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`SPL.iNTERS FROM THE BOARD ·
`DEirinatology at the Crossroads: Choices~: and ctlauerig$s t: M. Freedberg
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`.··EDITORIALS
`tti- Bovine Collagen Jmplantst Additional Evidence for
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`A. s. Paller, j,"D. Fine,
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`Exhibit 1060
`Exh. 1060
`
`

`
`The Treatment of Bullous Pemphigoid
`With Tetracycline and Niacinamide
`A Preliminary Report
`
`Mark Allan Berk, MD, FRCP(C), Allan L. Lorincz, MD
`
`• Patients with moderate to severe bullous pemphig-
`oid are usually treated with systemic corticosteroids.
`Four patients were treated with tetracycline hydrochlo-
`ride and niacinamide because of the steroid-sparing
`anti-inflammatory properties of these agents. An excel-
`lent clinical response free of side effects was observed in
`all patients. The lesions recurred whenever treatment
`was discontinued. It is believed that these drugs sup-
`press the complement-mediated inflammatory response
`at the basement membrane zone by suppressing neutro-
`phil chemotaxis and mediators of the inflammatory
`response in this bullous disease.
`(Arch Dermato/1986;122:670-674)
`
`Bullous pemphigoid (BP) is a major blistering
`
`disease most common in elderly patients. The
`almost universal finding of linear deposition of IgG
`and C3 at the basement membrane zone (BMZ) on
`direct immunofluorescence (DIF) staining1 and the
`presence of anti-BMZ antibodies in more than two
`thirds2-4 of patients with BP by indirect immunofluo-
`rescence (IIF) staining strongly support an autoim-
`mune cause.
`Effective treatment for BP in the recent past has
`included the use of oraP and topical adrenocortico-
`steroids; immunosuppressive drugs, such as azathio-
`prine/·6 methotrexate/ and cyclophosphamide7
`; as
`well as sulfones.8 Most recently, high-dose pulse
`methylprednisolone therapy9 and plasma exchange10
`have been used in selected patients. The considerable
`morbidity caused by systemic adrenocorticosteroid
`
`Accepted for publication Jan 7, 1986.
`From the Section of Dermatology, Department of Medicine, The
`University of Chicago, Pritzker School of Medicine.
`Reprint requests to the Section of Dermatology, Department of
`Medicine, The University of Chicago, Pritzker School of Medicine,
`5841 S Maryland Ave, Box 409, Chicago, IL 60637 (Dr Berk).
`
`therapy given even for relatively short periods in
`elderly patients with other complicating medical
`problems often associated with BP11 has necessitated
`the trial of less potentially hazardous drugs for the
`treatment of this bullous disease.
`Herein, we describe four patjents who had signifi-
`cant clinical improvement and then control of their
`disease with the oral combinations of tetracycline or
`erythromycin and niacinamide. Two patients' condi-
`tions were controlled following the administration of
`therapy with tetracycline and niacinamide alone.
`One patient was treated successfully with tetracy-
`cline or erythromycin and niacinamide, and one was
`able to suddenly discontinue dapsone therapy due to
`a complication.
`
`REPORT OF CASES
`CASE 1.-An 84-year-old man was sent to The University
`of Chicago Medical Center (UCMC) with a six-month
`history of a blistering skin rash. Tense, mildly pruritic
`blisters would erupt on the extensor surfaces of the arms
`and anterior aspects of the thighs and then would rupture,
`leaving denuded areas. He had a history of hypothyroidism
`and congestive heart failure. At the time of presentation,
`the patient was taking oral digoxin (0.25 mg) and oral
`levo-thyroxine (0.1 mg) daily. Therapy with various topical
`corticosteroid creams and ointments was ineffective. His
`family physician had administered intramuscular injec-
`tions of triamcinolone acetonide on several occasions early
`in the eruption, with only temporary minimal improve-
`ment. On examination, the patient had mildly pruritic,
`large, tense bullae and erythematous plaques on the exten-
`sor surfaces of both arms and the anterior thighs as well as
`hyperpigmented and erythematous patches on the upper
`extremities and trunk. Several new blisters appeared daily.
`Nikolsky's sign was negative. Sections of a 3-mm punch
`biopsy specimen of a lesion stained with hematoxylin-eosin
`(Figure) showed a subepidermal blister containing fibrin
`and a modest number of eosinophils. The underlying
`dermis showed scattered infiltrates of lymphocytes and
`neutrophils as well as numerous eosinophils, consistent
`
`670 Arch Dermatoi-Vol 122, June 1986
`
`Bullous Pemphigoid-Bark & Lorincz
`
`Exh. 1060
`
`

`
`CASE 2.-An 80-year-old man was referred to UCMC
`with a one-month history of blisters on the upper arms and
`chest and erosions in the mouth. At the time of presenta-
`tion, one or two new blisters were appearing daily. He had
`a four-year history of diabetes mellitus, which was con-
`trolled first by diet and then by hypoglycemic agents. The
`patient also had ather,osclerotic heart disease and Paget's
`disease of the pelvic bones. He was taking oral digoxin
`(0.25 mg/day) and oral tolbutamide (1 g twice daily).
`Physical examination revealed an obese elderly man
`with erythematous, mildly pruritic erosions and plaques
`on the malar area of the face. There were several erosions
`of the buccal mucosa and one on the lower right gingiva.
`Nonpruritic, intact, tense bullae were seen on the medial
`aspects of the upper arms. Laboratory studies revealed a
`random blood glucose level of 325 mg/dL (normal, 60 to 140
`mg/dL). A skin biopsy specimen of a bulla revealed a
`subepidermal blister with a dermal infiltrate of eosino-
`phils and polymorphonuclear cells, and DIF studies
`revealed linear deposition of IgG and C3 at the epidermal
`BMZ, confirming the clinical and histopathologic indica-
`tions of BP; IIF studies on a specimen of serum using
`monkey esophagus as substrate revealed anti-BMZ anti-
`bodies in trace amounts. Therapy with oral niacinamide
`( 500 mg three times daily) and oral tetracycline hydrochlo-
`ride (250 mg four times daily) was begun. Over the next
`two months, there was significant improvement in his skin
`disease, with infrequent oral erosions only. The patient
`then decreased the oral tetracycline hydrochloride dosage
`to 750 mg/ day; several new erosions appeared in the mouth
`within the first few days. The dosage was increased to
`1,500 mg/day, and complete healing of the lesions ensued
`within a week. Over the next eight months, the patient
`decreased the medication to 500 mg of oral niacinamide
`and 250 mg of oral tetracycline hydrochloride twice daily.
`With this regimen, infrequent erosions occurred in the oral
`cavity. These would clear within a week's time with an
`increase in dosage to 500 mg of oral niacinamide twice
`daily and 1,000 to 1,500 mg/ day of oral tetracycline hydro-
`chloride. An endocrinology consultant initiated therapy
`with isophane insulin suspension (50 IU every morning)
`and regular insulin (10 IU every morning and every
`evening) subcutaneously for better control of his diabetes.
`Two years after presentation, the patient's condition is
`still under good control with 500 mg of oral niacinamide
`and 500 mg of oral tetracycline hydrochloride three times
`daily.
`CASE 3.-An 80-year-old man, a patient in a chronic-care
`facility, presented to UCMC with a three-week history of a
`moderately pruritic blistering rash on the right upper arm,
`anterior aspect of the chest, abdomen, and upper back and
`in the axillae. He had tried topical corticosteroid oint-
`ments, antifungal creams, and diphenhydramine hydro-
`chloride without relief. Approximately 20 years prior to
`presentation, he had had a massive right cerebrovascular
`accident, resulting in left hemipl.egia. A childhood accident
`had necessitated a left below-the-knee amputation. The
`patient had had bilateral cataract extractions in the recent
`past, but he had no history of diabetes. Two years prior to
`this skin eruption, he had had a much milder but similar
`rash, which cleared following treatment with topical corti-
`costeroid ointment.
`Physical examination revealed tense bullae on erythem-
`atous, pruritic, indurated, excoriated plaques on the trunk,
`in the axillae, and on the right upper arm. There were no
`mucous membrane lesions, and Nikolsky's sign was nega-
`tive. Representative sections of a skin biopsy specimen
`stained with hematoxylin-eosin showed modest acanthosis
`
`Low- (top) and high- (bottom) power magnifications showing
`focal acanthosis and subepidermal blisters containing eosino-
`phils and fibrin. Numerous eosinophils and scattered infiltrates
`of lymphocytes and neutrophils in dermis are consistent with
`cell-rich bullous pemphigoid.
`
`with cell-rich BP. Direct immunofluorescence studies of
`the biopsy specimen revealed linear deposition of IgG and
`C3 at the epidermal BMZ, also consistent with BP. Indirect
`immunofluorescence studies of a specimen of serum using
`monkey esophagus as substrate revealed anti-BMZ anti-
`bodies with a titer of 1:40. Therapy was initiated with
`niacinamide ( 500 mg orally three times a day) as well as a
`polymyxin-bacitracin ointment, which was applied twice
`daily to his lesions. Over the next few days, new blisters
`stopped appearing, erythematous plaques began to heal,
`and his pruritus resolved. Over the next two months, his
`lesions completely healed. Five months later, several tense
`bullae reappeared on the extensor surfaces of the arms.
`Increasing the dosage of oral niacinamide to 2,500 mg/ day
`and adding 0.1% triamcinolone acetonide ointment twice
`daily did not improve his skin condition substantially.
`Tetracycline hydrochloride (1,500 mg daily in three divided
`doses) therapy was added. Once again, within two weeks,
`his skin condition had almost completely cleared. He was
`free of lesions six months later while still receiving oral
`niacinamide (2,500 mg/ day) and tetracycline hydrochlo-
`ride (1,500 mg/day in divided doses).
`
`Arch Dermatoi-Vol 122, June 1986
`
`Bullous Pemphigoid-Berk & Lorincz
`
`671
`
`Exh. 1060
`
`

`
`and spongiosis in the epidermis. Subepidermal separation
`with accumulations of neutrophils and a few eosinophils
`and a moderately dense mixed perivascular infiltrate of
`lymphocytes, histiocytes, neutrophils, and eosinophils
`were also seen. Between the perivascular infiltrates,
`numerous eosinophils were seen. Direct immunofluores-
`cence studies of a skin biopsy specimen showed linear
`deposits of IgG and C3 along the BMZ. Indirect immuno-
`fluorescence studies of a serum specimen using both
`monkey esophagus and normal human skin as substrates
`revealed anti-BMZ antibodies with a titer of 1:1. The
`histopathologic and immunopathologic diagnosis of cell-
`rich BP was made.
`Although the patient received one oral 60-mg dose of
`prednisone, because of his infirm state, it was decided to
`treat him with the steroid-sparing regimen of 500 mg of
`oral tetracycline hydrochloride and 50'0 mg of oral niacin-
`amide three times daily. For approximately two weeks,
`0.1% triamcinolone acetonide ointment also was applied to
`lesional skin. New lesions stopped appearing after two
`days of treatment, and his condition totally cleared four
`weeks after presentation. Because of poor patient compli-
`ance over the next 15 months, he had three recurrences of
`his BP. Restarting oral tetracycline and niacinamide ther-
`apy caused clearing on two occasions. At the time of one
`recurrence, the patient was given 400 mg of oral erythro-
`mycin ethylsuccinate three times daily, resulting in com-
`plete remission. At the time of the last follow-up visit 18
`months after presentation the patient was well while
`receiving 500 mg of oral tetracycline hydrochloride and 500
`mg of oral niacinamide three times daily.
`CASE 4.-A 68-year-old woman was referred to UCMC
`for treatment of a bullous eruption. She had a three-month
`history of mildly pruritic blisters on the arms, legs, thighs,
`buttocks, and anterior aspect of the chest. These would
`leave intensely pruritic erosions that were unresponsive to
`treatment with topical potent corticosteroid ointments.
`Therapy with 500 mg of oral tetracycline hydrochloride
`three times daily was begun, with, by history, a modest
`improvement. Her sister had systemic lupus erythemato-
`sus, but there was no history of diabetes. Physical exami-
`nation revealed diffuse erythematous plaques on the
`extensor surfaces of the arms, anterior aspects of the chest
`and thighs, and lower legs. Several tense bullae were
`present on the lower legs and chest. At the time of referral,
`the hemoglobin level was 13.0 g/ dL (normal, 11.5 to 15
`g/dL), hematocrit was 38.3% (normal, 37% to 50%); and
`results of a 17 -channel blood chemistry panel were normal,
`as were those of a glucose-6-phosphate dehydrogenase
`screen. Findings of a biopsy specimen examination of a
`bulla were consistent with BP, and DIF studies revealed
`deposition of IgG and C3 at the epidermal BMZ, also
`consistent with BP. Indirect immunofluorescence studies
`of a specimen of serum using monkey esophagus as sub-
`strate revealed anti-BMZ antibodies with a titer of 1:320.
`Therapy with oral niacinamide (500 mg four times daily),
`oral tetracycline hydrochloride ( 500 mg four times daily),
`and oral dapsone (50 and then 150 mg/day) was begun.
`Over the next two weeks, pruritus was relieved, with only a
`few occasional blisters after two months of therapy. Niaci-
`namide therapy was discontinued. Complete blood cell
`counts, blood film results, and liver function test results
`were well within acceptable limits. Two months after
`beginning dapsone therapy, the hemoglobin level fell to 8.6
`g/dL, hematocrit was 25.7%, and there was a modest
`increase in aspartate aminotransferase, alanine amino-
`transferase, and alkaline phosphatase levels. Dapsone
`therapy was discontinued. Over the next few days, a flare
`
`of her disease, consisting of tense blisters on erythematous
`plaques on the trunk, was noted. These blisters rapidly
`disappeared over the next week with the addition of 500 mg
`of oral niacinamide four times daily. Over the next three
`months, her blood cell counts and liver function test
`results were norntal. Eighteen months later, her skin
`remains clear whife she is receiving 1,250 mg of oral
`tetracycline hydrochloride daily.
`
`•
`
`'
`
`COMMENT
`Autoantibodies specifically complexing with the
`BP antigen, a protein with a molecular weight of
`220,000 in the lamina lucida layer of the BMZ, 12 are
`believed to cause activation of both the classic and
`alternative complement pathways. 13 Direct immuno-
`fluorescence staining with CIQ, C4, C3, C5, C3P A
`and properdin14
`15 has been shown in the BMZ. Che~
`motactic factors liberated by complement activation
`and mast cell degranulation are the major causes of
`the characteristic leukocytic infiltration of neutro-
`phils and eosinophils.
`If human skin is incubated with BP blister fluid,
`there is cleavage at the BMZ, even without supple-
`mentary complement and neutrophils. 16
`17 Baba et aP 8
`noted the presence of an eosinophilic chemotactic
`factor (ECF) in BP blister fluid. Czarnetzki et aP9
`demonstrated ECF in the sera of four patients with
`BP. Thus, the activation of complement by the
`complement-activating antigen-antibody complexes
`at the BMZ produces anaphylatoxins and chemotac-
`tic factors that attract polymorphonuclear leuko-
`cytes and eosinophils and may also degranulate mast
`cells to subsequently cause a still further infiltration
`of inflammatory cells. The liberation of proteases
`then causes direct damage to the epidermal BMZ and
`subepidermal blister formation.
`Niacinamide is a physiologic nutrient that has
`proved to be relatively nontoxic even at very high
`pharmacologic doses. The acidic form of this B
`vitamin was first found to be useful in the treatment
`of bullous disease with the early clinical observation
`of the efficacy of niacin in dermatitis herpetiformis,
`if given in adequate doses.20
`Niacinamide has been shown to block antigen
`IgE-induced histamine release both in vitro and in
`vivo. 22 It has been shown to prevent degranulation of
`mast cells in sensitized guinea pig tissues. 23 Blister
`fluid from patients with BP contains high levels of
`histamine, IgE/8 prekallikrein activator, Factor XII
`cleaver/4 and various enzymes believed to be involved
`in the inflammatory process. Niacinamide may work
`partly by stabilizing the mast cell, prohibiting the
`release of ECF and other mediators of inflammation
`by anaphylatoxins produced by complement activa-
`tion.
`leukocytes is
`The release of proteases from
`decreased when leukocytes are incubated in vitro
`with pharmacologic doses of agents that specifically
`increase adenosine 3' ,5' -cyclic phosphate.25 These
`agents have a stabilizing effect on
`leukocytes.
`Niacinamide has been shown to be a potent inhibitor
`of adenosine 3 ',5 '-cyclic phosphate phosphodiester-
`
`21
`•
`
`672 Arch Dermatoi-Vol 122, June 1986
`
`Bullous Pemphigoid-Bark & Lorincz
`
`Exh. 1060
`
`

`
`ase in vitro in rat liverS.26 Moreover, pyridoxal phos-
`phate was shown by Korchak et aF7 to inhibit
`lysosomal enzyme secretion in human leukocytes by
`the inhibition of fusion of lysosomes with cellular
`plasma membranes, but it did not interfere with
`phagocytosis. Niacinamide, with its basic similar
`pyridine ring structure, may have the same effect.
`Prolonged administration of daily doses of niacin-
`amide in excess of 3 g on one occasion has been
`reported to be hepatotoxic.28 Nicotinic acid (niacin)
`has, in high doses, produced flushing, acanthosis
`nigricans,Z9 and ichthyosiform skin changes. These
`side effects, in the experience at UCMC, have not
`been seen with niacinamide, even at doses of 2,500
`mg/ day for many months.
`Tetracycline causes marked suppression of leuko-
`cyte chemotaxis in vitro30 arid in vivo at therapeutic
`serum concentrations. Esterly et aP 1 postulated that
`tetracycline hydrochloride and some other antimi-
`crobials might suppress inflammatory skin disease
`by this action. Evidence for this was found with the
`observation that neutrophils of patients with inflam-
`matory acne vulgaris have heightened random
`migration and chemotactic response to zymosan-
`activated serum chemotactic factor. Moreover, poly-
`morphonuclear leukocytes from patients with acne
`who are treated with oral tetracycline show signifi-
`cant suppression of both random migration and
`chemotaxis, with the greatest suppression at ados-
`age of 1 g/day. 32 Tetracycline may work in a similar
`way as an anti-inflammatory agent in the treatment
`of various other inflammatory diseases. A synergis-
`tic role along with niacinamide has already been
`shown in the treatment of erythema elevatum diu-
`tinum, another disease in which neutrophil chemo-
`taxis is believed to be excessive.33
`Erythromycin has recently been used as an anti-
`inflammatory drug. 35 Plewig and Schopf/6 in experi-
`mentally induced potassium iodide pustular derma-
`titis, found that erythromycin and tetracycline
`hydrochloride, administered both topically and sys-
`temically, produced marked improvement in the
`pustular erythematous eruption. The absence of a
`microbial element in the cause of these lesions
`suggested that the improvement was related to some
`anti-inflammatory property of the drugs and not to
`their antibacterial actions. Erythromycin is actively
`transported and then concentrated in polymorpho-
`nuclear leukocytes. 37 It is postulated that the anti-
`inflammatory properties of erythromycin are very
`similar to those of tetracycline hydrochloride. This,
`
`34
`•
`
`presumably, is why it is effective in the treatment of
`BP.
`Various alternate treatment modalities have been
`suggested for patients with BP. The time-honored
`regimen of oral steroid therapy has well-recognized
`deleterious side effects. Bullous pemphigoid is a
`disease that primarily affects the elderly, many of
`whom have associated multisystern disease. Certain-
`ly, any treatment that would be steroid sparing
`would be an excellent choice either alone, in combi-
`nation with other steroid sparing agents, or together
`with oral prednisone in the treatment of this poten-
`tially serious disease.
`Oral prednisone therapy and its problems were
`avoided or minimized in treating the patients
`described herein. The first patient's condition was
`controlled with niacinamide therapy alone for sever-
`al months, after topical steroid therapy had failed. A
`flare of his disease necessitated the addition of
`tetracycline hydrochloride in a pharmacologically
`effective anti-inflammatory dose along with topical
`steroids to his treatment regimen. Patient 2 had
`insulin-dependent diabetes mellitus and managed to
`avoid systemic steroid therapy with the combination
`of
`tetracycline hydrochloride and niacinamide.
`Patient 3 was in a chronic-care facility not capable of
`caring for an infirm patient receiving steroid thera-
`PY. Steroid -sparing anti-inflammatory medication
`controlled his BP while he was compliant with the
`medication. Patient 4 had a hemolytic reaction to
`therapy with sulfones and was spared an imminent
`flare of her disease by the sudden discontinuation of
`dapsone therapy with the addition of niacinamide
`therapy.
`We suggest that a trial of an anti-inflammatory
`antibiotic and niacinamide be considered in patients
`with BP using tetracycline hydrochloride or erythro-
`mycin in dosages of 1,000 to 2,500 mg/day concomi-
`tantly with niacinamide in dosages of 1,500 to 2,500
`mg/day. If this regimen alone is insufficient, an
`anti-inflammatory antibiotic and niacinamide would
`then be given in combination with other drugs, such
`as dapsone or steroids, to minimize dosage require-
`ments of these other effective but more hazardous
`medicines, thereby decreasing the possibility of
`harmful side effects. If complete remission occurs
`while the patient is undergoing treatment with the
`antibiotic and niacinamide, after six months of ther-
`apy, a trial of gradual drug withdrawal would be
`appropriate.
`
`References
`
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`fluorescent studies of pemphigus and bullous pemphigoid. Arch
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`2. Tuffanelli DL: Cutaneous immunopathology: Recent observa-
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`DermatoZ1977;113:1043-1046.
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`8. Person JR, Rogers RS III: Bullous pemphigoid responding to
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`Arch Dermatoi-Vol 122, June 1986
`
`Bullous Pemphigoid-Berk & Lorincz 673
`
`Exh. 1060
`
`

`
`(
`
`9. Siegel J, Eaglstein WH: High-dose methylprednisolone in the
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`10. Roujeau J-C, Morel P, Dalle E, et al: Plasma exchange in
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`11. Chuang TY, Korkij W, Soltani K, et al: Increased frequency
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`674 Arch Dermatoi-Vol 122, June 1986
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`Bullous Pemphigoid-Bark & Lorincz
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