Erythrodermic bullous pemphigoid Report o f a case

Gerhard Tappeiner, M.D. , Klaus Konrad, M.D. , and Karl Holubar, M.D. Vienna, Austria

A patient is described who suffered from erythroderma and a blistering skin eruption. Upon histologic and immunohistologic investigation of erythematous and of blistering skin, a diagnosis of bullous pemphigoid (BP) was made and confirmed by the demonstration by immunoelectron microscopy of circulating antibodies in the patient's serum reacting with the lamina lucida of the junctional zone of normal skin. We conclude that we have thus observed a case of erythroderrnic BP, a hitherto undescribed variant of this disease. (J AM ACAD DEBMATOL 6:489-492, 1982.)

The application of immunopathologic technics to problems of differential diagnosis in dermatol- ogy has resulted in the recognition of disease spectra such as lupus erythematosus or certain bullous eruptions, e .g . , pemphigus and bullous pemphigoid (BP), all of which comprise of vari- ous clinical manifestations.

Clinical characteristics of the individual variet- ies of a disease spectrum may differ considerably from the classical form and from each other, for instance, erythematourticarial, localized, atro- phic, and vesicular (bullous) pemphigoid, l or chronic discoid and lupus profundus. The follow- ing case report adds another clinical form to the spectrum of BP.

CASE REPORT

An 89-year-old woman was admitted to the hospital because of severe blistering of her skin. Physical exam- ination revealed erythroderma (Fig. 1); in addition, there were disseminated large erosive areas and rather tense blisters of variable sizes on her abdomen and the

From the Department of Dermatology I, University of Vienna.

Accepted for publication July 22, 1981.

Reprint requests to: Dr. Gerhard Tappeiner, Department of Der- matology I, University of Vienna, Alserstrasse 4, A-1090 Vienna, Austria/222-4289-2526.

0190-9622/82/040489+04500.40/0 © 1982 Am Acad Dermatol

Fig. 1. Severely ill patient with generalized erythro- derma. Multiple eroded and crusted areas, Fig. 2. Tense blisters on erythematous skin of the thigh.

flexural aspects of both arms and on the thighs (Fig. 2). Nikolski's sign was positive on erythematous areas. The mucous membranes were not involved, and there was no lymphadenopathy. No other physical abhor-

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Fig. 3. Immunoelectron microscopy, Low magnification. A, Electron dense reaction prod- uct in a linear distribution within the lamina lucida (arrows). LD, Lamina densa; K, keratinocyte; D, dermis. B, Control. The lamina lucida is devoid of reaction product. LL, Lamina lucida; LD, lamina densa; AF, anchoring fiber. (×23,000,)

realities were found. The disease had begun 3 weeks previously with blistering on the abdomen. Her condi- tion had then remained stable for 2 weeks, at which time it began to deteriorate rapidly.

The patient is known to have suffered from a mild form of psoriasis for many decades; so does one of her two children. There is no further pertinent history, particularly of drug intake or of PUVA treatment, or family history.

Laboratory evaluation yielded an erythrocyte sedi- mentation rate of 10 mm in the first hour. Red and white differential blood counts were within normal limits; a urinalysis was positive for ketones and traces of albumin; the urinary sediment showed many eryth- rocytes, some leukocytes, epithelial cells, and urate crystals.

Serum studies yielded the following pathologic val- ues: glucose, 198 mg/dl, blood urea nitrogen, 53 mg/dl, creatinine, 1.6 mg/dl, uric acid, 8.3 mg/dl, total serum protein, 5.3 gm/dl. Serum protein elec- trophoresis was within normal limits.

Histopathology from a biopsy taken from a blister on the right thigh was read out as diagnostic for BP; direct immunofluorescence of a biopsy specimen from eryth-

rodermic skin showed linear deposits of C3 in the basement membrane zone (BMZ); indirect immuno- fluorescence yielded an antibasement membrane zone antibody titer of 1,280 in both serum and blister fluid.

A diagnosis of BP, of diabetes, and of latent renal insufficiency was made. The diabetes was controlled with insulin; in addition, ampicillin and oxacillin were given as a protective measure. Treatment with 200 rag/day of intravenous methylprednisolone resulted in a remarkable improvement of the skin disease; there were no complications from the corticosteroid therapy. The patient died from acute renal failure 2 weeks after admission, however.

Autopsy revealed bilateral pneumonia and general arteriosclerosis with kidney involvement, in addition to the skin changes.

I m m u n o f l u o r e s c e n c e and i m m u n o e l e c t r o n m i c r o s c o p y

Direct and indirect immunofluorescence were per- formed according to established procedures," using commercially obtained* monospecific FITC-conjugated

*Behdngwerke AG, Marburg/Lahn, West Germany.

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Fig. 4. Immunoelectron microscopy. High magnification. A, Electron dense reaction product (arrows) within the lamina lucida. K, Keratinocyte; LD, lamina densa; AF, anchoring fiber. (X70,000.) B, Control. The lamina lucida (LL) does not show any reac- tion product. LD, lamina densa; D, dermis; K, keratinocyte. (×70,000.)

antisera against IgG, IgA, IgM, C3, and fibrinogen at a specific antibody concentration of 75 to 150 p.g/ml; commercially obtained sections of monkey esophagus* were used as substrates for the titration of serum and blister fluid antibody levels in indirect immunofluo- rescence.

There was linear deposition of C3 along the BMZ in the patient's skin; immunoglobulins or fibrinogen could not be detected. Both serum and blister fluid, however, contained IgG antibodies to BMZ in a titer of 1,280.

In order to prove that the anatomic binding site of the patient's antibodies does indeed correspond to the known binding site of pemphigoid antibodies, a indirect immunoelectron microscopy was done by incubation of normal human skin as a substrate with patient's serum and then with commercially obtained]" peroxidase- coupled antiheavy chain IgG diluted 1 : 10 according to established procedures. 4 The immunologic reaction was visualized by incubation in Graham-Karnovsky me- dium and then processed for electron microscopy. 'a The proper positive and negative controls were included.

*Bio Dx, Denville, NJ. tDako lmmunoglobulins, Copenhagen, Denmark.

IgG deposits in the lamina lucida of the BMZ of the skin were found. Binding of anti-BMZ antibodies to the characteristic target site of BP 3 could thus be demon- strated (Figs. 3 and 4).

DISCUSSION

Erythrodermic BP to our knowledge has not been described previously. Possibly this form is related to the erythematourticarial type, with par- ticularty extensive involvement of the entire in- tegument and blister formation.

The diagnosis of erythroderma per se is a clini- cal one. The interpretation of the erythroderma as being related to BP is based on (1) clinical grounds (positive Nikolski sign signifying a propensity of nonbullous erythematous skin to participate in the disease process) and (2) immunologic parameters (linear deposition of C3 at the B M Z in the pa- tient's skin as shown by direct immunofluores- cence and demonstration of circulating a n t i - B M Z antibody in patient 's serum and blister fluid by indirect immunofluorescence in a titer of 1,280).

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Obviously, the character of the bullous eruption as being BP cannot be questioned since the pa- tient's antibodies were shown to bind to the lamina lucida by immunoelectron microscopy (Figs. 3 and 4).

Despite the extensive skin involvement, the dis- ease of our patient seemed to follow the relatively benign course characteristic of BP, as evidenced by the fairly rapid response to moderately high doses of corticosteroids; the intervening acute re- nal failure does not seem to be connected to the skin rash, since chronic renal insufficiency had already been present at the time the patient was admitted to the hospital and autopsy had revealed arterioscle- rotic kidney disease.

Two problems remain open: the fact that the patient has a history of psoriasis and the theoreti -~ cal possibility of a drug-induced toxic epidermal necrolysis.

Regarding psoriasis, the histopathologic exami- nation of a biopsy specimen did not disclose any evidence for this diagnosis. The association of psoriasis with BP is known,a'6 but its implications and possible relations to treatment modalities are not clear. At any rate, our patient has not had any of the regimens thought to be potential promoters o f BP in psoriatics. ~-7 Whether latent psoriasis could have been a promoting factor in the develop- ment of erythroderrna cannot be answered readily.

Toxic epidermal necrolysis (drug-induced form) can be ruled out by circumstantial evidence. There was no pertinent history of intake of drugs known to cause this disease, and actually there was no history of drug intake at all. Moreover, the target site of the immune reaction within the lamina Iucida speaks against such an assumption and for the interpretation as BP; the same holds true for histopathology.

Unfortunately, we could not determine whether this patient's serum did contain immune com- plexes, a feature found in about 25% of pem- phigoid patients at some time in their disease,S and whether there was renal deposition of such com- plexes contributing to the development of renal failure; presence of immune complexes would have constituted another confirmatory finding in favor of BP.

Our report indicates that BP should also be considered in the differential diagnosis in patients with erythroderma.

REFERENCES 1. Michel B: Localized chronic pemphigoid of Brunsting and

Perry: Its relationship to bullous pemphigoid, in Beutner EH, Chorzelski TP, Bean SF, editors: Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 265-271.

2. Jordon RE: Immunohistopathology of the skin, in Rose NR, Friedman H, editors: Manual of clinical immunol- ogy. Washington, DC, 1976, American Society of Mi- crobiology, pp. 701-709.

3. Holubar K, Wolff K, Konrad K, Beutner EH: Ultrastmc- tural tocalisation of immunoglobulins in bullous pemphi- gold skin. Employment of a new peroxidase-antiperoxidase multistep method. J Invest Dermatol 64:220-227, 1975.

4. Albini B, Holubar K, Shu S, Wolff K: Enzyme antibody methods in immunodermatopathology, in Beutner EH, Chorzelski TP, Bean SF, editors: Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 93-134.

5. Koerber WA, Price NM, Watson W: Coexistent psoriasis and bullous pemphigoid. A report of six cases. Arch Der- matol 114:1643-1646, 1978.

6. Person JR, Rogers RS III: Bullous pemphigoid and psori- asis: Does subclinical bullous pemphigoid exist? Br J Dermatol 95:535-540, 1976.

7. Bart B J, Bean S: Bull~us pemphigoid following the topi- cal use of fluorouracil. Arch Dermatol 102:457-460, 1970.

8. Tappeiner G, Heine KG, Kahl JC, Jordon RE: Clq- binding substances in pemphigus and bullous pemphigoid: Detection with a '3'l-Clq-binding assay. Clin Exp Immu- nol 28:40-48, 1977.