtsch Dermatol Ges. 2020;18:516.
39. Hodge BD, Roach J, Reserva JL, Patel T, Googe A, Schulmeier J, et al. The spectrum of histopathologic findings in pemphigoid:avoiding diagnostic pitfalls. J Cutan Pathol. 2018;45:831-8.
40. Gregoriou S, Efthymiou O, Stefanaki C, Rigopoulos D. Management of pemphigus vulgaris:challenges and solutions. Clin Cosmet Investig Dermatol. 2015;8:521.
41. Jindal A, Rao R, Bhogal BS. Advanced diagnostic techniques in autoimmune bullous diseases. Indian J Dermatol. 2017;62:268.
42. Rastogi V, Sharma R, Misra SR, Yadav L. Diagnostic procedures for autoimmune vesiculobullous diseases:A review. J Oral Maxillofac Pathol. 2014;18:390.
43. Witte M, Zillikens D, Schmidt E. Diagnosis of autoimmune blistering diseases. Front Med (Lausanne). 2018;5:296.
44. Chen Y, Chen GL, Zhu CQ, Lu X, Ye S. Severe systemic lupus erythematosus in emergency department:a retrospective single-center study from China. Clin Rheumatol. 2011;30:1463.
45. Jung JH, Soh MS, Ahn YH, Um YJ, Jung JY, Suh CH, et al. Thrombocytopenia in systemic lupus erythematosus:clinical manifestations, treatment, and prognosis in 230 patients. Medicine (Baltimore). 2016;95:e2818.
46. Hannah JR, D’Cruz DP. Pulmonary complications of systemic lupus erythematosus. Semin Respir Crit Care Med. 2019;40:227-34.
47. Hanly JG, O’Keeffe AG, Su L, Urowitz MB, Romero-Diaz J, Gordon C, et al. The frequency and outcome of lupus nephritis:results from an international inception cohort study. Rheumatology (Oxford). 2016;55:252-62.
48. Haghighi AB, Haza SG. Neuropsychiatric manifestations of systemic lupus erythematosus:Iranian experience. Ann Indian Acad Neurol. 2010;13:108.
49. Monga B, Ghosh S, Jain VK. Case Report. Toxic Epidermal Necrolysis-like Rash of Lupus:A Dermatologist’s Dilemma. Indian J Dermatol. 2014;59:401-2.
50. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71:1400-12.
51. Schneider M. Pitfalls in lupus. Autoimmun Rev. 2016;15:1089-93.
52. Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78:736-45.
53. Stohl W, Schwarting A, Okada M, Scheinberg M, Doria A, Hammer AE, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus:a Fifty-Two. Week randomized, Double-Blind, Placebo-Controlled study. Arthritis Rheumatol. 2017;69:1016-27.
54. Burger E, Gou D, Vandergriff T, Dominguez A, Mauskar M. Acute syndrome of pan-epidermolysis and thrombotic storm arising in a patient with systemic lupus erythematosus. JAAD Case Rep. 2018;4:877-9.
55. Okogbaa J, Batiste L. Dermatomyositis:an acute flare and current treatments. Clin Med Insights Case Rep. 2019;12:1179547619855370.
56. Hallowell RW, Ascherman DP, Danoff SK. Pulmonary manifestations of polymyositis/dermatomyositis. Semin Respir Crit Care Med. 2014;35:239-48.
57. DeWane ME, Waldman R, Lu J. Dermatomyositis:clinical features and pathogenesis. J Am Acad Dermatol. 2020;82:267-81.
58. Lu Z, Guo-chun W, Li M, Ning Z. Cardiac involvement in adult polymyositis or dermatomyositis:a systematic review. Clin Cardiol. 2012;35:685-91.
59. Ebert EC. The gastrointestinal complications of myositis. Aliment Pharmacol Ther. 2010;31:359-65.
60. Bowerman K, Pearson DR, Okawa J, Werth VP. Malignancy in dermatomyositis:A retrospective study of 201 patients seen at the University of Pennsylvania. J Am Acad Dermatol. 2020;83:117-22.
61. Olazagasti JM, Baez PJ, Wetter DA, Ernste FC. Cancer risk in dermatomyositis:a meta-analysis of cohort studies. Am J Clin Dermatol. 2015;16:89-98.
62. Andersson H, Sem M, Lund MB, Aalkken TM, Günther A, Walle-Hansen R, et al. Long-term experience with rituximab in anti-synthetase syndrome-related interstitial lung disease. Rheumatology. 2015;54:1420-8.
63. Dasa O, Ruzieh M, Oraibi O. Successful treatment of life-threatening interstitial lung disease secondary to antisynthetase syndrome using rituximab:A case report and review of the literature. Am J Ther. 2016;23:e639-45.
64. Sharp C, McCabe M, Dodds N, Edey A, Mayers L, Adamali H, et al. Rituximab in autoimmune connective tissue disease associated interstitial lung disease. Rheumatology. 2016;55:1318-24.
65. Bakewell CJ, Raghu G. Polymyositis associated with severe interstitial lung disease:remission after three doses of IV immunoglobulin. Chest. 2011;139:441-3.
66. Cossio M, Menon Y, Wilson W, deBoisblanc BP. Life-threatening complications of systemic sclerosis. Crit Care Clin. 2002;18:819-39.
67. Shanmugam VK, Steen VD. Renal disease in scleroderma:an update on evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol. 2012;24:669.
68. Rangarajan V, Matiasz R, Freed BH. Cardiac complications of systemic sclerosis and management:recent progress. Curr Opin Rheumatol. 2017;29:574-84.
69. Nie LY, Wang XD, Zhang T, Xue J. Cardiac complications in systemic sclerosis:early diagnosis and treatment. Chin Med J. 2019;132:2865.
70. Sobolewski P, Maślińska M, Wieczorek M, Łagun Z, Malewska A, Roszkiewicz M, et al. Systemic sclerosis multidisciplinary disease:clinical features and treatment. Reumatologia. 2019;57:221.
71. Asamoah-Odei E. Scleroderma Renal Crisis in a Normotensive Patient. Kidney Int Rep. 2016;1:311-5.
72. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II):a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4:708-19.
73. Lee JJ, Pope JE. Diagnosis and management of systemic sclerosis:a practical approach. Drugs. 2016;76:203-13.
Notes
Request permissions
If you wish to reuse any or all of this article please use the e-mail (brzezoo77@yahoo.com) to contact with publisher.
| Related Articles | Search Authors in |
|
|
 http://orcid.org/0000-0001-6330-2856 |
