Two decades of using the combination of tetracycline

derivatives and niacinamide as steroid-sparing agents

in the management of pemphigus: Defining a niche
for these low toxicity agents
Morgan McCarty, DO,a and David Fivenson, MDb
Ann Arbor, Michigan
Background: The twin goals of long-term disease control and minimizing toxicities related to
immunosuppression necessitate efforts to find effective steroid-sparing agents in the management of
patients with autoimmune bullous diseases. Pemphigus especially requires a long view, because the
disease can persist throughout a patients lifetime, yet few clinical trial reports exist to guide the
practitioner.
Objectives: We review the response of pemphigus patients to tetracycline, doxycycline, or minocycline
plus niacinamide (TCN/NAM) as steroid-sparing therapy and to determine the effects of TCN/NAM on
autoantibody levels during the long-term treatment of pemphigus.
Methods: This was a retrospective chart review in a private medical dermatology practice setting of all
pemphigus patients treated between 1993 and 2013. Clinical responses to TCN/NAM therapy after initial
high-dose steroid induction therapy and pemphigus antibody levels were recorded over the course of
disease flares and treatment cycles along with any related side effects. Antiedesmoglein 1 and 3 titers were
compared in a subset of patients over time, and a statistical analysis was performed to correlate the clinical
response with antibody levels.
Results: Fifty-one pemphigus patients (43 with pemphigus vulgaris, 7 with pemphigus foliaceous, and 1
with pemphigus erythematosus) received at least 3 months of TCN/NAM, and 16 patients with pemphigus
vulgaris had 1 set of pemphigus antibody titers correlating to a baseline/flare and clinical remission. TCN/
NAM was associated with disease control in 43 of 51 patients, with a duration of response ranging from 1 to
13 years (mean, 3.14 6 2.97 years). Thirteen of 51 patients needed no additional treatment for complete
disease control, while 33 of 51 needed intermittent topical clobetasol or short courses of oral steroids for
long-term management. There were 5 nonresponders. Antidesmoglein titers trended lower in TCN/NAM
responders, but only desmoglein 3 approached statistical significance (antiedesmoglein 1, P = .21;
antiedesmoglein 3, P = .02).
Limitations: This is a retrospective analysis from a single practice. A lack of serial autoantibody titers
limited statistical analyses.
Conclusion: TCN/NAM may be useful as a steroid-sparing therapy for pemphigus. ( J Am Acad Dermatol
2014;71:475-9.)
Key words: autoimmune; bullous diseases; cadherins; desmoglein 1; desmoglein 3; doxycycline;
minocycline; niacinamide; nicotinamide; pemphigus; steroid-sparing; tetracycline.

From the Dermatology Residency Program,a Saint Joseph Mercy

Health System, and David Fivenson, MD, Dermatology PLLC,b
Ann Arbor.
Funding sources: None.
Conflicts of interest: No relevant conflicts declared.
Accepted for publication April 12, 2014.
Reprints not available from the authors.

Correspondence to: David Fivenson, MD, David Fivenson,

MD, Dermatology PLLC, 3001 Miller Rd, Ann Arbor, MI 48103.
E-mail: dfivenson@comcast.net.
Published online June 3, 2014.
0190-9622/$36.00
2014 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2014.04.040

475

J AM ACAD DERMATOL

476 McCarty and Fivenson

SEPTEMBER 2014

The treatment of pemphigus vulgaris (PV) and

regimen. Side effects related to TCN/NAM therapy
pemphigus foliaceous (PF) includes systemic and
were also collected.
topical steroids and many immunosuppressive and
immunomodulatory agents for their steroid-sparing
Serologic testing
effects.1-5 The use of tetracycline, doxycycline, or
Antiedesmoglein 1 (DSG1) and antiedesmoglein
minocycline plus niacinamide (TCN/NAM) has
3 (DSG3) enzyme-linked immunosorbent assays
proven a successful treatment regimen in bullous
(ELISAs) were performed in commercial immunopemphigoid, but has been
dermatology laboratories at
less supported in the treateither Mayo Laboratories
CAPSULE SUMMARY
ment of pemphigus.6-9 Berk
(Rochester, MN) or ARUP
and Lorincz10 first reported
Laboratories (Salt Lake City,
Pemphigus often requires many years of
TCN/NAM therapy for the
UT). DSG1 (normal, \14.0
immunosuppressive therapy.
treatment of bullous pemphi/mL) and DSG3 (normal,
In a single-center, retrospective review,
goid. Fivenson et al6 later
\9.0 /mL) autoantibodies
tetracyclines plus niacinamide were
reported this combination as
were determined using pauseful as steroid-sparing treatment for
efficacious when compared
tient sera. Indirect immunopemphigus, with a 90% response rate
to oral corticosteroids in
fluorescence testing was also
and corresponding decreases in
a double-blind, placeboperformed using patient sera
pemphigus antibodies with clinical
controlled trial. TCN/NAM
at one of these laboratories
improvement.
now is widely used as a
and reported as the highest
steroid-sparing therapy for
serial
dilution
showing
bullous pemphigoid. In
positive staining in an interpemphigus, only 2 case series have been reported.
cellular (ICS) pattern on monkey esophagus
Chaffins et al8 reported 11 patients (5 complete
substrate.
responders, 4 partial responders, and 2 nonresponders) to TCN/NAM in 1993, and Alpsoy11 reStatistical methods
ported 10 patients (2 complete responders, 3 partial
Statistical analysis was conducted with Sofa
responders, and 5 nonresponders) in 1995. This
Statistics software (v 1.3.5; Paton-Simpson and
retrospective review details [20 years of 1 practiAssociates, Ltd, Auckland, New Zealand) to evaluate
tioners (D.F.) experience using TCN/NAM as steroidDSG1 and DSG3 titer changes over time. Only
sparing agents in the management of pemphigus.
patients with sets of titers related to baseline/flare
and clinical remission were analyzed.
d

METHODS

RESULTS

Clinical demographics
After institutional review board approval, a retrospective chart review was performed of all
pemphigus patients in a private medical dermatology office setting, including records from 1993 to
2013. Data were obtained from 11 years of electronic
medical records. Paper record reviews from previous
sites of care supplemented data from patients who
were treated by the senior author before the electronic record system was established. Data from all
newly diagnosed or flaring pemphigus patients who
were treated with TCN/NAM after initial oral steroid
induction therapy for active pemphigus were
analyzed. Patients who underwent all other therapies were excluded (n = 32). Clinical assessments
used definitions of disease activity and therapeutic
response described by Murrell et al12 (ie, remission,
controlled on minimal therapy, transient lesions, or
active disease). A TCN/NAM responder was defined
as disease remission, control on minimal therapy, or
only transient lesions within 3 months of starting this

Clinical responses
There were 83 pemphigus patients treated over
the 20-year review period. Of these, 32 were
taking a variety of therapeutic agents and did not
qualify for the study. All 51 pemphigus patients
presenting with active disease were initially treated
with oral corticosteroids (1-2 mg/kg/day) with
TCN/NAM (either tetracycline 500 mg 4 times
daily, doxycycline 100 mg twice daily, or minocycline 100 mg twice daily) being initiated as soon as
active blistering had stopped. Oral corticosteroids
were then tapered 10% per week over 2 to 3
months. The duration of clinical response, after
initiation of TCN/NAM therapy, ranged from 1 to
13 years (n = 43; mean, 3.14 6 2.97 years), and
disease duration ranged from 1 to 23 years (mean,
8.63 6 4.63 years). Forty-six patients responded
with disease control after 3 months on TCN/NAM
being defined as minimal or no therapy (Murell
et al12), but 3 were lost to follow-up after 3
months. Thirteen patients (9 with PV and 4 with

J AM ACAD DERMATOL

McCarty and Fivenson 477

VOLUME 71, NUMBER 3

Abbreviations used:
DSG1:
DSG3:
ELISA:
ICS:
PE:
PF:
PV:
TCN/NAM:

antiedesmoglein 1 antibody
antiedesmoglein 3 antibody
enzyme-linked immunosorbent assay
intracellular substance
pemphigus erythematosus
pemphigus foliaceous
pemphigus vulgaris
tetracycline, doxycycline, or
minocycline plus niacinamide

PF) were completely controlled on TCN/NAM

alone. Twenty-eight patients (23 with PV, 4 with
PF, and 1 with PE) were partially controlled on
this regimen, with transient lesions or minor flares
(predominately oral erosions) necessitating the
intermittent use of topical clobetasol or short
courses of oral steroids (0.5 mg/kg for 4-8 weeks
maximum in 8 patients). Because patients were
followed for many years, there were several of
these minor flare/remission cycles during the
observation period. Some patients needed only
topical clobetasol for transient lesions at 1 point in
their disease, but needed short courses of oral
steroids at other times despite overall disease
maintenance with TCN/NAM. There were 5 PV
patients who did not respond to TCN/NAM with
disease control on minimal or no other therapy
after 3 months (10%). Therefore, 46 of 51 (90%)
patients treated with TCN/NAM met the Murell
et al12 consensus criteria for disease control on
minimal therapy, with an average follow-up while
responding to therapy of 3.14 6 2.97 years.
Several responders went on to remission (disease
control on no therapy), but accurate numbers
were not possible because of the lack of followup in patients who were clear and who were
taking no medications. Our patients were maintained on TCN/NAM for approximately 1 year after
all symptoms of pemphigus resolved and then
were weaned from therapy over the course of 6
months.
Medication side effects noted in those receiving
TCN/NAM included vestibular disturbance (n = 1)
and minocycline-related hyperpigmentation (n = 2).
There were no significant complaints of nausea,
vomiting, diarrhea, headaches, or flushing that
limited TCN/NAM treatment.
Serologic testing
Initial DSG1 or DSG3 titers did not predict
response to TCN/NAM, with responders having titers
up to 250 /mL DSG3 and indirect immunofluorescence titers up to 1:2560 at presentation. Overall, 16
PV patients treated with TCN/NAM had 1 set of serial

DSG1 and DSG3 titers that matched to a baseline/

flare and clinical remission. The mean plus or minus
the standard deviation for DSG1 and DSG3 titers at
baseline was 15.5 6 32.5 and 101.0 6 72.3, respectively; in remission, these were 8.0 6 10.5 and
57.3 6 72.9, respectively. Serologic levels were
generally lower when an individual patient was in
remission, with a positive response defined arbitrarily as at least a 25% reduction from baseline. Of
those that were comparable, 12 of 16 patients treated
for a flare for at least 3 months with TCN/NAM had a
drop in DSG3 titers that followed clinical improvement. DSG1 titers were elevated at baseline/flare in 4
of 16 patients and 3 of 16 normalized with disease
response. Ten out of 12 patients who were undergoing TCN/NAM therapy had high ICS ([1:640) and/
or high DSG3 ([200) levels become negative after
complete control of disease was achieved.
Statistical analysis
The 2-tailed t test analysis of all subjects with at
least 1 set of DSG titers at baseline/flare and in
remission showed a trend toward a statistically
significant decrease in only DSG3 titers (P = .02)
with clinical response. DSG1 titer decreases with
response were not significant (P = .21). The Pearson
R statistic was 0.394 for changes in DSG1 and 0.589
for changes in DSG3 with clinical response. ICS titers
were not analyzed because of a lack of data.

DISCUSSION
The treatment of immunobullous disorders is a
clinical labyrinth. Long-term disease control and
minimizing toxicities related to immunosuppression
necessitate efforts to find effective steroid-sparing
alternatives. We have reviewed [2 decades of
clinical experience in the management of
pemphigus and show the efficacy of TCN/NAM
therapy in 90% of all new disease flares that were
treated, with 1 to 13 years of response and an average
time on this regimen of [3 years. Our patients were
referred primarily from other dermatologists because
the senior author is a regional bullous disease
specialist. We use this regimen in all new pemphigus
flares, unless the patient presents while taking
another immunosuppressive agent or TCN/NAM
has proven to be ineffective in the past; there are
no other selection criteria that are recommended in
using TCN/NAM. We found that the majority (60%) of
patients effectively managed with TCN/NAM still
required the intermittent use of topical clobetasol for
transient lesions (usually oral), and few needed a
short course of oral corticosteroids for flares of
disease, meeting the definition of clinical remission
on minimal therapy as published by Murrell et al.12

J AM ACAD DERMATOL

478 McCarty and Fivenson

SEPTEMBER 2014

Table I. Immunosuppressive adjuncts in the treatment of pemphigus*

Drug or drug combination

Disease status (N)

Prednisone plus azathioprine

Prednisone plus cyclophosphamide
Methotrexate

28% in remission (20)

32% in remission (28)
No remission (9)

Cyclosporine
Gold
Dapsone
Intravenous immunoglobulin
Plasmapheresis
Rituximab
TCN/NAM therapy (current study)

No difference from prednisone

15% in remission (26)
Inconclusive (19)
100% in remission (21)
Inconclusive (40)
61% in remission (24)
90% in remission (51)

Duration of response

Source

Max 173 days

NR
Mean 23 days; disease
returned on cessation
Similar to prednisone
Mean 32 months
Inconclusive
Mean 20 months
Inconclusive
12-70 months
Mean 35 months

Bystryn et al26
Martin et al4
Smith et al27
Frew et al3
Pandya et al28
Werth et al5
Ahmed et al29
Martin et al4
Reguiai et al25

NR, Not reported; TCN/NAM, tetracycline, doxycycline, or minocycline plus niacinamide.

*Remission data adapted from Mutasiml.13

Overall, TCN/NAM was well tolerated with no

serious side effects, and could be used as long-term
maintenance therapy (at the time of this review, 1
patient has been undergoing TCN/NAM therapy
continuously for 13 years). This level of efficacy
compares favorably with other pemphigus treatments, including azathioprine, cyclophosphamide,
methotrexate, cyclosporine, gold, dapsone, intravenous immunoglobulin G, plasmapheresis, and rituximab (Table I).13
The exact manner in which TCN/NAM therapy
suppresses autoantibody-mediated bullae formation
is unknown. Tetracyclines have been shown to
decrease interleukin (IL)-1b and matrix metalloproteinases, specifically matrix metalloproteinase-13.
The resulting downregulation of inflammation and
matrix degradation have both been suggested as part
of the therapeutic mechanism of action in bullous
disease.14-17 Niacinamide has multiple potential
effects on inflammatory processes, including the
inhibition of serum phosphodiesterase, increasing
cyclic adenosine monophosphate, inhibiting
antigen-immunoglobulin Eeinduced histamine
release (ie, mast cell stabilization), and inhibition of
ILs-1b, -6, and -8, tumor necrosis factorealfa, transforming growth factor beta-2, and macrophage
chemotactic protein, resulting in decreased leukocyte chemotaxis and lymphocyte transformation.18,19
Pemphigus is characterized by the development
of autoantibodies to desmosomal cadherin proteins,
specifically DSG1 and DSG3.20 Results using DSG1
and DSG3 ELISAs to monitor disease progression
have been mixed, with a trend toward lower levels
noted in responders.21,22 We found that serologic
levels were highly variable between patients but
trended lower when an individual patients disease
was in control (either on or off therapy). We
arbitrarily defined a trend as a $ 25% reduction

from baseline in our long-term follow-up group who

had evaluable serial DSG and/or ICS titers. Statistical
analyses revealed a stronger correlation with decreases in DSG3 versus DSG1 titers with TCN/NAM
treatment in 16 PV patients, which contrasts with the
findings of others21-25 and may be related to the fact
that only 4 of 16 PV patients had elevated DSG1 titers
before treatment. In our series of patients, it was the
relative titer decrease that seemed to be a predictor
of response, and no absolute value for either DSG1
or DSG3 could be used to define disease control or
remission. We had several patients who had persistently high ([100 /mL) DSG3 levels when clinically
clear but had even higher levels ([200 /mL) when
flaring. These findings were consistent with other
published data.22-25
Recently, the pathogenesis of pemphigus has
been proposed to be autoantibody targeting of
calcium-dependent binding sites on cadherin moieties of the desmosome.20 ELISAs currently in use
only quantify autoantibodies against the nonecalcium-dependent epitopes of DSG1 and DSG3, which
have been suggested to be an artifact of epitope
spread.13 The ability to distinguish between pathologic and nonpathologic autoantibodies has recently
been shown using an ethylenediaminetetraacetic
acidetreated DSG ELISA.20 Because tetracyclines
are known to bind calcium ions, it is possible that
they may block this calcium-dependent binding site
for antidesmoglein antibodies and would make this
assay a potential tool to help delineate the mechanism of action for TCN/NAM efficacy in pemphigus.
In conclusion, this review of [20 years of
experience in the management of pemphigus patients shows the usefulness of TCN/NAM as a
steroid-sparing regimen in 90% of those treated,
and that responders trend toward lower DSG3 titers.
While some patients may eventually need other

J AM ACAD DERMATOL
VOLUME 71, NUMBER 3

therapies for disease control, TCN/NAM should be

considered a first-line steroid-sparing therapy of
pemphigus and may help avoid or delay the use of
stronger immunosuppressive agents and their associated toxicities.
We acknowledge the thoughtful review of this manuscript by Drs Dedee Murell and Pascal Joly.
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