Tetracyclines as an Therapeutic Tool for Dermatologists: Comparison
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Tetracyclines are a group of antibiotics. In addition to their antibacterial activity, they are able to inhibit metalloproteinases and exhibit anti-inflammatory, anti-apoptotic and antioxidant effects. The side effects have been thoroughly studied over the years, the most characteristic and important ones in daily dermatological practice being: phototoxicity, hyperpigmentation, onycholysis, photoonycholysis, induced lupus erythematosus, and idiopathic intracranial hypertension. 

  • tetracyclines
  • doxycycline
  • limecycline
  • minocycline
  • pleiotrophy
  • non-antibiotic properties

​​​​​​​​1. Introduction

Tetracyclines are natural compounds produced by Streptomyces species that were discovered by Benjamin Duggar in 1948. Today, we have a whole class of drugs derived from the substance discovered then.
The product of soil bacteria from the Streptomyces family was quickly subjected to careful analysis and subsequent modification. Tetracyclines began to be obtained cheaply and rapidly by fermentation [1]. This contributed to their widespread use in the treatment of human and animal diseases, animal growth promotion and aquaculture [2,3][2][3] (see Table 1).
Table 1.
Characteristics of tetracycline group.
 

Broad Spectrum

Narrow Spectrum

References
 

1st generation

2nd generation

3rd generation

  
 

Tetracycline

Doxycycline

Minocycline

Lymecycline

Sarecycline

  

Chemical structure

Tetracyclic naphtacene-carboxyamide ring system and conventional numbering of the condensed ring and key positions

  

methyl and hydroxyl groups at C6 carbon

hydroxyl group at C5 carbon and methyl group at C6 carbon

dimethylamine group at carbon C7

Combination tetracycline with L-lysine

aminomethyl group at the C7 carbon

[4,5,6][4][5][6]

Intake

mandatory meal interval

can be taken with food

can be taken with food

can be taken with food

can be taken with food

[2]
 

2. Types of Tetracyclines

2.1. Tetracycline

Tetracycline is the first representative of the group. It is formed of four six-carbon rings with attached methyl and hydroxyl groups at the C6 carbon [40][7].
After oral administration it is rapidly absorbed from the digestive tract, with the maximal concentration being reached after 1–3 h. However, the absorption may be reduced in the presence of milk products or preparations including metal ions.

2.2. Doxycycline

Doxycycline consists of four identical six-carbon rings with an additional hydroxyl group at the C5 carbon and a methyl group at the C6 carbon [41][8].
It was approved by the FDA in the treatment of severe forms of acne at the dose of 50–100 mg 1–2 times daily [42][9].
As regards doxycycline, the effectiveness of the dose, not including the bacteriostatic activity, was precisely demonstrated, both in acne vulgaris and in acne rosacea.
In Europe and the United States, doxycycline with exclusive anti-inflammatory activity is available at the dose of 40 mg, which includes 30 mg of immediate-release monohydrate and 10 mg in slow-release microgranule form. The preparation is entirely devoid of antibacterial activity. In 2006 it was approved by the FDA for the treatment of acne rosacea [43][10].
Doxycycline at a dose of 20 mg was registered for the treatment of periodontal diseases in adults, and its efficacy in this indication was ascribed to the inhibiting activity of collagenase and matrix metalloproteinase [44,45][11][12].
Doxycycline is the first-line treatment in wide range of infections including Treponema pallidum (syphilis), Borrelia burgdorferi, B. afzelii, B. garinii (borreliosis), Coxiella burnetii (Q fever), Rickettsia rickettsii (Rocky Mountain spotted fever) and Yersinia pestis (plague) [46][13].

2.3. Lymecycline

Lymecycline is a semisynthetic tetracycline, developed by combining tetracycline with L-lysine. Compared with tetracycline it is characterized by higher absorption levels, enhanced tissue penetration, higher serum levels, and slower elimination [47][14].
Due to the highest oral absorption of all tetracyclines [48][15], lymecycline is administered as a simple, once-daily regimen. It induces fewer adverse effects than previously used drugs from this group [49][16].
It is unavailable in North America.
A multicenter, randomized blinded study conducted to compare the efficacy, safety and cost-effectiveness of using lymecycline and minocycline revealed that both drugs had a similar safety and efficacy profile, while the cost of treatment with lymecycline was 4-fold lower [50,51,52][17][18][19].

2.4. Minocycline

Minocycline consists of a tetracyclic ring with an additional dimethyl amino group at the C7 carbon which makes it the most lipophilic tetracycline.
Due to this property, it crosses the blood–brain barrier and reaches high concentrations in the central nervous system, which explains more frequent occurrence of adverse effects such as nausea, vomiting and vertigo [53][20].
It was approved by the FDA in the treatment of severe acne at a dose of 50–135 mg/day.
When treatment is continued for more than 6 months it may cause characteristic pigmentation, lupus-like lesions and irritable bowel syndrome [22,54][21][22].

2.5. Sarecycline

Sarecycline is a new narrow-spectrum antibiotic with bacteriostatic activity. Similarly to the remaining tetracyclines, it inhibits the synthesis of proteins by the disruption of the 30S subunit binding.
It was developed mainly for the treatment of acne lesions. It contains a tetracyclic ring which is modified by the binding aminomethyl group at the C7 carbon [55][23].
Such a modification may be responsible for maintaining antibacterial activity against Cutibacterium acnes and decreasing the activity against the bacteria that make up the intestinal microflora [55,56][23][24]. Apart from bacteriostatic activity, it inhibits neutrophil chemotaxis and the activity of extracellular matrix metalloproteinases.

3. Adverse Effects of Tetracyclines

3.1. Phototoxicity

Tetracyclines usually trigger phototoxicity, but not photoallergy. The former is independent from the immune response, so it may also occur during the first exposure to the drug. However, due to the dose-dependence phenomenon, it occurs when the suitable amount of the drug is concentrated in the skin and it is exposed to suitable quantities of non-ionizing electromagnetic radiation.
UVA (320–400 nm) is the part of the solar spectrum which is most commonly considered as being related with phototoxicity. However, UVB (290–320 nm) and visible light may contribute to the development of such a reaction [57][25].
Clinically speaking, a phototoxic reaction resembles a severe excessive sunburn characterized by erythema, edema, occasional vesicles, and burning followed by exfoliation.
Depending on skin type and pigmentation, a reaction appears within several minutes or hours after exposure to light [58][26].
Older generations of tetracyclines were much more likely to trigger skin reactions. The family of tetracyclines includes numerous molecules. Not all of them induce significant phototoxic reactions. Until recently, the use of tetracyclines in summer had still been discussed. Research revealed a number of significant events ascribed to minocycline and lymecycline, while the majority of studies concerned doxycycline. There is a tendency towards the standardization of the family of tetracyclines to be defined as “photosensitizing drugs” without differentiating between various molecules.

3.2. Hyperpigmentation

This adverse effect is characteristic of minocycline. It is induced by the precipitation of the minocycline–iron complex in the skin [59][27]. The incidence of discolorations induced by minocycline ranges from 2.4% to 41% and is the highest in patients with rheumatoid arthritis. Depending on the type, discolorations are located on the face within the inflammatory areas (type 1), on the healthy skin within the forearm and shin (type 2) or diffuse discolorations which affect sun-exposed skin (type 3—the least common) [60][28].

3.3. Onycholysis, Photoonycholysis

Both onycholysis and photoonycholysis have been described in the context of tetracyclines. They can affect both hands and feet, also with some nails spared. The more frequent involvement of the fingers than the feet, which are less commonly exposed, confirms a mechanism involving UV radiation.
The first case of photoonycholysis after limecycline was described in 2014 [61][29].
As regards doxycycline, onycholysis of the distal part of the nail plate and nail discoloration occur at a frequency of less than 1:1000 [62][30].

3.4. Induced Lupus Erythematosus

The development of systemic lupus is an important and possible consequence of tetracycline use. It may be triggered by the use of older-generation tetracyclines, but is most commonly described in relation to minocycline.
Approximately 57 cases of minocycline-induced lupus have been fully reported to date. Arthritis was the presenting symptom in 100% of patients. It involved small and large joints of the upper and lower limbs. Skin lesions were observed in about 1/5 of patients, with the typical lupus-like butterfly-shaped erythema or discoid rash [63][31] affecting only one patient [64][32].
Tests such as antibodies to DNA, antihistones or anti-Sm antibodies seem to be less sensitive to minocycline-induced lupus.

3.5. Idiopathic Intracranial Hypertension

The possibility of developing increased intracranial pressure is one of the most dangerous side effects of tetracyclines. The symptom complex also described by the synonym “pseudotumor cerebri” is manifested by a headache, tinnitus synchronous with pulse and transient visual disturbances. The headache involves the frontal region, is most severe shortly after awakening and worsens when lying down [65][33].
According to the latest systematic review conducted in 2019, the highest category V of drugs that may cause intracranial hypertension includes tetracyclines, vitamin A and its derivatives (including isotretinoin and tretinoin), and recombinant growth hormone [66][34].
The pathophysiology of intracranial hypertension is not fully elucidated. It is likely that tetracyclines reduce cerebrospinal fluid outflow through the arachnoid villi, and that the metabolites of oral retinoids (retinols) have a direct toxic effect on them [67,68][35][36].
The use of tetracyclines in the treatment of infectious dermatological diseases.
In everyday dermatological practice, acne is often treated with a combination of oral antibiotics and oral retinoids. However, as tetracyclines and isotretinoin belong to the high-risk category of hypertension, concomitant use of these drugs is not recommended.
Although all tetracyclines are structurally similar, they differ significantly in their antimicrobial activity and range of side effects, which affects their clinical application.

4. Bacteriostatic Activity

In many dermatologic and venereal conditions, tetracyclines have been the mainstay of treatment for years because of their bacteriostatic effect. The first-line treatment for all forms of Lyme boreliosis (except late neuroboreliosis) is doxycycline at a dose of 100 mg twice a day for 14 to 28 days [69][37]. In early syphilis, doxycycline is an alternative treatment in case of allergy to penicillin [70][38]. Doxycycline given at a dose of 100 mg twice a day is the treatment of choice in nongonococcal urethritis caused by chlamydia (for 7 days) and lymphogranuloma venereum (for 21 days) [71,72][39][40]. For granuloma inguinalis, tetracyclines are a second therapeutic option and should be used for a minimum of 3 weeks or until the lesions are completely healed [73][41]. New and increasingly common infectious diseases of global concern caused by the group of bacteria of the genus Rickettsia are defined as spotted fevers. Most spotted fevers, which include Rocky Mountain spotted fever, Mediterranean spotted fever, Typhus group and Q fever, resolve after treatment with doxycycline for at least 10 days [74][42].

5. Non-Antibiotic Activity

The use of tetracyclines in the treatment of non-infectious dermatological diseases (see Table 2).
Table 2.
Non-antibiotic activity of tetracyclines—use in inflammatory diseases.
 

Mechanism of Action

Recommended Dosage Pattern

References

Acne

Inhibition of neutrophil chemotaxis induced by P. acnes

Inhibition of IL-8 (a chemotactic cytokine and activator of neutrophils)

Inhibition of MMP

Reactive oxygen species scavenging

Inhibition of phospholipase A2

Tetracycline:

1 g daily given in divided doses; when improvement occurs in 1–2 weeks, decrease slowly to a maintenance dosage of 125–500 mg daily

Doxycycline:

200 mg on the first day of treatment (administered 100 mg every 12 h) followed by a maintenance dose of 100 mg/Day

Minocycline:

50 mg 1–3 times daily

Limecycline:

300 mg once daily for 12 weeks

[75,76,77][43][44][45]

Rosacea

Inhibition of the activation and degranulation of neutrophils

Suppression of pro-inflammatory cytokines TNFα and IL-1β

Decreasing the levels of MMP (especially MMP 9)

Inhibition of the expression of nitric oxide synthase

Tetracycline 250–500 mg twice daily for 4–8 weeks p.o.

Doxycycline 50–100 mg once or twice daily for 4–8 weeks p.o.

[78][46]

Autoimmune bullous disorder

Inhibition of MMP activity

Inhibition of mast cell activation

Doxycycline 2 × 200 mg

[79][47]

Neutrophilic disorders:

Pyoderma gangrenosum

Sweet’s syndrome

Neutrophilic dermatosis of the dorsal hands

Inhibition of IL-8 and neutrophil activation

1.5–2 g daily given in divided doses p.o.

[80,81][48][49]

Granulomatous diseases:

Sarcoidosis

Necrobiosis lipoidica

Inhibition of granuloma formation in vitro

1.5–2 g daily given in divided doses p.o.

[82][50]

Aphtosis, periodontitis

Inhibition of MMP

Doxycycline 20 mg p.o.

Tetracycline (250 mg) used as a mouth rinse and subsequently swallowed

[83,84][51][52]

Palmoplantar pustular psoriasis

Due to limited data the exact mechanism has not been clear

Tetracycline 250 mg, twice daily p.o.

[85][53]

Hidradenitis suppurativa

Inhibition of proinflammatory cytokine levels

Inhibition of the activation and degranulation of neutrophils

Scavenging reactive oxygen species (ROS)

Tetracycline 500 mg twice daily for 4 months p.o.

[86][54]

References

  1. Duggar, B.M. Aureomycin: A product of the continuing search for new antibiotics. Ann. N. Y. Acad. Sci. 1948, 51, 177–181.
  2. Ian, C.; Marilyn, R. Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance. Microbiol. Mol. Biol. Rev. 2001, 65, 232–260.
  3. Zakeri, B.W.G. Chemical biology of tetracycline antibiotics. Biochem. Cell Biol. 2008, 86, 124–136.
  4. Nelson, M.L. Chemical and biological dynamics of tetracyclines. Adv. Dent. Res. 1998, 12, 5–11.
  5. Griffin, M.O.; Ceballos, G.; Villarreal, F.J. Tetracycline compounds with non-antimicrobial organ protective properties: Possible mechanisms of action. Pharmacol. Res. 2011, 63, 102–107.
  6. Golub, L.M.; Ramamurthy, N.S.; McNamara, T.F.; Greenwald, R.A.; Rifkin, B.R. Tetracyclines inhibit connective tissue breakdown: New therapeutic implications for an old family of drugs. Crit. Rev. Oral Biol. Med. 1991, 2, 297–321.
  7. Mitscher, L.A. The Chemistry of the Tetracycline Antibiotics; Marcel Dekker: New York, NY, USA, 1978.
  8. Barza, M.; Brown, R.B.; Shanks, C.; Gamble, C.; Weinstein, L. Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs. Antimicrob Agents Chemother. 1975, 8, 713–720.
  9. Thiboutot, D.; Gollnick, H.; Bettoli, V. New insights into the management of acne: An update from the Global Alliance to Improve Outcomes in Acne group. J. Am. Acad. Dermatol. 2009, 60, 1–50.
  10. Di Caprio, R.; Lembo, S.; Di Costanzo, L.; Balato, A.; Monfrecola, G. Anti-inflammatory properties of low and high doxycycline doses: An in vitro study. Mediators Inflamm. 2015, 329418.
  11. Sorsa, T.; Tjäderhane, L.; Konttinen, Y.T. Matrix metalloproteinases: Contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann. Med. 2006, 38, 306–321.
  12. Gomis-Rüth, F.X. Third time lucky? Getting a grip on matrix metalloproteinases. J. Biol. Chem. 2017, 292, 17975–17976.
  13. Hoyt, J.C.; Ballering, J.; Numanami, H.; Hayden, J.M.; Robbins, R.A. Doxycycline modulates nitric oxide production in murine lung epithelial cells. J. Immunol. 2006, 176, 567–572.
  14. Cunliffe, W.J.; Meynadier, J.; Alirezai, M. Is combined oral and topical therapy better than oral therapy alone in patients with moderate to moderately severe acne vulgaris? A comparison of the efficacy and safety of lymecycline plus adapalene gel 0.1%, versus lymecycline plus gel vehicle. J. Am. Acad. Dermatol. 2003, 49, 218–226.
  15. Chen, Y.; Wu, J.; Yan, H. Lymecycline reverses acquired EGFR-TKI resistance in non-small-cell lung cancer by targeting GRB2. Pharmacol. Res. 2020, 159, 105007.
  16. Maglie, R.; Quintarelli, L.; Caproni, M.; Antiga, E. Impressive response of erosive pustular dermatosis of the scalp to lymecycline monotherapy. J. Dtsch. Dermatol. Ges. 2019, 17, 1177–1178.
  17. Bossuyt, L.; Bosschaert, J.; Richert, B.; Cromphaut, P.; Mitchell, T.; Al Abadie, M.; Henry, I.; Bewley, A.; Poyner, T.; Mann, N.; et al. Lymecycline in the treatment of acne: An efficacious, safe and cost-effective alternative to minocycline. Eur. J. Dermatol. 2003, 13, 130–135.
  18. Grosshans, E.; Belaïch, S.; Meynadier, J.; Alirezai, M.; Thomas, L. A comparison of the efficacy and safety of lymecycline and minocycline in patients with moderately severe acne vulgaris. Eur. J. Dermatol. 1998, 8, 161–166.
  19. Ocampo-Candiani, J.; Velazquez-Arenas, L.L.; de la Fuente-Garcia, A.; Trevino-Gomezharper, C.; Berber, A. Safety and efficacy comparison of minocycline microgranules vs lymecycline in the treatment of mild to moderate acne: Randomized, evaluator-blinded, parallel, and prospective clinical trial for 8 weeks. J. Drugs Dermatol. 2014, 13, 671–676.
  20. Zhanel, G.G.; Homenuik, K.; Nichol, K. The glycylcyclines: A comparative review with the tetracyclines. Drugs 2004, 64, 63–88.
  21. Arvelo, F.; Cotte, C. Metalloproteinases in tumor progression. Review. Invest. Clin. 2006, 47, 185–205.
  22. Garrido-Mesa, N.; Zarzuelo, A.; Galvez, J. Minocycline: Far beyond an antibiotic. Br. J. Pharmacol. 2013, 169, 337–352.
  23. Zhanel, G.; Critchley, I.; Lin, L.Y.; Alvandi, N. Microbiological Profile of Sarecycline, a Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris. Antimicrob. Agents Chemother. 2018, 21, e01297-18.
  24. Kaul, G.; Saxena, D.; Dasgupta, A.; Chopra, S. Sarecycline hydrochloride for the treatment of acne vulgaris. Drugs Today 2019, 55, 615–625.
  25. Lee, A.; Thomson, J. Drug-Induced Skin Reactions, 2nd ed.; Pharmaceutical Press: London, UK, 2006; pp. 125–156.
  26. Odorici, G.; Monfrecola, G.; Bettoli, V. Tetracyclines and photosensitive skin reactions: A narrative review. Dermatol. Ther. 2021, 34, e14978.
  27. Gordon, G.; Sparano, B.M.; Iatropoulos, M.J. Hiperpigmentation of the Skin Associated With Minocycline Therapy. Arch. Dermatol. 1985, 121, 618–623.
  28. Abdelghany, M.; Kivitz, A.J. Minocycline-induced hyperpigmentation. Cleve Clin. J. Med. 2016, 83, 876–877.
  29. Wlodek, C.; Narayan, S. A reminder about photo-onycholysis induced by tetracycline, and the first report of a case induced by lymecycline. Clin. Exp. Dermatol. 2014, 39, 746–747.
  30. Czap, C.; Weckopp, S. Distal Phototoxic Onycholysis. Dtsch Arztebl Int. 2020, 20, 196.
  31. Tan, E.M.; Cohen, A.S.; Fries, J.F.; Masi, A.T.; McShane, D.J.; Rothfield, N.F.; Schaller, J.G.; Talal, N.; Winchester, R.J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982, 25, 1271–1277.
  32. Schlienger, R.G.; Bircher, A.J.; Meier, C.R. Minocycline-Induced Lupus. Dermatology 2000, 200, 223–231.
  33. Wall, M. Update on Idiopathic Intracranial Hypertension. Neurol. Clin. 2017, 35, 45–57.
  34. Tan, M.G.; Worley, B.; Kim, W.B.; Ten Hove, M.; Beecker, J. Drug-Induced Intracranial Hypertension: A Systematic Review and Critical Assessment of Drug-Induced Causes. Am J Clin Dermatol. 2020, 21, 163–172.
  35. Bababeygy, S.R.; Repka, M.X.; Subramanian, P.S. Minocycline-associated pseudotumor cerebri with severe papilledema. J. Ophthalmol. 2009, 203583.
  36. Warner, J.E.; Bernstein, P.S.; Yemelyanov, A.; Alder, S.C.; Farnsworth, S.T.; Digre, K.B. Vitamin A in the cerebrospinal fluid of patients with and without idiopathic intracranial hypertension. Ann. Neurol. 2002, 52, 647–650.
  37. Lantos, P.M.; Rumbaugh, J.; Bockenstedt, L.K. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease. Arthritis Rheumatol. 2021, 73, 12–20.
  38. Janier, M.; Unemo, M.; Dupin, N.; Tiplica, G.S.; Potočnik, M.; Patel, R. 2020 European guideline on the management of syphilis. J. Eur. Acad. Dermatol. Venereol. 2021, 35, 574–588.
  39. Lanjouw, E.; Ouburg, S.; de Vries, H.J.; Stary, A.; Radcliffe, K.; Unemo, M. European guideline on the management of Chlamydia trachomatis infections. Int. J. STD Aids 2016, 27, 333–348.
  40. de Vries, H.J.C.; de Barbeyrac, B.; de Vrieze, N.H.N. European guideline on the management of lymphogranuloma venereum. J Eur. Acad. Dermatol. Venereol. 2019, 33, 1821–1828.
  41. O’Farrell, N.; Moi, H. European guideline on donovanosis. Int. J. STD Aids 2016, 27, 605–607.
  42. Fralish, M.S.; Mangalindan, K.E.; Farris, C.M.; Jiang, J.; Green, M.C.; Blaylock, J.M. African Tick-Bite Fever. Am. J. Med. 2020, 133, 1051–1053.
  43. Garcia-Martinez, E.; Sanz-Blasco, S.; Karachitos, A. Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochemistry 2010, 79, 239–250.
  44. Sapadin, A.N.; Fleischmajer, R. Tetracyclines: Nonantibiotic properties and their clinical implications. J. Am. Acad. Dermatol. 2006, 54, 258–265.
  45. Zaenglein, A.L.; Pathy, A.L.; Schlosser, B.J. Guidelines of care for the management of acne vulgaris. J. Am. Acad. Dermatol. 2016, 74, 945–973.
  46. Amin, A.R.; Patel, R.N.; Thakker, G.D. Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett. 1997, 410, 259–264.
  47. Monk, E.; Shalita, A.; Siegel, D.M. Clinical applications of nonantimicrobial tetracyclines in dermatology. Pharm. Res. 2011, 63, 130–145.
  48. Joshi, R.K.; Atukorala, D.N.; Abanmi, A. Successful treatment of Sweet’s syndrome with doxycycline. Br. J. Dermatol. 1993, 128, 584–586.
  49. Berth-Jones, J.; Tan, S.V.; Graham-Brown, R.A.C. The successful use of minocycline in pyoderma gangrenosum—A report of seven cases and review of the literature. J. Dermatol. Treatment 1989, 1, 23–25.
  50. Webster, G.F.; Toso, S.M.; Hegemann, L.R. Inhibition of in vitro granuloma formation by tetracyclines and ciprofloxacin: Involvement of protein kinase C. Arch. Dermatol. 1994, 130, 748–752.
  51. Peterson, J.T. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail. Rev. 2004, 9, 63–79.
  52. Kennedy, R.; Alibhai, M.; Shakib, K. Tetracycline: A cure all? Br. J. Oral Maxillofac. Surg. 2014, 52, 382–383.
  53. Marsland, A.M.; Griffiths, C.E. Treatments for chronic palmoplantar pustular psoriasis. Ski. Ther. Lett. 2001, 6, 3–5.
  54. Gulliver, W.; Zouboulis, C.C.; Prens, E.; Jemec, G.B.; Tzellos, T. Evidence-based approach to the treatment of hidradenitis suppurativa/acne inversa, based on the European guidelines for hidradenitis suppurativa. Rev. Endocr. Metab. Disord. 2016, 17, 343–351.
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