Niacinamide (nicotinamide), a physiologically active form of niacin (nicotinic acid), has a variety of potential mechanisms of action in the treatment of inflammatory skin diseases including its effects on leukocyte chemotaxis, lysosomal release, lymphocytic transformation, mast cell degranulation and decreased proinflammatory cytokine production. The tetracycline family of bacteriostatic antibiotics also has many anti-inflammatory mechanisms of action and has been used alone or in combination with niacinamide for a variety of inflammatory diseases. The goal of this short review is to summarize the data reported for these agents in the therapy of autoimmune bullous diseases. A comprehensive literature review showed efficacy as steroid sparing adjuvants in pemphigoid, pemphigus, linear IgA diseases and dermatitis herpetiformis. Few prospective trials exist but in aggregate these agents alone or in combination have reports of good responses in a total of 197/242 bullous pemphigoid patients, 34/43 cicatricial pemphigoid patients, 95/109 pemphigus patients, 7 linear IgA bullous dermatitis patients and 4 dermatitis herpetiformis patients. This is encouraging for future prospective trials to evaluate these agents and helps better define the role of tetracycline and niacinamide in steroid sparing medications for this challenging group of diseases.

Autoimmune bullous diseases, Pemphigus, Pemphigoid, Dermatitis herpetiformis, Linear IgA bullous dermatosis, Blistering disease, Therapy, Tetracycline, Minocycline, Doxycycline, Niacinamide, Nicotinamide, Steroid sparing

AIBD: Autoimmune bullous disease; LABD: Linear IgA bullous dermatosis; DH: Dermatitis herpetiformis; BP: Bullous pemphigoid; CP: Cicatricial pemphigoid; MMP: Mucous membrane pemphigoid; OCP: Ocular cicatricial pemphigoid; PG: Pemphigoid gestationis; HG: Herpes gestationis; PV: Pemphigus vulgaris; PF: Pemphigus foliaceus; TCN: Tetracycline, minocycline, doxycycline; NAM: Niacinamide or nicotinamide; Combination therapy with a tetracycline + niacinamide (TCN/ NAM)

 Tetracyclines (tetracycline, minocycline and doxycycline) are bacteriostatic antibiotics with a variety of antiinflammatory properties that have been used widely throughout dermatology [1]. These include: decreases in lymphocyte mitogenic responses, antibody production, complement activation, chemotaxis of neutrophils and eosinophils, prostaglandin synthesis, and Inhibition of various tissue enzymes including collagenase, lipase and tissue metalloproteinases 2 and 9 [2,3].

Niacinamide (NAM, aka nicotinamide) is one of the dietary forms of NAD precursors which are important for their role in NAD/NADPH pathway of electron transport (Canto et al 2012). NAM has an amide side chain that prevents the vasodilatory flushing and hypotension that can be associated with high doses of niacin (aka nicotinic acid) supplementation. NAM has been associated with a wide range of biochemical and immunologic effects when used in higher doses including free radical scavenger function, inhibition of phosphodiesterase and other proteases, stimulation of adenylyl cyclase, driving tryptophan metabolism to increase serotonin, inhibition of lymphocyte mitogenic responses, suppression of IgE-mediated release of histamine from mast cells and degranulation of neutrophils and eosinophils [4,5].

Recently it has been hypothesized that many autoimmune processes result in NAD depletion via combination of persistent indoleamine 2,3 dioxygenase (IDO) activation and iNOSperoxynitrite activation of nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 plays a significant role in DNA repair, maintenance of genomic stability, and cellular response to injury including inflammation and apoptosis and NAM supplementation has been shown to be an inhibitor PARP-1 [6,7].

These pathways may explain why NAM supplementation has beneficial effects in a wide range of inflammatory diseases including: rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, depression, hyperkinesis, epilepsy and schizophrenia in patients or in animal models. NAM also has reported uses as a radiosensitizer, inhibitor of tumor promoter genes, and slow metastatic spread of experimental cancers and prevents carbon tetrachloride induced hepatotoxicity in rats. Dermatologic uses including: autoimmune bullous diseases, necrobiosis lipoidica, granuloma annulare, polymorphous light eruption, acne, aphthous ulcers, erythema elevatum diutinum, atopic dermatitis, pellagra, Hartnup disease, and discoid lupus in dogs [4,9,10]. In acne lesions, there is also activation of transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1), which is inhibited by NAM through PARP-1 inhibition [5]. This brief review will summarize the published data using TCN and/or NAM as steroid sparing adjuvants in autoimmune bullous diseases.

Pubmed.gov and Google Scholar searches were done in August 2020 with MESH terms of pemphigoid, pemphigus, linear IgA bullous dermatosis (LABD), chronic bullous disease of childhood, dermatitis herpetiformis (DH), bullous pemphigoid (BP), localized pemphigoid, cicatricial pemphigoid (CP), mucous membrane pemphigoid (MMP), ocular cicatricial pemphigoid (OCP), Brunstig-Perry pemphigoid, radiation induced pemphigoid, pemphigoid gestationis (PG), herpes gestationis (HG), pemphigus vulgaris (PV), pemphigus foliaceus (PF), pemphigus vegetans, treatment, therapy, tetracycline, minocycline, doxycycline, niacinamide and/or nicotinamide. All studies with retrievable abstracts or full text articles were reviewed and any that contained treatment outcomes for one or more patients with any of the tetracyclines (collectively abbreviated TCN throughout the results and discussion), niacinamide or nicotinamide (abbreviated NAM throughout the results and discussion) or a combination of any tetracycline plus niacinamide (abbreviated TCN/NAM throughout the results and discussion) were included in the results.

Large and small cases series or single case reports were all included, but distinction between partial responders from complete responders and those that were monotherapy vs adjuvant therapy to aid in steroid sparing was not possible, thus all results are reported for any responders vs nonresponders to allow aggregation of data. The results are presented by disease entities and the reference list is organized to match each group of diseases.

Bullous Pemphigoid

Berk and Lorincz first reported 4 patients to respond to tetracycline and NAM in 1986. The author received a FDA-Orphan Products grant in 1990 for the only double blind trial of these agents in comparison to steroid monotherapy published to date, enrolling 20 patients over 3 years with 12 TCN/NAM responders and 8 steroid responders [11]. Including these reports, there have been a total of 180/225 patients reported with BP responding to TCN/NAM [11-17]. There have also been 12/12 patients reported treated with TCN monotherapy [18-21].

Localized BP has only been reported twice. A single case in a breast reconstruction site was treated successfully with just NAM [22] and another with just TCN [23]. Radiation induced BP was treated successfully in 3/3 patients with TCN/NAM and 1 with just TCN [24-27]. 

Cicatricial Pemphigoid case reports and small series favored TCN monotherapy as adjuvants to steroids or other immunosuppressors with 25/30 reported responders [28-32]. TCN/NAM was reported as effective in 9/12 cases [29,33-36].

Lichen Planus Pemphigoides and P200 Pemphigoid are both very rare forms of subepidermal bullous disease and each has had a single case report of TCN/NAM therapy being effective, [37,38].

Pemphigoid Gestationis (Herpes Gestationis) has been reported in 2 publications and a total of 3 patients. All 3 were treated with doxycycline and niacinamide with no adverse pregnancy outcomes reported [39,40].

Dermatitis Herpetiformis

DH has been reported to be effectively treated with TCN/ NAM in 4 patients in 3 publications [41-43].

Linear IgA Bullous Disease

LABD has been reported to be effectively treated with TCN/ NAM by us and others totaling 6 patients and dapsone was combined with NAM in one patient [44-49].

Pemphigus vulgaris

PV has several cases series as well as numerous case reports of TCN/NAM therapy. One of the largest has been from the author’s patient population that was analyzed and reported in 2014 and updated with more strict outcome parameters in a publication this year with a total of 60/67 patients being responders [50,51]. In aggregate, there have been 66/74 TCN/ NAM patients reported as responders with pemphigus and 20/24 with TCN monotherapy. Almost all series were patients initially treated with oral steroids with the TCN/NAM therapy used as a steroid sparing adjuvant [45,50-54,].

Pemphigus foliaceous has been reported as effectively responding to TCN/NAM in 7 of 8 patients in 4 different publications including 4 of 5 from our patient population [45,56- 58].

Rare forms of pemphigus including pemphigus vegetans (n=2) and pemphigus herpetiformis (n=1) have been reported to be effectively treated with TCN/NAM [59,60].

In the late 1940’s to early 1950’s there were numerous case reports of pemphigus treatment with chlortetracycline (aka Aureomycin- the first form of TCN produced in first in 1945) alone or in combination with the antimalarial agent quinacrine. However this agent is no longer in use and it was not until 1984 that TCN/NAM was reported [12]. The use of TCN and/or NAM separately or in combination appears to be effective steroid sparing agents in the AIBDs based on the findings summarized here.

AIBDs as a group are challenging to treat due to their necessity of relatively aggressive immunosuppression being needed to gain disease control in many presentations.

Steroid sparing agents traditionally used in AIBDs include dapsone, IVIG, methotrexate, mycophenolate mofetil, azathioprine, as well as newer targeted immunobiologics like rituximab [61]. Side effects related to most of these steroid sparing agents can be dose limiting and result in considerable increased morbidity and mortality. While side effects of TCN (photosensitivity, gi upset, etc..) and NAM (very rare flushing, gi upset, abnormal liver enzyme levels) are reported, caution with minocycline use in this patient population is warranted as dyspigmentation, vertigo, pseudotumor cerebri and autoimmune pneumonitis or hepatitis have all been seen with its use [62,63].

As mentioned in the introduction, TCN/NAM has also been used in a variety of other dermatologic conditions and is well known for its utility in veterinary dermatology as well [64]. The long track record of this combination and diverse applications make it a good option as first line steroid sparing therapy.

Many reports are single case reports and most of the series reviewed were retrospective and tetracycline(s) or NAM was often used as adjuvant therapy during steroid reduction. Partial responses vs complete responses were not clearly delineated in most articles so all responders were included in this review.

The combination of TCN/NAM has a growing literature for its utility as a steroid sparing regimen in the autoimmune bullous diseases. BP and PV have the most robust support in the literature. Prospective and randomized double blind studies are needed to properly assess the impact of these agents singularly or in combination.

However, given that these are older agents with long track records of use and both are available as generic or over the counter products, it is reasonable to consider their use in the management of blistering diseases.

1. Barbieri JS, Bhate K, Hartnett KP, Fleming-Dutra KE, Margolis DJ. Trends in Oral Antibiotic Prescription in Dermatology, 2008 to 2016. JAMA Dermatol. 2019; 155: 290-297.

2. Griffin MO, Ceballos G, Villarreal FJ. Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action. Pharmacol Res. 2011; 63: 102-107.

3. Liu J, Khalil RA. Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders. Prog Mol Biol Transl Sci. 2017; 148: 355-420.

4. Fivenson DP. The mechanisms of action of nicotinamide and zinc in inflammatory skin disease. Cutis. 2006; 77: 5-10.

5. Bains P, Kaur M, Kaur J, Sharma S. Nicotinamide: Mechanism of action and indications in dermatology. Indian J Dermatol Venereol Leprol. 2018; 84: 234-237.

6. Pacher P, Szabo C. Role of the peroxynitrite-poly (ADP-ribose) polymerase pathway in human disease. Am J Pathol. 2008; 173: 2-13.

7. Penberthy WT. Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. Curr Drug Metab. 2007; 8: 245-266.

8. Tullius SG, Biefer H, Li S, Trachtenberg AJ, Edtinger K, Quante M, et al. NAD+protects against EAE by regulating CD4+ T-cell differentiation. Nat Commun. 2014; 5: 5101.

9. Wohlrab J, Kreft D. Niacinamide - mechanisms of action and its topical use in dermatology. Skin Pharmacol Physiol. 2014; 27: 311-315.

10.Namazi MR. Nicotinamide in dermatology: a capsule summary. Int J Dermatol. 2007; 46: 1229-1231.

11.Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D. Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol. 1994; 130: 753-758.

12.Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and niacinamide. A preliminary report. Arch Dermatol. 1986; 122: 670-674.

13.Kawahara Y, Hashimoto T, Ohata K, Nishikawa T. Eleven cases of bullous pemphigoid treated with combination of minocycline and nicotinamide. Eur J Dermato. 1996; 6: 427-429.

14.Hornschuh B, Hamm H, Wever S, Hashimoto T, Schröder U, Bröcker EB, et al. Treatment of 16 patients with bullous pemphigoid with oral tetracycline and niacinamide and topical clobetasol. J Am Acad Dermatol. 1997; 36: 101-103.

15.Goon AT, Tan SH, Khoo LS, Tan T. Tetracycline and nicotinamide for the treatment of bullous pemphigoid: our experience in Singapore. Singapore Med J. 2000; 41: 327-330.

16.Williams HC, Wojnarowska F, Kirtschig G, Mason J, Godec TR, Schmidt E, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomized controlled trial. Lancet. 2017; 389: 1630-1638.

17.Kalinska-Bienias A, Kowalczyk E, Jagielski P, Kowalewski C, Wozniak K. Tetracycline, nicotinamide, and lesionally administered clobetasol as a therapeutic option to prednisone in patients with bullous pemphigoid: a comparative, retrospective analysis of 106 patients with long-term follow-up. Int J Dermatol. 2019; 58: 172-177.

18.Thornfeldt CR, Menkes AW. Bullous Pemphigoid controlled by tetracycline. J Am Acad Dermatol. 1987; 16: 305-310.

19.Thomas I, Khorenian S, Arbesfeld DM. Treatment of generalized bullous pemphigoid with oral tetracycline. J Am Acad Dermatol. 1993; 28: 74-77.

20.Pereyo NG, Davis LS. Generalized bullous pemphigoid controlled by tetracycline therapy alone. J Am Acad Dermatol. 1995; 32: 138-139.

21.Safa G, Darrieux L. Nonbullous pemphigoid treated with doxycycline monotherapy: report of 4 cases. J Am Acad Dermatol. 2011; 64: e116-e118.

22.Honl BA, Elston DM. Autoimmune bullous eruption localized to a breast reconstruction site: response to niacinamide. Cutis. 1998; 62: 85-86.

23.Kakurai M, Demitsu T, Azuma R, Yamada T, Suzuki M, Yoneda K, et al. Localized pemphigoid (pretibial type) with IgG antibody to BP180 NC16a domain successfully treated with minocycline and topical corticosteroid. Clin Exp Dermatol. 2007; 32: 759-761.

24.Duschet P, Schwarz T, Gschnait F. Bullous pemphigoid after radiation therapy. J Am Acad Dermatol. 1988; 18: 441-444.

25.Folliero G, Zurlo A, Amanti C, Tombolini V, Di Paola M. Bullous pemphigoid induced by radiation therapy. Clin Oncol (R Coll Radiol). 1995; 7: 266-267.

26.Clayton AS, Angeloni V. Bullous pemphigoid in a previously irradiated site. Cutis 1998; 61: 73-76.

27.Parikh SK, Ravi A, Kuo DY, Nori D. Bullous pemphigoid masquerading as acute radiation dermatitis: case report. Eur J Gynaecol Oncol. 2001; 22: 322-324.

28.Rønbeck BA, Lind PO, Thrane PS. Desquamative gingivitis: preliminary observations with tetracycline treatment. Oral Surg Oral Med Oral Pathol. 1990; 69: 694-697.

29.Poskitt L, Wojnarowska F. Minimizing cicatricial pemphigoid orodynia with minocycline. Br J Dermatol. 1995; 132: 784-789.

30.Fukushima S, Egawa K, Nishi H, Wakasugi S, Ishii N, Hashimoto T, et al. Two cases of anti-epiligrin cicatricial pemphigoid with and without associated malignancy. Acta Derm Venereol. 2008; 88: 484-487.

31.Carrozzo M, Arduino PG, Baldovino S, Di Zenzo G, Salzano S, Calabresi V, et al. Minocycline in combination with mycophenolate mofetil in oral mucous membrane pemphigoid. Eur J Dermatol. 2008; 18: 198- 200.

32.Carrozzo M, Arduino P, Bertolusso G, Cozzani E, Parodi A. Systemic minocycline as a therapeutic option in predominantly oral mucous membrane pemphigoid: a cautionary report. Int J Oral Maxillofac Surg. 2009; 38: 1071-1076.

33.Mallon E, Wojnarowska F. Cicatricial pemphigoid presenting with unusual palmar involvement, successfully treated with a combination of nicotinamide and tetracycline. Clin Exp Dermatol. 1994; 19: 526- 530.

34.Reiche L, Wojnarowska F, Mallon E. Combination therapy with nicotinamide and tetracyclines for cicatricial pemphigoid: further support for its efficacy. Clin Exp Dermatol. 1998; 23: 254-257.

35.Kreyden OP, Borradori L, Trüeb RM, Burg G, Nestle FO. Successful therapy with tetracycline and nicotinamide in cicatricial pemphigoid. Hautarzt. 2001; 52: 247-250.

36.Sakamoto K, Mori K, Hashimoto T, Yancey KB, Nakashima T. Antiepiligrin cicatricial pemphigoid of the larynx successfully treated with a combination of tetracycline and niacinamide. Arch Otolaryngol Head Neck Surg. 2002; 128: 1420-1423.

37.Fivenson DP, Kimbrough TL. Lichen planus pemphigoides: combination therapy with tetracycline and nicotinamide. J Am Acad Dermatol. 1997; 36: 638-640.

38.Mascaró JM Jr, Zillikens D, Giudice GJ, Cauz F, Fleming MG, Katz HM, et al. A subepidermal bullous eruption associated with IgG autoantibodies to a 200 kd dermal antigen: the first case report from the United States. J Am Acad Dermatol. 2000; 42: 309-315.

39.Loo WJ, Dean D, Wojnarowska F. A severe persistent case of recurrent pemphigoid gestationis successfully treated with minocycline and nicotinamide. Clin Exp Dermatol. 2001; 26: 726-727.

40.Amato L, Coronella G, Berti S, Gallerani I, Moretti S, Fabbri P. Successful treatment with doxycycline and nicotinamide of two cases of persistent pemphigoid gestationis. J Dermatolog Treat. 2002; 13: 143-146.

41.Zemtsov A, Neldner KH. Successful treatment of dermatitis herpetiformis with tetracycline and nicotinamide in a patient unable to tolerate dapsone. J Am Acad Dermatol. 1993; 28: 505-506.

42.Shah SA, Ormerod AD. Dermatitis herpetiformis effectively treated with heparin, tetracycline and nicotinamide. Clin Exp Dermatol. 2000; 25: 204-205.

43.Wang Y, Yang B, Zhou G, Zhang F. Two Cases of Dermatitis Herpetiformis Successfully Treated with Tetracycline and Niacinamide. Acta Dermatovenerol Croat. 2018; 26: 273-275.

44.Peoples D, Fivenson DP. Linear IgA bullous dermatosis: successful treatment with tetracycline and nicotinamide. J Am Acad Dermatol. 1992; 26: 498-489.

45.Chaffins ML, Collison D, Fivenson DP. Treatment of pemphigus and linear IgA dermatosis with nicotinamide and tetracycline: a review of 13 cases. J Am Acad Dermatol. 1993; 28: 998-1000.

46.Yomada M, Komai A, Hashimato T. Sublamina densa-type linear IgA bullous dermatosis successfully treated with oral tetracycline and niacinamide. Br J Dermatol. 1999; 141: 608-609.

47.Khanna N, Pandhi RK, Gupta S, Singh MK. Response of chronic bullous dermatosis of childhood to a combination of dapsone and nicotinamide. J Eur Acad Dermatol Venereol. 2001; 15: 368.

48.Cui YX, Yang BQ, Zhou GZ, Zhang FR. Childhood linear IgA bullous dermatosis successfully treated with oral nicotinamide. Clin Exp Dermatol. 2016; 41: 816-818.

49.Shan XF, Zhang FR, Tian HQ, Wang N, Zhou SJ, Wang GJ. A case of linear IgA dermatosis successfully treated with tetracycline and niacinamide. Int J Dermatol. 2016; 55: e216-217.

50.McCarty M, Fivenson D. 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. J Am Acad Dermatol. 2014; 71: 475-459.

51.Fivenson D, Qiblawi S. Long Term Follow up and Sequential Therapies in Pemphigus: Many Paths to Disease Control and Minimizing Corticosteroid Usage. J Dermatolog Clin Res. 2020; 8: 1128.

52.Calebotta A, Sáenz AM, González F, Carvalho M, Castillo R. Pemphigus vulgaris: benefits of tetracycline as adjuvant therapy in a series of thirteen patients. Int J Dermatol. 1999; 38: 217-221.

53.Häusermann P, Gutersohn T, Beltraminelli H, Schiller P, Büchner SA, Rufli T. Enoraler Pemphigus vulgaris Erfolgreiche Monotherapie mit Minocyclin und Nicotinamid [Oral pemphigus vulgaris. Successful treatment with minocycline and nicotinamide. Hautarzt. 2002; 53: 813-815.

54.Assmann T, Voss R, Ruzicka T, Megahed M. Therapy-resistant pemphigus vulgaris. Dermatologist. 2003; 54: 979-981.

55.Gaspar ZS, Walkden V, Wojnarowska F. Minocycline is a useful adjuvant therapy for pemphigus. Australas J Dermatol. 1996; 37: 93- 95.

56.Izu K, Yamamoto O, Asahi S, Masuyuki K, Komai R, Yasumotos S, Hashimoto T. A case of pemphigus foliaceus complicated by bullous impetigo and successfully treated with minocycline/nicotinamide combination therapy. J UOEH. 2001; 23: 59-67.

57.Scheinfeld N. A case of co-incident phenylketonuria, pemphigus foliaceus, and tinea amiantacea treated with tetracycline and nicotinamide. J Drugs Dermatol. 2003; 2: 202-205.

58.Chen S, Lu X, Zhou G. Mild pemphigus foliaceus responding to combination therapy with niacinamide and tetracycline. Int J Dermatol. 2003; 42: 981-982.

59.von Köckritz A, Ständer S, Zeidler C, Metze D, Luger T, Bonsmann G. Successful monotherapy of pemphigus vegetans with minocycline and nicotinamide. J Eur Acad Dermatol Venereol. 2017; 31: 85-88.

60.Wu C, Zuo Y, Jin H, Chen J, Li L. Treatment of pemphigus herpetiformis with minocycline and nicotinamide. Chin Med J (Engl). 2014; 127: 3514.

61.Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L. Autoimmune Subepidermal Bullous Diseases of the Skin and Mucosae: Clinical Features, Diagnosis, and Management. Clin Rev Allergy Immunol. 2018; 54: 26-51.

62.Hara H, Fujitsuka A, Morishima C, Kurihara N, Yamaguchi Z, Morishima T. Severe drug-induced pneumonitis associated with minocycline and nicotinamide therapy of a bullous pemphigoid. Acta Derm Venereol. 1998; 78: 393-394.

63.Medline Plus Tetracycline side effects. 2020.

64.White SD, Rosychuk RA, Reinke SI, Paradis M. Use of tetracycline and niacinamide for treatment of autoimmune skin disease in 31 dogs. J Am Vet Med Assoc.1992; 200: 1497-1500.