CYCLING BACK TO DOXYCYCLINE’S ROOTS AS THERAPY FOR BULLOUS PEMPHIGOID
By Warren R. Heymann, MD, FAAD July 26, 2023 Vol. 5, No. 30
Patients with moderate to severe bullous pemphigoid are usually treated with systemic corticosteroids. Four patients were treated with tetracycline hydrochloride and niacinamide because of the steroid-sparing anti-inflammatory properties of these agents. An excellent clinical response free of side effects was observed in all patients. The lesions recurred whenever treatment was discontinued. It is believed that these drugs suppress the complement-mediated inflammatory response at the basement membrane zone by suppressing neutrophil chemotaxis and mediators of the inflammatory response in this bullous disease.
This 1986 abstract from the seminal article by Berk and Lorincz crystallized the use of tetracyclines as anti-inflammatory agents, rather than antimicrobial drugs, as steroid-sparing agents for treating bullous pemphigoid (BP) in concert with niacinamide. (1) The concept of antibiotics (usually doxycycline or minocycline) as anti-inflammatory agents was novel in the 1980s and has become a standard first-line treatment for BP, aside from corticosteroids (ultrapotent topical or systemic). Treating BP requires a thorough medical knowledge of the patient and their comorbidities — tailoring therapy to include second-line agents (azathioprine, mycophenolate mofetil, dapsone, or methotrexate) or third-line therapies (IVIG, rituximab, omalizumab, dupilumab, and others) must be individualized to the patient's overall health. (2)
This commentary will focus on the use of doxycycline for BP. Can its efficacy be solely due to its anti-inflammatory effect?
Doxycycline was FDA-approved as an antibiotic in 1967. It is a broad-spectrum bacteriostatic agent that inhibits bacterial protein synthesis by targeting the 30S ribosomal subunit of gram-positive and gram-negative bacteria. The anti-inflammatory effects of doxycycline have been reviewed by Henehan et al and include inhibition of multiple matrix metalloproteinases, diminishing protease-activated receptor 2 (PAR2), reducing both random migration and guided chemotaxis of neutrophils, decreasing pathogenic nitrous oxide synthase levels, reducing IgE production, scavenging radicals thereby reducing oxidative stress, hindering granuloma formation, and inducing apoptosis via caspase pathways. (3)
Eosinophils are potent pro-inflammatory cells; the tetracyclines (tetracycline, doxycycline, minocycline) have been used to advantage in disorders such as asthma or BP where eosinophils play a pathogenic role. Gehring et al have demonstrated that the tetracyclines significantly induce eosinophil apoptosis and strongly overcome the strong survival-enhancing effects of pro-eosinophilic cytokines and Staphylococcus aureus (SA) enterotoxins. (4)
(Niacinamide, also known as nicotinamide, was initially observed to be beneficial for dermatitis herpetiformis, hence its use in BP. Niacinamide is the pyridine-3-carboxamide form of niacin, a component of the vitamin B complex. It is the precursor for nicotinamide adenine dinucleotide and acts as an inhibitor of poly- [adenosine diphosphate–ribose] polymerase, which plays an essential role in the expression of cytokines, chemokines, and adhesion molecules via enhanced transcription of nuclear factor kB. It also blocks IgE-induced histamine release.) (1,5)
The anti-inflammatory effects of doxycycline, which seemed revolutionary decades ago, are now accepted as routine. For years, I have been telling patients that we are administering the drug as an anti-inflammatory agent, not for its role as an antibiotic. That statement is correct when using doxycycline in subantimicrobial doses — in typical doses, however, perhaps doxycycline is exerting its antibiotic effect.
Any seasoned dermatologist will be on the prowl for secondary infection in patients with BP. In a retrospective review of 110 hospitalized patients with BP, infections were present in 40% (44/110) of the patients. Staphylococcus aureus (72.7%, 32/44) was the most common bacterium, and it was highly resistant to penicillin (81.3%, 26/32), erythromycin (62.5%, 20/32), and clindamycin (56.3%, 18/32), but 100.0% sensitive to vancomycin and tigecycline. (6) BP may be complicated by methicillin-resistant SA (MRSA) and sepsis. (7)
Image from DermNetNZ.
The complex interplay of SA with skin disease is well-known in atopic dermatitis when SA is isolated from patients during flares; as the normal microbiota is reduced, many species that produce inhibitors of SA are also decreased. (8) Scaglione et al studied microbiota of patients with pemphigus vulgaris (PV) and BP using high-throughput sequencing of the V1-V3 hyper-variable regions of 16S rRNA to compare the bacterial community composition of stool, skin, and oral mucosae swabs in a cohort of PV and BP patients. They determined that the Firmicutes phylum and Staphylococcus genus were the most represented bacteria in oral cavity and cutaneous swabs of PV and BP microbial populations. (9)
Last week, we discussed the "intimate dance" of SA and cutaneous T-cell lymphoma. Could SA be a trigger of BP aside from being a potential infectious complication? Is doxycycline working as an antibiotic AND an anti-inflammatory agent?
Messingham et al propose that the antimicrobial effects of tetracyclines play an important therapeutic role in BP by the clearance of SA. Their abstract follows: "A potential role of S. aureus in bullous pemphigoid was explored by examining the colonization rate in patients with new-onset disease compared with that in age- and sex-matched controls. S. aureus colonization was observed in 85% of bullous pemphigoid lesions, 3-6-fold higher than the nares or unaffected skin from the same patients (P ≤ 0.003) and 6-fold higher than the nares or skin of controls (P ≤ 0.0015). Furthermore, 96% of the lesional isolates produced the toxic shock syndrome toxin-1 superantigen, and most of these additionally exhibited homogeneous expression of the enterotoxin gene cluster toxins. Toxic shock syndrome toxin-1‒neutralizing antibodies were not protective against colonization. However, S. aureus colonization was not observed in patients who had recently received antibiotics, and the addition of antibiotics with staphylococcal coverage eliminated S. aureus and resulted in clinical improvement. This study shows that toxic shock syndrome toxin-1‒positive S. aureus is prevalent in bullous pemphigoid lesions and suggests that early implementation of antibiotics may be of benefit. Furthermore, our results suggest that S. aureuscolonization could provide a source of infection in patients with bullous pemphigoid, particularly in the setting of high-dose immunosuppression." (10)
I reread Berk and Lorincz's article. (1) None of the four cases had any wound cultures performed.
The latest data about doxycycline's anti-inflammatory capabilities, especially in eosinophil-rich disorders, and the purported role SA plays in triggering (or complicating) them, solidifies its position as a first-line therapeutic agent for BP. Despite its potential benefit, clinicians must use antibiotics judiciously in this age of increasing antimicrobial resistance to SA and other bacteria. (11)
Point to Remember: Staphylococcus aureus has the potential to trigger or complicate bullous pemphigoid by infection. Tetracyclines may exert their efficacy via their anti-inflammatory and antimicrobial properties.
Our expert's viewpoint
Janet Fairley, MD, FAAD Chair, John S. Strauss Professor and Head of Dermatology University of Iowa Carver College of Medicine
Tetracycline antibiotics have been used in bullous pemphigoid (BP) for almost 30 years. Multiple mechanisms have been proposed for their beneficial effects in BP, including antioxidant effects, inhibition of matrix metalloproteinases, and through their antimicrobial activity (12,13,14). These possibilities are not exclusive, and it is likely the beneficial effect of tetracyclines in BP is multifactorial.
BP patients are typically elderly with multiple co-morbidities, and most will receive therapeutic immunosuppression. In addition, BP patients suffer increased hospitalizations and mortality within the first year of diagnosis, with the most common causes being infectious complications, including sepsis and pneumonia (15, 16). Thus, clinicians should be aware of the widespread S. aureus colonization of BP lesions (10) and consider that early implementation of antimicrobial therapy may be of benefit, particularly in patients receiving immunosuppressants.
In practice, doxycycline is usually included in the initial therapy for our BP patients. Based on our detection of S. aureus toxins in BP blister fluid, we have used short-term clindamycin in patients with severe disease since it inhibits toxin production in a manner independent of its antimicrobial activity (17). Rapid elimination of S. aureus toxins may be important in BP patients due to the direct effect of these toxins on immune cell dysregulation, keratinocyte inflammatory responses, and upregulation of damaging matrix metalloproteinases, all of which are of concern for potential worsening of BP (18, 19, 20).
Our understanding of role of S. aureus in BP is evolving but this topic story is of interest to those of us who treat this disease. Stay tuned.
Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and niacinamide. A preliminary report. Arch Dermatol. 1986 Jun;122(6):670-4. PMID: 2940979.
Bilgiç A, Murrell DF. Bullous pemphigoid. In Lebwohl MG, Heymann WR, Coulson IH, Murrell DF (eds) Treatment of Skin Disease, Sixth Edition. Elsevier, 2022, pp 115-118.
Henehan M, Montuno M, De Benedetto A. Doxycycline as an anti-inflammatory agent: updates in dermatology. J Eur Acad Dermatol Venereol. 2017 Nov;31(11):1800-1808. doi: 10.1111/jdv.14345. Epub 2017 Jun 7. PMID: 28516469
Gehring M, Wieczorek D, Kapp A, Wedi B. Potent Anti-Inflammatory Effects of Tetracyclines on Human Eosinophils. Front Allergy. 2021 Oct 4;2:754501. doi: 10.3389/falgy.2021.754501. PMID: 35386966; PMCID: PMC8974775.
Heymann WR. Nicotinamide and reflections on Alan Shalita and George Hambrick Jr. Cutis. 2014 Mar;93(3):151-2. PMID: 24738097.
Li F, Bian W, Wu Y, Zhu X, Chen X, Wang M. Bacterial Skin Infections in Hospitalized Patients with Bullous Pemphigoid. Adv Skin Wound Care. 2021 Jul 1;34(7):365-370. doi: 10.1097/01.ASW.0000752704.10152.30. PMID: 34125726.
Souaid R, Wang J, Landow SM, Noska A. Bullous Pemphigoid Complicated by MRSA Cellulitis and Bacteremia. R I Med J (2013). 2019 Jun 4;102(5):46-48. PMID: 31167529.
Geoghegan JA, Irvine AD, Foster TJ. Staphylococcus aureus and Atopic Dermatitis: A Complex and Evolving Relationship. Trends Microbiol. 2018 Jun;26(6):484-497. doi: 10.1016/j.tim.2017.11.008. Epub 2017 Dec 9. PMID: 29233606. Scaglione GL, Fania L, De
Paolis E, De Bonis M, Mazzanti C, Di Zenzo G, Lechiancole S, Messinese S, Capoluongo E. Evaluation of cutaneous, oral and intestinal microbiota in patients affected by pemphigus and bullous pemphigoid: A pilot study. Exp Mol Pathol. 2020 Feb;112:104331. doi: 10.1016/j.yexmp.2019.104331. Epub 2019 Nov 6. PMID: 31705881.
Messingham KN, Cahill MP, Kilgore SH, Munjal A, Schlievert PM, Fairley JA. TSST-1+Staphylococcus aureus in Bullous Pemphigoid. J Invest Dermatol. 2022 Apr;142(4):1032-1039.e6. doi: 10.1016/j.jid.2021.08.438. Epub 2021 Oct 1. PMID: 34606884.
George S, Muhaj FF, Nguyen CD, Tyring SK. Part I Antimicrobial resistance: Bacterial pathogens of dermatologic significance and implications of rising resistance. J Am Acad Dermatol. 2022 Feb 2;86(6):1189–204. doi: 10.1016/j.jaad.2021.11.066. Epub ahead of print. PMID: 35122894; PMCID: PMC8808428.
C. Feliciani, P. Joly, M.F. Jonkman, G. Zambruno, D. Zillikens, D. Ioannides, et al. Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Acad Dermatol and Venereol. 2015. Br J Dermatol, 172:867-877.
M. Schaller. Anti-inflammatory effects of tetracyclines. 2017. J Eur Acad Dermatol Venereol, 31 (2017), p. 1774.
H.C. Williams, F. Wojnarowska, G. Kirtschig, J. Mason, T.R. Godec, E. Schmidt, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial [published correction appears in Lancet 2017;390:1948]. 2017. Lancet, 389:1630-1638
P. Joly, S. Baricault, A Sparsa, et al. Incidence and mortality of bullous pemphigoid in France. 2012. J Invest Dermatol 132:1998-2004.
Z. Ren, D.Y. Hsu, J. Brieva, N.B. Silverberg, S.M. Langan, J.I. Silverberg. Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the U.S.A. 2017. Br J Dermatol, 176: 87-99.
D. L.Stevens, Y. Ma, D. B. Salmi, E. McIndoo, R. J. Wallace, A. E. Bryant. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. 2007/ J Infectious diseases. 195:202-11.
P. M. Schlievert, F. A. Gourronc, D. Y. M. Leung, A. J. Klingelhutz. Human Keratinocyte Response to Superantigens. 2020. mSphere. 5(5):803-20.
L. M. Breshears, P. M. Schlievert, M. L. Peterson. A disintegrin and metalloproteinase 17 (ADAM17) and epidermal growth factor receptor (EGFR) signaling drive the epithelial response to Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1). J Biol Chem. 2012 Sep 21;287(39):32578-87.
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