Immunobullous Disease and Cutaneous Lupus: Autoantibodies Against the Skin

The skin as a riveted structure

To understand these diseases, picture the skin as a brick wall held together at two different levels. Within the epidermis, individual keratinocytes are riveted to each other by junctions called desmosomes, whose key adhesion molecules are the desmogleins. Below the epidermis, the whole sheet is anchored down to the dermis at the basement membrane by hemidesmosomes, built from proteins named BP180 and BP230. Immunobullous disease is what happens when autoantibodies target one of these two adhesion systems. Attack the desmogleins inside the epidermis and the cells fall apart from one another — an intraepidermal, fragile blister: pemphigus. Attack the hemidesmosome anchors at the base and the whole epidermis lifts off the dermis in one piece — a subepidermal, tense blister: pemphigoid. The level of the split decides everything about how the disease looks and behaves.

Pemphigus vulgaris vs bullous pemphigoid

Pemphigus vulgaris is the more dangerous of the two. Autoantibodies (mainly IgG) against desmoglein 3 (and often desmoglein 1) split the epidermis from within. The blisters are flaccid and rupture easily, the mucosa is characteristically involved — painful mouth erosions are often the first sign — and the Nikolsky sign is positive. Untreated, it carries real mortality. Bullous pemphigoid, by contrast, is a disease of the elderly: IgG against the hemidesmosome proteins BP180 and BP230 lifts the epidermis off the dermis, producing large, tense, fluid-filled blisters on an often red, intensely itchy base, typically sparing the mouth. Because the roof of a pemphigoid blister is the full thickness of the epidermis, it is tough and slow to burst — the opposite of pemphigus. Diagnosis of both rests on skin biopsy with direct immunofluorescence, which lights up exactly where the antibody is bound, plus serum tests for the circulating autoantibodies.

Treatment principle: gain control, then spare the steroid

The pharmacology follows one rhythm across almost every autoimmune skin disease: a fast, powerful drug to seize control, then a gentler one to hold it. The first move in significant pemphigus or widespread pemphigoid is high-dose systemic corticosteroids (such as prednisolone) to shut down the inflammatory assault quickly. But steroids at the doses and durations these diseases demand are themselves toxic — weight gain, diabetes, osteoporosis, hypertension, infection — so they cannot be the long-term answer. Enter the steroid-sparing immunosuppressants, added to let the steroid dose be tapered down: azathioprine and mycophenolate mofetil are the mainstays. Azathioprine blocks purine synthesis and so starves proliferating lymphocytes; its safe use depends on checking TPMT enzyme activity first, because patients who metabolise it poorly are at risk of dangerous marrow suppression. Mycophenolate similarly inhibits purine synthesis in lymphocytes (via the enzyme IMPDH) and is a well-tolerated alternative. These are the very same agents taught in full in the Inflammation & Joints section, where they steroid-spare in rheumatoid arthritis and lupus — the pharmacology travels across specialties.

Rituximab: switching off the antibody factory

The transformative advance in pemphigus is rituximab, a monoclonal antibody against CD20 — a marker on the surface of B lymphocytes. Because it is the B cells that mature into the plasma cells churning out the anti-desmoglein antibody, depleting them strikes the disease at its source rather than merely suppressing the downstream inflammation. Landmark trials showed that rituximab combined with a short steroid course achieved lasting remission far more often, and with less cumulative steroid exposure, than steroids alone — and it is now first-line therapy for moderate-to-severe pemphigus vulgaris rather than a last resort. Rituximab is the same anti-CD20 agent used across autoimmunity and lymphoma, and its behaviour is covered more fully in the Inflammation & Joints section. Its main hazard is infection from B-cell depletion, including reactivation of hepatitis B, so screening before treatment is mandatory. For the most severe or refractory disease, two rescue options remain: intravenous immunoglobulin (IVIG), which modulates the immune system by several mechanisms, and plasma exchange, which physically filters the pathogenic autoantibodies out of the blood.

Bullous pemphigoid is often milder, and its treatment reflects that. Localised bullous pemphigoid can frequently be controlled by potent topical corticosteroids alone — a high-potency ointment such as clobetasol applied over the affected skin, which large studies showed to be as effective as, and safer than, oral steroids for many patients (sparing them the systemic burden). More widespread disease still uses systemic steroids with a steroid-sparing agent, but pemphigoid offers a distinctive extra option: doxycycline, a tetracycline antibiotic, used here not for its antibacterial action but as an anti-inflammatory, steroid-sparing drug. A major trial established doxycycline as a reasonable first strategy in bullous pemphigoid, trading a little less blister control for markedly fewer serious steroid side effects in a frail elderly population. This anti-inflammatory use of a tetracycline echoes its role in the Antimicrobials chapter and in rosacea, where the same sub-antimicrobial principle applies.

Dermatitis herpetiformis: the skin face of coeliac disease

Dermatitis herpetiformis is one of the most satisfying diagnoses in dermatology because it points to a hidden gut disease. It presents as intensely itchy, grouped vesicles and papules — classically on the elbows, knees, buttocks and scalp — often so excoriated by scratching that the intact blisters are hard to find. It is the cutaneous manifestation of coeliac disease: the same gluten sensitivity, driving IgA antibodies that deposit in the tips of the dermal papillae, where direct immunofluorescence reveals characteristic granular IgA deposits. The definitive treatment is therefore a strict, lifelong gluten-free diet, which addresses the underlying immune trigger. But the diet works slowly, and the itch is unbearable, so patients also need a drug for rapid relief: dapsone.

Dapsone is a sulphone with a striking, almost overnight effect on the itch of dermatitis herpetiformis — and a toxicity profile you must respect. Dapsone's anti-inflammatory action here comes largely from suppressing neutrophil function — it interferes with the neutrophil chemotaxis and the myeloperoxidase-driven oxidative burst that fuel the skin damage — which is why it is useful across a range of neutrophil-driven dermatoses, not just dermatitis herpetiformis. But its defining hazard is haematological, and it is exam gold: dapsone causes dose-dependent haemolysis and methaemoglobinaemia. In someone with glucose-6-phosphate dehydrogenase (G6PD) deficiency, that haemolysis can be severe and sudden. Therefore checking G6PD status before starting dapsone is mandatory, and blood counts are monitored during treatment. Methaemoglobinaemia — haemoglobin oxidised to a form that cannot carry oxygen — can cause a deceptive blue-grey cyanosis with a normal arterial oxygen partial pressure. This haematology sits squarely in the Haematology chapter, where G6PD deficiency, oxidative haemolysis and methaemoglobinaemia are dissected in full.

Cutaneous lupus: sun, steroids, and antimalarials

Cutaneous lupus erythematosus is another face of autoimmunity turned on the skin. Discoid lupus produces well-defined, scaly, disc-shaped plaques that can scar and cause permanent hair loss; subacute cutaneous lupus produces widespread, ring-shaped or psoriasis-like photosensitive lesions. Whatever the subtype, one feature dominates management: these lesions are provoked by ultraviolet light. So the first and non-negotiable step is rigorous sun protection — high-SPF broad-spectrum sunscreen, clothing, and avoidance — because no drug will control the disease in a patient still triggering flares in the sun. On top of that, localised disease is treated with topical corticosteroids or topical calcineurin inhibitors (tacrolimus, pimecrolimus), the latter especially useful on the face where steroids risk atrophy — the same agents covered in the topical anti-inflammatory chapter.

The keystone systemic drug for cutaneous lupus is the antimalarial hydroxychloroquine. Its exact mechanism in lupus is not fully settled, but it accumulates in acidic intracellular compartments, interferes with toll-like receptor signalling and antigen presentation, and dampens the interferon-driven immune activation central to lupus. It is first-line systemic therapy, well tolerated, and — importantly — also protective in systemic lupus more broadly, which is why it links directly to the SLE material in the Inflammation & Joints section. Its signature long-term risk is retinal toxicity: cumulative deposition in the retina can, rarely, cause an irreversible maculopathy, so patients need a baseline eye examination and regular ophthalmological screening. A related antimalarial, quinacrine (mepacrine), can be added for extra effect without adding to the retinal risk, since it does not deposit in the retina. When cutaneous lupus is refractory to antimalarials, treatment escalates to systemic immunosuppression — methotrexate or mycophenolate — and, for lupus more broadly, the targeted biologic belimumab, which blocks the B-cell survival factor BAFF. Once again the ladder is corticosteroid → steroid-sparing agent → targeted biologic.