Understanding blistering skin diseases

When Skin Blisters

by Dr Audrey Tan

Numerous skin conditions may blister, and range from mild and transient diseases to less common and severe ones. Blisters may be small vesicles or larger bullae. Blistering diseases include inherited forms of blistering conditions, autoimmune bullous diseases, drug-induced reactions, contact dermatitis, various infections of the skin and arthropod bites.

The clinical evaluation of cutaneous blisters begins with a thorough history and physical examination. Relevant information includes the duration of blistering, medication history, contactants, and the influence of trauma or friction on the development of lesions. Essential aspects of the physical examination include determining if the blisters are flaccid (superficial split in the skin) or tense (deeper split in the skin), assessing the distribution and extent of blistering, and examining mucosal surfaces (oral, ocular, genital) for involvement.

Arthropod Bite Reactions

Vesiculobullous arthropod bite reactions are quite commonly seen in children following bites by sandflies or other insects. Exaggerated arthropod bite reactions presenting as papulovesicular and bullous lesions may be associated with chronic lymphocytic leukaemia (CLL). These bite reactions usually appear after the diagnosis of CLL but can occasionally precede the diagnosis.1


Impetigo is a contagious bacterial skin infection caused by Staphylococcus aureus and Streptococcus pyogenes, primarily affecting children. The bullous form of impetigo is caused by S. aureus, where blistering is induced by staphylococcal toxins. Clinically, the bullae are superficial, rupturing easily, leaving behind erosions. In contrast, the non-bullous form of impetigo may present as an inflamed vesicle or pustule that becomes covered with a honey-coloured yellow crust. A bacterial lower limb cellulitis may also occasionally become bullous when inflammation and oedema are intense. Cutaneous viral infections that may begin with vesicles include herpes simplex infection, varicella and zoster.

Figure 1. A tense bulla filled with serous fluid.

Figure 1. A tense bulla filled with serous fluid.

Contact Dermatitis

The acute stages of an allergic or irritant contact dermatitis may present with blistering and weepy plaques localised to the area in contact with the allergen or irritant. Urushiol resin found in poison ivy, for example, can result in a severe blistering allergic contact reaction in susceptible individuals. Other common allergens include nickel, fragrance, paraphenylenediamine (PPD) found in permanent hair dyes, and neomycin. Irritants resulting in contact dermatitis include various acids, alkalis, solvents and detergents.

Adverse Drug Reactions

A number of cutaneous adverse drug reactions may involve blistering of the skin. These range from milder reactions such as fixed drug eruptions (FDE) to the more severe forms of drug reactions such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). FDE may be localised to one or more sites, favouring the lips, genitalia, hands and feet. Lesions recur at the same site/sites with re-administration of the causative drug. In SJS and TEN, painful epidermal detachment occurs to varying extents, and the mucous membranes are frequently involved. Ocular involvement carries with it a risk of long-term corneal scarring and visual impairment. Sulfonamides, NSAIDs, anti-convulsants and allopurinol are common causative drugs in SJS and TEN. Recognising that the cutaneous eruption is drug-induced and prompt cessation of the offending drug are crucial in managing individuals with adverse drug reactions, as morbidity and mortality are significant in some cases.


Figure 2. Exuberant bullous reaction to an arthropod bite.

The autoimmune bullous diseases are a major group of blistering skin diseases. In the acquired immunobullous diseases, antigens are directed against autoantigens in the epidermis or epidermal basement membrane.

Pemphigus is a group of autoimmune blistering diseases characterised by loss of cell-cell adhesion between keratinocytes in the epidermis (acantholysis). The main forms of pemphigus include pemphigus vulgaris (PV), pemphigus foliaceus (PF) and paraneoplastic pemphigus (PNP). PNP is associated with both malignant and benign neoplasms, including non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia, Castleman disease and thymoma. The clinical hallmark of PNP is severe oral mucositis consisting of ulcers and erosions that affect the lips and oropharynx. This is often resistant to therapy, resulting in a poor overall prognosis and high mortality rate.2

Rituximab is a chimeric monoclonal IgG antibody that binds to the CD20 antigen on pre-B, immature and mature B cells, resulting in B cell depletion. It is approved for the treatment of CD20+ B-cell non-Hodgkin’s lymphoma as well as autoimmune conditions including rheumatoid arthritis and idiopathic thrombocytopenic purpura. There are increasing reports in medical literature demonstrating the efficacy of rituximab in the management of refractory pemphigus vulgaris and pemphigus foliaceus.3 Prolonged remission rates achieved with rituximab treatment as well as the ability to taper off other systemic immunosuppressive agents in pemphigus patients treated with one or more cycles of rituximab are encouraging findings.4

 Figure 2. Exuberant bullous reaction to an arthropod bite.

Figure 2. Exuberant bullous reaction to an arthropod bite.

The subepidermal immunobullous diseases are characterised by autoantibodies directed against autoantigens in the epidermal basement membrane. These autoantigens include BPAG1 (bullous pemphigoid), BPAG2 (bullous pemphigoid, linear IgA bullous dermatosis, mucous membrane pemphigoid, pemphigoid gestationis), laminin 5 (anti-laminin-332 pemphigoid), laminin gamma1 (anti-laminin gamma1 pemphigoid) and type VII collagen (epidermolysis bullosa acquisita). Clinical and histological overlaps exist amongst these diseases, and differentiating one from the other rests on diagnostic techniques such as immunofluoresence microscopy and immunochemical studies. More recently identified subepidermal diseases include anti-laminin-332 pemphigoid and anti-laminin gamma1 pemphigoid.

Anti-laminin gamma1 pemphigoid is an autoimmune subepidermal bullous disease first described in 1996, and is now regarded as a distinct entity from other subepidermal immunobullous diseases such as epidermolysis bullosa acquisita and bullous pemphigoid.5 Circulating antibodies in patients with anti-laminin gamma1 pemphigoid react to the 200-kDa laminin gamma1 extracellular matrix glycoprotein, which consists of several forms of laminin heterotrimers.6 The disease mimics bullous pemphigoid, epidermolysis bullosa acquisita (EBA) or dermatitis herpetiformis (DH) in clinical features; linear IgA disease or DH in histopathological features;7 and EBA in serum indirect immunofluorescence findings.


Figure 4. Flaccid bullae and superficial erosions of pemphigus vulgaris.

There is a paucity of controlled trials in the therapy of the subepidermal immunobullous diseases. Corticosteroids remain the first line of treatment. Other therapeutic modalities and adjuvant agents include immunosuppressive drugs such as methotrexate, azathioprine, chlorambucil and mycophenolate mofetil; tetracycline antibiotics in combination with nicotinamide; high dose intravenous immunoglobulins, and more recently, rituximab. There are fewer reports in medical literature concerning the use of rituximab in the management of refractory subepidermal immunobullous diseases than with pemphigus. As an adjuvant agent, rituximab has been reported to be of benefit in some patients with bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita, but responses could be mixed.8 Rituximab is generally well tolerated. Infusion-related adverse effects include nausea, vomiting and chills. Severe bacterial infections are amongst the more serious adverse effects reported to date.

Figure 5. Tense bullae and erosions of bullous pemphigoid.

Figure 5. Tense bullae and erosions of bullous pemphigoid.


The careful evaluation of a blistering rash is essential in assisting the clinician in arriving at a clinical diagnosis. Of note, not all blistering rashes are immunobullous in nature. Appropriate investigations include skin patch testing, skin biopsies for histopathological analysis and tissue and blood immunofluorescence studies. Management strategies include targeted therapy and meticulous skin care, anticipating and treating disease complications and medication adverse effects, as well as patient education.

Dr Audrey Tan

Dr Audrey Tan is a Dermatologist at Thomson Specialist Skin Centre. She completed her basic medical education (MBBS) at the National University of Singapore in 1996. After receiving her postgraduate degree in Internal Medicine (MRCP, UK) in 2000, she specialised in Dermatology, achieving her specialist accreditation in Dermatology in 2004 (FAMS). Dr Tan trained in various aspects of Medical and Inpatient Dermatology at the University of British Columbia, Vancouver, Canada, in 2005 and 2006 under the Human Manpower Development Programme of the Ministry of Health. Prior to joining the Thomson Specialist Skin Centre, Dr Tan was a Consultant Dermatologist at the National Skin Centre, Singapore.


1 Pedersen J, Carganello J, van der Weyden MB. Exaggerated reaction to insect bites in patients with chronic lymphocytic leukaemia. Clinical and histological findings. Pathology 1990;22(3):141-3.

2 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(10):1165-72.

3 Leshem YA, Hodak E, David M, Anhalt GJ, Mimouni D. Successful treatment of pemphigus with biweekly 1g infusions of rituximab: A retrospective study of 47 patients.J Am Acad Dermatol 2012; October (epub).

4 Cianchini G, Lupi F, Masini C, Corona R, Puddu P, DePita O. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow up. J Am Acad Dermatol 2012;67(4):617-22.

5 Dilling A, Rose C, Hashimoto T, Zillikens D, Shimanovich I. Anti-p200 pemphigoid: a novel autoimmune subepidermal blistering disease. J Dermatol 2007;34(1):1-8.

6 Dainichi T, Koga H, Tsuji T, Ohyama B, Ueda A, Natsuaki Y, et al. From anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid. J Dermatol 2010;37(3):231-8.

7 Rose C, Weyers W, Denisjuk N, Hillen U, Zillikens D, Shimanovich I. Histopathology of anti-p200 pemphigoid. Am J Dermatopathol 2007;29(2):119-124.

8 Lourari S, Herve C, Doffoel-Hantz V, Meyer N, Bulai-Livideanu C, Viraben R et al. Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol. 2011;25(10):1238-40.

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