Hilary E. Baldwin – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Tue, 25 Sep 2018 16:32:36 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Systemic Therapy for Rosacea https://www.skintherapyletter.com/rosacea/systemic-therapy/ Thu, 01 Mar 2007 22:00:52 +0000 https://www.skintherapyletter.com/?p=1079
H. E. Baldwin, MD

Department of Dermatology, State University of New York, Brooklyn, NY, USA

ABSTRACT

Rosacea is a common condition that affects people of all races. In addition to the visible aspects of this disease, it can have a psychosocial impact that must be evaluated when considering the treatment options. More aggressive and innovative uses of existing oral agents have resulted in novel therapeutic approaches, which can provide long-term therapy and sustained remission.

Key Words:
Rosacea, Erythematotelangiectatic Rosacea, Papulopustular Rosacea, Phymatous Rosacea, Ocular Rosacea, Granulomatous Variant

Rosacea is a common disorder that is thought to affect 13-14 million people in the US alone.1,2 It is likely that the actual number is substantially higher. Rosacea affects all races, although erythema may be less prevalent in patients with skin types IV and V. The rate of occurrence appears to be higher in women; however, men are more likely to develop phymas. Patients are most often diagnosed with this condition in their 30s-50s.

To truly understand the effects of rosacea on patients, the psychosocial impact must be evaluated along with the visible aspects of this disease. For many of our patients, the stigma of a “drinker’s nose” and the social and professional isolation that can result from low self-esteem is far more significant than the clinical reality.

Contributing to the frustration experienced by patients with rosacea is the fact that as clinicians, we do not truly treat rosacea, but rather manage it. We cannot offer patients cures, simply improvements. As with all chronic conditions, continual therapy inevitably leads to non-adherence. The benefits derived from a combination of both medical and psychological approaches cannot be overemphasized. The overall objective is the improvement of the quality of life of patients, and in 2007, this goal is easier to attain thanks to topical medications that reduce skin irritation. Furthermore, with the advent of safer, once-daily systemic medications, it is possible to liberate patients from the use of topical products.

Classification of Rosacea

Rosacea is a condition characterized by a constellation of symptoms including central facial erythema and telangiectasias, papules and pustules, granulomatous nodules, phyma formation, and ocular changes. The disorder is capricious with flares and remissions occurring without rationale.
For the task of discussing therapy, rosacea is best viewed as a collection of several conditions with a common name. Although many patients have polymorphic disease, most have one predominating feature.

The most commonly used classification system is based on predominant lesion morphology and was developed by a committee of the National Rosacea Society and published in 2002.3 Patients are classified as having one of four types of rosacea: erythematotelangiectatic, papulopustular, phymatous, or ocular with a variant form referred to as granulomatous. Individual patients may straddle one or more subtypes, but this system allows us to determine therapy based on similar lesion types. Therapeutic options for the various lesion types are easily categorized and there are few medications or modalities that are significantly effective in more than one category.

Pathophysiology of Rosacea

Our lack of understanding with regard to the pathogenesis of rosacea hampers our therapeutic efforts. Still unclear at this time is the fundamental issue of whether or not the papules and pustules are based in the follicle. There is a growing consensus that bacterial infection does not play a role in rosacea etiology. The neurologic or hormonal mechanisms that may generate the flushing reaction and phyma formation are similarly unknown. It is also unclear if accumulated sun damage, which bears many biochemical and clinical similarities to vascular rosacea, is involved in its pathogenesis.

What is known is that inflammation plays an important role in lesion formation. Inflammatory cells release proinflammatory cytokines and degradative enzymes that induce angiogenesis and damage dermal constituents.4

The outcome of our poor understanding of its pathogenesis is that treatment has been traditionally based on disease endpoints rather than targeting the underlying anomalies. Inflammation is treated with anti-inflammatory agents, flushing with vasoconstrictors, and telangiectasias with laser and light therapy. Until recently, papules and pustules were treated with antibiotics and no target organism.

Oral Therapeutic Options

Antibiotics

Oral antibiotics have been used off-label for the treatment of rosacea since the 1950s because it was believed that microorganisms were causative. We now know that there is little to no evidence supporting this premise. Although not curative, the observed benefits of oral antibiotic treatment in patients with rosacea have made clinicians and patients reluctant to exclude these agents from their therapeutic armamentarium, much less to downgrade them from their first-line status.

Due to the chronicity of this disease, antibiotic use is often long-term and can produce side-effects. Furthermore, overuse of antibiotics is associated with the emergence of resistant strains of bacteria that have the potential to result in adverse global health consequences.

Tetracyclines

Tetracycline received US FDA approval in 1952 and the derivatives doxycycline and minocycline soon followed in 1966 and 1972, respectively. At the time of their introduction, they were known to be bacteriostatic and have broad-spectrum action. Since then, we have come to recognize the anti-inflammatory properties of the tetracycline class of antibiotics.

Tetracyclines are known to down-regulate the production of proinflammatory cytokines such as IL-1 and TNF-alpha.5 They also inhibit neutrophil chemotaxis and the production of nitric oxide, reactive oxygen species, and matrix metalloproteinases (MMP).6,7 This ability of tetracyclines to modulate the inflammatory response pathway, reducing the inflammatory response, is believed to be the rationale for its effectiveness in treating rosacea.5

Tetracyclines are highly effective for papulopustular rosacea, requiring only 3-4 weeks of treatment for substantial improvement. Tetracycline 250-1000mg q.d., doxycycline 100-200mg q.d., and minocycline 100-200mg q.d. are most common. Use of oral tetracyclines until clinical improvement is seen, followed by a transition to topical antibiotics offers an alternative therapeutic regimen. There are patients for whom low-dose, long-term use of antibiotics are necessary to maintain control of their rosacea.

Long-term treatment with antibiotics is problematic for numerous reasons including significant side-effects.8-10 Oral use of tetracyclines can result in disorders such as candidal vulvovaginitis, gastrointestinal distress, and even pseudotumor cerebri. Treatment with doxycycline can result in photosensitivity, and minocycline in vertigo and blue dyspigmentation. Minocycline has also been implicated in the development of lupus-like syndromes and hypersensitivity reactions. Of world-wide importance is the concern regarding emerging antibiotic resistance due to over/ misuse of antibiotics.

Anti-inflammatory dose doxycycline (20mg doxycycline hyclate) was FDA approved in 1998 for the treatment of adult periodontitis. The labeling permits continuous use for up to 12 months, and as such it is the only tetracycline approved for long-term use. It has been shown to be effective in treating papulopustular rosacea with a low incidence of adverse effects. Bikowski treated 50 patients with all types of rosacea and, at 4 weeks, noted an 80%-100% improvement in inflammatory lesions, and a 50% reduction in erythema.10

Although doxycycline has been shown to be highly effective, perhaps its major contribution is that dosage at 20mg results in sub-antimicrobial blood levels. Several studies have reported no effect on antibiotic susceptibility patterns in up to 18 months of continuous therapy and in 9 months post-treatment.12-14

Golub, in 1998, showed that doxycycline hyclate (Periostat®, CollaGenex) had anti-chemotactic activity, was a scavenger of reactive oxygen species and inhibited the enzyme MMP from being released.12 Of primary importance is the ability of doxycycline hyclate to inhibit activation of the MMP-2 and MMP-9 enzymes that break down the capillary vessel basement membrane.

In 2006, a once-daily controlled-release formulation of doxycycline monohydrate became available (Oracea®, CollaGenex Pharmaceuticals). As the first FDA-approved oral treatment for rosacea, the once-daily 40mg capsule combines 30mg immediate-release and 10mg delayed-release doxycycline. The low dose remains below the antibiotic threshold and the controlled release allows for once-daily dosing. Acting as an anti-inflammatory medication rather than an antibiotic, controlled-release doxycycline does not exert selective pressure on microorganisms and as such does not cause bacterial overgrowth (i.e., folliculitis, vaginal candidiasis) or encourage the development of bacterial resistance. Clinical studies have shown the formulation to be both efficacious and safe.15 With once-daily dosing, compliance should also be improved.

Macrolide Antibiotics

Erythromycin is an effective antibiotic in the treatment of papulopustular rosacea, but its use is often limited by GI distress. Erythromycin in doses of 250-1000mg/day is generally used in patients who are intolerant to tetracyclines and in pregnant women in whom tetracyclines are contraindicated.

Second generation macrolides such as clarithromycin and azithromycin have been shown to work faster and with less GI distress than erythromycin.16 One study that followed patients for 3 years showed that subjects taking clarithromycin required less treatment time per year than those taking doxycycline (10.2 weeks/yr vs. 14.6 weeks/yr).17 A 12-week trial of azithromycin in tapering doses showed an 89% reduction in inflammatory lesions.18

The relatively small advantages of the second generation macrolides, however, need to be weighed against the cost differential in the US of a 30-pill supply: erythromycin enteric coated capsules $8.99, clarithromycin $107.49, and azithromycin $214.95.19

Antibiotic Resistance

In the last decade, there has been increasing concern over the prevalence of antibiotic resistance. Dahl reported the rate of antibiotic-resistant Propionibacterium acnes (P. acnes) is up to 60%.20 Globally, antibiotic-resistant P. acnes increased from 20% to 62% from 1978-1996.21 European studies saw increases of 20% and 50% for tetracycline and erythromycin resistance respectively.22,23 Consequently, there are concerns that increasing P. acnes resistance would result in a reduction in treatment success over time in rosacea patients.

Even greater cause for concern is the ability of P. acnes to transfer resistance to other, more pathogenic bacteria. Levy evaluated the long-term (>6 months) use of antibiotics in 105 acne patients.24 He found that 85% of patients cultured positive for tetracycline resistant Streptococcus pyogenes in the oropharynx compared with 20% in the control group. Margolis, et al. suggested that this was not purely of academic interest, but translated into actual increase in disease.25 In a large, retrospective study, an increase in upper respiratory infections in acne patients treated with either topical or oral antibiotics for greater than 6 weeks was seen. With the recent epidemic of methicillin-resistant Staphylococcus, tetracycline resistance has alarming implications.26,27

Concerns about resistance have resulted in the suggestion by several authors that long-term use of antibiotics be discontinued in acne therapy;21,28,29 and serves as an even more appropriate recommendation in rosacea where there is no evidence of a microbial pathogenesis. Because bacterial resistance is not as much of a concern, the use of anti-inflammatory dose doxycycline and other non-antibiotic alternatives in the treatment of rosacea is preferable whenever clinically appropriate.

Metronidazole

Although effective in the treatment of rosacea, metronidazole has been associated with potential (although rare) side-effects such as neuropathy and seizures.30 Alcohol abstinence is required during use to avoid a disulfiram-like reaction and headache.31 Although rarely used in the US, oral metronidazole is prescribed frequently in Europe for long-term therapy of rosacea at doses of 200mg b.i.d.31-34 In a double blind study of patients with papulopustular rosacea, it was shown to be as effective as oral oxytetracycline 250mg b.i.d.35 Pregnancy category B labeling makes it an option for pregnant women.

Isotretinoin

Isotretinoin is highly effective in the treatment of rosacea. It is one of the few medications that is capable of treating more than one subtype of disease. Onset of action is slower than that seen with the use of oral antibiotics.36,37 In 1981, Nikolowski and Plewig showed that treatment resistant patients taking isotretinoin experienced fewer papules and pustules, a reduction in erythema, and decreased nasal volume.38 Irvine, et al. demonstrated that this drug could halt rhinophyma by diminishing sebaceous gland size and number.39

More studies are needed to determine appropriate dosing schedules as well as optimal treatment duration. Unlike in acne vulgaris, it is not clear that isotretinoin can produce a permanent remission in rosacea. Schmidt and Raff documented remissions lasting up to 2 years after a course of isotretinoin.40 More recently, Erdogan, et al. utilized low-dose isotretinoin at 10mg q.d. for 4 months and showed significant reduction in inflammatory lesions, erythema and telangiectasia at 9 weeks.37

In our continuing search for a therapy that does not result in antibiotic resistance, isotretinoin may be a viable alternative, especially in males and older women past child-bearing years. Low dose (10mg q.d. or q.o.d.), long-term use of isotretinoin can result in minimal risks of side-effects. Birth defects, however, are possible at any dose of this drug; low dose does not mean low vigilance.

Dapsone

Reports in the literature support using dapsone in severe, refractory rosacea.41 It is particularly helpful in patients for whom isotretinoin is contraindicated.

Drugs That Antagonize Flushing

Many anecdotal reports exist regarding the use of agents that antagonize the flushing reaction, including vasoconstricting agents, and drugs that alter flushing reactions in response to emotional stimuli.

Beta blockers in low doses (i.e., nadolol,9 naloxone,42 ondansetron,43 aspirin,44 and numerous selective serotonin reuptake inhibitors19) have been reported in isolated cases to be effective. However, there is no evidence-based research to support their use.

Craige and Cohen recently revisited the use of propranolol in the control of flushing and blushing.45 At starting doses of 10mg t.i.d., none of their nine patients improved. Six of nine patients improved when doses were escalated to 20-30 mg t.i.d. At such high doses, three patients withdrew from the study due to side-effects. This study shows that the perceived ineffectiveness of beta blockers may be due to inadequate dosing.

Clonidine has also been reported to improve flushing and blushing reactions at doses of 0.05mg b.i.d.46 At this dose there was no reduction in blood pressure, but lower baseline malar temperature may have been reduced by peripheral vasoconstriction. Although some patients do remarkably well on clonidine, responders are not clinically identifiable before treatment. Since control of this feature of rosacea is so difficult, a trial course may be indicated.

Therapy Based on Rosacea Subtype

Erythematotelangiectatic Rosacea

The erythematotelangiectatic subtype of rosacea is the most difficult to treat. There is little evidence that topical or oral antibiotics have any role in the treatment of erythema, telangiectasias and flushing-blushing reactions. Isotretinoin may improve erythema resulting from inflammation, but this effect may be transient. Drugs that antagonize flushing may be helpful in some patients. Vascular laser and light therapy is the most effective modality in this subtype.

Papulopustular Rosacea

The papulopustular type of rosacea is the easiest subtype to treat. Most of these patients respond readily to topical medications such as metronidazole, benzoyl peroxide, clindamycin, erythromycin, and azelaic acid. In several studies, topical medications were shown to be equally effective to oral medications although therapy may take longer to be effective.

Since 2006 there has been a paradigm shift in the therapeutic decision-making process for treating rosacea. In the past, topical agents were considered as first-line therapy, and oral agents were introduced only when topical medications were ineffective, or were used in patients for whom immediate response was paramount. With the advent of once-daily, non-antibiotic dosing of doxycycline, oral therapy has become more commonly prescribed as first-line treatment. Often oral and topical antibiotics are used in combination; the resulting effect may be synergistic. Ultimately the patient may be converted to topical therapy alone for maintenance purposes. However long-term, anti-inflammatory dose doxycycline offers a viable alternative.

Isotretinoin is highly effective in this type of rosacea, especially given that low-dose, long-term therapy is an option particularly in men and women of nonchildbearing potential.

Dapsone may be necessary in refractory rosacea or in a patient for whom isotretinoin is contraindicated.

Phymatous Rosacea

Surgical or laser ablation is often necessary to eradicate existing lesions of significant size. Isotretinoin has been reported to halt the progression of rhinophymata and to shrink overall volume of phymata by reducing the size of the sebaceous glands, but it does not appear to be curative.37,39,40,47-50

Ocular Rosacea

Mild, chronic ocular rosacea responds well to topical agents and eyelid hygiene. More significant disease responds promptly and substantially to virtually any oral antibiotic. Tetracyclines, because of their safety profile, are most often used.51,52 Isotretinoin use may improve the more severe presentations of ocular rosacea, including coloboma formation and corneal erosions. Potential side-effects for this type of rosacea include dry eyes and gritty irritation during therapy.

Granulomatous Variant

The granulomatous variant of rosacea is treated in the same manner as papulopustular rosacea reviewed above. Severe disease also responds to the use of oral and intralesional corticosteroids.

Conclusions

Until recently, there had been little change in the systemic treatment options for rosacea over the last several decades. In 2007, more aggressive and innovative uses of existing oral agents have resulted in novel therapeutic approaches. The development of anti-inflammatory dose doxycycline monohydrate is an intriguing alternative to long-term or episodic use of full-dose antibiotics. Once-daily dosing with the controlled-release formulation of doxycycline monohydrate can be expected to improve compliance and therefore efficacy. Furthermore, anti-inflammatory dose doxycycline and isotretinoin are helpful modalities for preventing treatment failures. Agents with good or acceptable safety profiles allow for long-term therapy and provide sustained remission. More importantly, the use of oral agents that do not increase the likelihood of future bacterial resistance is of global importance.

References

  1. National Rosacea Society. 14 million Americans have rosacea: and most of them don’t know it. Available at: www.rosacea.org. Last accessed February 21, 2007.
  2. Zuber TJ. Rosacea. Prim Care 27(2):309-18 (2000 Jun).
  3. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 46(4):584-7 (2002 Apr).
  4. Wilkin J, DeWitt S. Treatment of rosacea: topical clindamycin versus oral tetracycline. Int J Dermatol 32(1):65-7 (1993 Jan).
  5. Greenwald R, Moak S, Ramamurthy N, Golub LM. Tetracycline suppresses matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. J Rheumatol 19(6):927-38 (1992 Jun).
  6. Golub LM, Ciancio S, Ramamurthy NS, Leung M, McNamara TF. Low-dose doxycycline therapy: effect on gingival and crevicular fluid collagenase activity in humans. J Periodontal Res 25(6):321-30 (1990 Nov).
  7. Alexander MB, Damoulis PD. The role of cytokines in the pathogenesis of periodontal disease. Curr Opin Periodontol 39-53 (1994).
  8. Del Rosso JQ. Systemic therapy for rosacea: focus on oral antibiotic therapy and safety. Cutis 66(4 Suppl):7-13 (2000 Oct).
  9. Rebora A. The management of rosacea. Am J Clin Dermatol 3(7):489-96 (2002).
  10. Bikowski JB. Rosacea: a tiered approach to therapy. Cutis 66(suppl 4):3-6 (2000 Oct).
  11. Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed 2(4):234-45 (2003 Jul-Aug).
  12. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inbihit connective tissue breakdown by multiple nonantimicrobial mechanisms. Adv Dent Res 12(2):12-26 (1998 Nov).
  13. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol 139(4):459-64 (2003 Apr).
  14. Thomas J, Walker C, Bradshaw M. Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility. J Periodontol 71(9):1472-83 (2000 Sep).
  15. Data on file, CollaGenex Pharmaceuticals.
  16. Torresani C, Pavesi A, Manata GC. Clarithromycin versus doxycycline in the treatment of rosacea. Int J Dermatol 36(12):942-6 (1997 Dec).
  17. Torresani C. Clarithromycin: a new perspective in rosacea treatment. Int J Dermatol 37(5):347-9 (1998 May).
  18. Bakar O, Demircay Z, Gurbuz O. Therapeutic potential of azithromycin in rosacea. Int J Dermatol 43(2):151-4 (2004 Feb).
  19. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol 51(4):499-512 (2004 Oct).
  20. Dahl MV. Pathogenesis of rosacea. Adv Dermatol 17:29-45 (2001).
  21. Espersen F. Resistance to antibiotics used in dermatological practice. Br J Dermatol 139(Suppl 53):4-8 (1998 Dec).
  22. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust 169(5):259-61 (1998 Sep).
  23. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol 148(3):467-78 (2003 Mar).
  24. Levy RM, Huang EY, Roling D, Leyden JJ, Margolis DJ. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol 139(4);467-71 (2003 Apr).
  25. Margolis DJ, Bowe WP, Hoffstad O, Berlin JA. Antibiotic treatment of acne may be associated with upper respiratory tract infections. Arch Dermatol 141(9):1132-6 (2005 Sep).
  26. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 355(7):666-74 (2006 Aug).
  27. Ruhe JJ, Monson T, Bradsher RW, Menon A. Use of long-acting tetracyclines for methicillin-resistant Staphylococcus aureus infections: case series and review of the literature. Clin Infect Dis 40(10):1429-34 (2005 May).
  28. Eady EA, Cove JH, Layton AM. Is antibiotic resistance in cutaneous Propionibacteria clinically relevant? Implications of resistance for acne patients and prescribers. Am J Clin Dermatol 4(12):813-831 (2003).
  29. Eady EA. Bacterial resistance in acne. Dermatology 196(1):59-66 (1998).
  30. Wienbren MJ, Perinpanayagam RM, Camba L, et al. Convulsions and encephalopathy in a patient with leukemia after treatment with metronidazole. J Clin Pathol 38:1076 (1985).
  31. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Dermatol 102(4):443-5 (1980 Apr).
  32. Pye RJ, Burton JL. Treatment of rosacea by metronidazole. Lancet 1(7971):1211-2 (1976 Jun).
  33. Guilhou JJ, Meynadier J, Guilhou E, Malbos S. [Treatment of rosacea with metronidazole]. Nouv Presse Med 7(22):1960-1 (1978 Jun).
  34. Stieger M. [Metronidazole (Flagyl) as a therapy variant in “rosacea” and in “perioral dermatitis” (preliminary report)]. Z Hautkr 54(14):671-2 (1979 Jul).
  35. Nielsen P. A double-blind study of 1% metronidazole cream versus systemic oxytetracycline therapy for rosacea. Br J Dermatol 109(1):63-5 (1983 Jul).
  36. Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol 130(3):319-24 (1994 Mar).
  37. Erdogan FG, Yurtsever P, Aksoy D, Eskioglu F. Efficacy of low-dose isotretinoin in patients with treatment-resistant rosacea. Arch Dermatol 134(7):884-5 (1998 Jul).
  38. Nikolowski J, Plewig G. [Oral treatment of rosacea with 13- cis-retinoic acid]. Hautarzt 32(11):575-84 (1981 Nov).
  39. Irvine C, Kumar P, Marks R. Isotretinoin in the treatment of rosacea and rhinophyma. In: Marks R, Plewig G, eds. Acne and related disorders: proceedings of an international symposium. London: Martin Dunitz; p301-305 (1988).
  40. Schmidt JB, Raff M. [13-cis-retinoic acid: a new form of treatment for rosacea]. Wien Klin Wochenschr 94(5):115-8 (1982 Mar).
  41. Krause MH, Torricelli R, Kundig T, Trueb RM, Hafner J. [Dapsone in granulomatous rosacea]. Hautarzt 48(4):246-8 (1997 Apr).
  42. Bernstein JE, Soltani K. Alcohol-induced rosacea flushing blocked by naloxone. Br J Dermatol 107(1):59-61 (1982 Jul).
  43. Wollina U. The response of erythematous rosacea to ondansetron. Br J Dermatol 140(3):561-2 (1999 Mar).
  44. Bikowski JB, Goldman MP. Rosacea: where are we now? J Drugs Dermatol 3(3):251-61 (2004 May-Jun).
  45. Craige H, Cohen JB. Symptomatic treatment of idiopathic and rosacea-associated cutaneous flushing with propranolol. J Am Acad Dermatol 53(5):881-4 (2005 Nov).
  46. Wilkin J. Effect of subdepressor clonidine on flushing reactions in rosacea. Change in malar thermal circulation index during provoked flushing reactions. Arch Dermatol 119(3):211-4 (1983 Mar).
  47. Schmidt JB, Gebhart W, Raff M, Spona J. 13-cis-Retinoic acid in rosacea. Clinical and laboratory findings. Acta Derm Venereol 64(1):15-21 (1984).
  48. Plewig G, Nikolowski J, Wolff HH. Action of isotretinoin in acne rosacea and gram-negative folliculitis. J Am Acad Dermatol 6(4 Pt 2 Suppl):766-85 (1982 Apr).
  49. Hoting E, Paul E, Plewig G. Treatment of rosacea with isotretinoin. Int J Dermatol 25(10):660-3 (1986 Dec).
  50. Marsden JR, Shuster S, Neugebauer M. Response of rosacea to isotretinoin. Clin Exp Dermatol 9(5):484-8 (1984 Sep).
  51. Bartholomew RS, Reid BJ, Cheesbrough MJ, Macdonald M, Galloway NR. Oxytetracycline in the treatment of ocular rosacea: a double-blind trial. Br J Ophthalmol 66(6):386-8 (1982 Jun).
  52. Quarterman MJ, Johnson DW, Abele DC, Lesher JL Jr, Hull DS, Davis LS. Ocular rosacea. Signs, symptoms, and tear studies before and after treatment with doxycycline. Arch Dermatol 133(1):49-54 (1997 Jan).
]]> Oral Therapy for the Treatment of Rosacea https://www.skintherapyletter.com/family-practice/oral-therapy-fp/ Sun, 01 Oct 2006 21:12:29 +0000 https://www.skintherapyletter.com/?p=2708 Hilary Baldwin, MD
Department of Dermatology, State University of New York, Brooklyn, NY, USA

The Disease

Rosacea is a common condition that is prevalent worldwide. Its incidence is said to be higher in fair-skinned patients, however it is also seen in Asians and African-Americans. Rosacea occurs in both men and women most often after the age of 30 years. It is characterized by the presence of one or more of the following:

  • Central facial erythema and telangiectasias
  • Papules and pustules
  • Granulomatous nodules
  • Phyma formation
  • Ocular changes

Known triggers include UV exposure alcohol intake, spicy foods, and changes in temperature. However, sometimes flares and remissions occur with no rationale.

Classification

A National Rosacea Society committee has classified rosacea into four types based on predominant lesion morphology:

Erythematotelangiectatic

  • Flushing and persistent central facial erythema with telangiectasias. Central facial edema, stinging and burning of the skin, as well as dryness occurs.
  • Most difficult subtype to treat
    • Topical and oral therapy largely ineffective
    • Laser and light therapy most effective

Papulopustular

  • Papules and pustules often seen with persistent facial erythema.
  • Easiest subtype to treat
    • May respond to topical therapy
    • Oral agents more effective. May be used as first-line therapy, when topicals are ineffective or when it is important to speed up the response time.

Phymatous

  • Thickening of the skin, often presenting as rhinophyma
  • Irregular surface nodules, enlarged follicles and sebaceous appearance.
  • The chin, forehead, cheeks, and ears may be involved.
  • Isotretinoin can halt progression and shrink volume, but willnot eradicate completely.
  • Surgical/laser ablation necessary to eradicate existing lesions.

Ocular

  • Sensation of burning, grittiness, dryness, “foreign body sensation”, telangectasia of the sclera. Often, blepharitis, conjunctivitis, chalazions, styes present. Rarely, corneal manifestations (keratitis, infiltrates, and ulcers) may occur.
  • May respond to topical agents and eyelid hygiene.
  • Oral antibiotics readily resolve ocular rosacea.
  • May remit after discontinuation.

This system allows therapy evaluation based on similar lesion types; there are few medications or therapies that are significantly effective in more than one category.2

Pathophysiology

Inflammation plays an important role in lesion formation, however the etiology of rosacea is not well understood. It is generally believed that there is no microorganism involved in
the pathogenesis of rosacea.

Common denominators are believed to include inflammation and degradation of the dermal connective tissue; angiogenesis caused by the upregulation of proinflammatory cytokines; neutrophil chemotaxis; and the production of nitric oxide, reactive oxygen species, and matrix metalloproteinases.

In the face of an absence of a defined pathogenesis, treatment has traditionally been based on disease endpoints rather than targeting the underlying problems:

  • Inflammation is treated with anti-inflammatory agents.
  • Flushing is treated with vasoconstrictors.
  • Telangiectasias are treated with vascular lasers.
  • Pustules are treated with antibiotics without a target organism.

Vasoconstricting Agents

A number of agents have been reported anecdotally to reduce flushing including beta blockers in low doses,3 naloxone,4 ondansetron,5 aspirin,6 and serotonin reuptake inhibitors.7 Clonidine, at 0.05mg b.i.d., has also been reported to be effective for reducing flushing.8 While this suboptimal dose does not reduce blood pressure, it does lower baseline malar temperature by peripheral vasoconstriction.

Antibiotics

Oral antibiotics have been used off-label since the 1950s, but until May of 2006 none had been approved for treating this condition. Antibiotics are highly effective in papulopustular rosacea. However, justification for their use must be based on the recognition that there is little or no evidence demonstrating that rosacea is the result of a bacterial infection, and that reports of antibiotic resistance have been increasing over the past 10 years.

Tetracyclines

Because tetracyclines act to reduce inflammation, they are very effective for papulopustular acne and rosacea with substantial improvement seen after 3–4 weeks. However, relapses often occur after discontinuation.9 Tetracycline 250–1000mg q.d., doxycycline 100–200mg q.d., and minocycline 100–200mg q.d. are most commonly used. Using oral tetracyclines until clinical improvement is seen, then tapering to topical antibiotics, offers a way to maintain control and minimize relapses. However, we should not ignore the lessons learned from the use of long-term oral antibiotics and the resultant potential for bacterial resistance that have developed while treating other skin diseases.

Anti-inflammatory Dose Doxycycline – A New Treatment Option

The reason why tetracyclines are so effective for treating rosacea is likely due to their anti-inflammatory properties, not their role as antibiotics. In May 2006, the FDA approved the first oral prescription therapy for the treatment of inflammatory lesions
(papules and pustules) of rosacea in adult patients. This product, doxycycline (Oracea™), is a once daily 40mg capsule containing 30mg immediate-release and 10mg delayed-release beads. It allows for blood levels of doxycycline to stay within a narrow window: high enough to act as an anti-inflammatory medication, but well beneath the antimicrobial threshold. In two Phase III, double-blind, placebo-controlled clinical trials, patients receiving this drug experienced a 61% and 46% mean reduction in inflammatory lesions compared with 29% and 20%, respectively for placebo (p < 0.001 for each study).10 Side-effects were similar to placebo. Most notably, since the low dose exerts no selection pressure on bacteria, there were no yeast infections reported and continued use did not result in antibacterial resistance.

Erythromycin

Erythromycin is effective for treating papulopustular rosacea, but patients often complain of GI side-effects. Second generation macrolides have been shown to be more effective than erythromycin. However, resistance has been noted in patients in whom an infectious etiology cannot be demonstrated.

Metronidazole

Oral metronidazole, 200mg b.i.d., is often used for long-term treatment of rosacea in Europe.11,12 In a double-blind study, this drug was shown to be as effective as oxytetracycline 250mg. b.i.d.12 Side-effects include rare neuropathy and seizures. Alcohol abstinence is required during use.2

Isotretinoin

Isotretinoin is less commonly used for the treatment of rosacea than it is for acne vulgaris. By reducing the size and number of sebaceous glands, treatment-resistant rosacea patients who were given this drug had fewer papules and pustules, a decrease in erythema, and a reduction in nasal volume in rhinophyma.13,14 Unlike acne therapy where isotretinoin is generally curative, improvement in rosacea is often not as long-lasting. Erdogan, et al. used a low dose of 10mg daily for 4 months with a significant reduction in inflammatory lesions, erythema and telangiectasia at 9 weeks.15 Long-term, low-dose therapy is highly effective in controlling papulopustular rosacea. Use of isotretinoin in adult females of child-bearing potential requires birth control monitoring and extensive counseling because of its teratogenic properties. Distribution of isotretinoin is restricted by a special computer-based risk management program approved by the FDA, designed to further the public health goal to eliminate fetal exposure to isotretinoin. For more information see www.ipledgeprogram.com

Conclusion

Novel uses of old medications and new formulations of systemic medications have broadened the therapeutic armamentarium for treating rosacea patients. It is of primary importance to offer patients safe and effective therapies for this chronic and incurable condition, improving both the clinical and psychosocial consequences of rosacea.

Editor’s Commentary

As Dr. Baldwin points out, there is increasing concern in the medical community about prolonged ingestion of oral antibiotics due to bacterial resistance patterns. This concern has been further validated by the recent elucidation of the complete genome of P. acnes and the finding that this organism possesses inherent mechanisms enabling it to transfer a variety of resistance genes to other microbial species.1,2 Thus, while oral antibiotics have long been the mainstay of rosacea therapy, apprehension about microbiological consequences has tempered enthusiasm for this type of treatment. Complete alcohol avoidance required of those receiving oral metronidazole, and the myriad of potential adverse events associated with isotretinoin have likewise made these alternate agents difficult to administer.

Prior investigation of very low-dose doxycycline suggested efficacy for rosacea.3 Thus, the recent FDA approval and commercial release of a subantimicrobial and purely antiinflammatory dose of this drug in a convenient once-daily formulation might, indeed, have several advantages, i.e. no development of resistance and fewer or no problems with yeast infections. However, comparative clinical trials to demonstrate such advantages have not been done. The goal of such therapy is to administer an antibiotic moiety in a dosage formulation that preserves anti-inflammatory properties but eliminates antiinfective properties, thereby avoiding ecologic pressure on bacteria to become resistant. The exact mechanism(s) by which anti-inflammatory doxycycline improves rosacea is uncertain. Suppression of cytokine and chemokine elaboration, inhibition of matrix metalloproteinases, decreased vasodilatation and other properties have been described.4 This formulation is also notable for its lack of photosensitivity, and for the minimal risk of secondary candidiasis and troublesome side-effects traditionally associated with the tetracycline family.

Another promising oral therapy for rosacea involves the use of an oral blend of nicotinamide and zinc (Nic/Zn).5 The formulation tested contained nicotinamide 750mg and zinc 25mg as active ingredients, along with small amounts of copper and folic acid.
Nearly 80% of subjects reported a patient global evaluation of “moderately” or “much” better when compared with baseline after 8 weeks. Similar to anti-inflammatory dose doxycycline, the precise mechanism of action is uncertain, but suppression of vascular permeability, reduced accumulation of inflammatory cells, depressed mast cell degranulation, and stabilization of lysosomes have all been implicated.6 If larger scale and longer duration studies verify the aforementioned data, then Nic/Zn may further expand our oral therapeutic options.

Rosacea patients often exhibit “irritable” skin, which may be hyper-reactive to a host of topical medications as well as to overthe- counter skin care products.7 Oral therapy may be mandatory for such individuals, and transitioning to topical maintenance should be deferred until significant improvement occurs.

References

  1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 46(4):584-7 (2002 Apr).
  2. Baldwin HE. Oral therapy for rosacea. J Drugs Dermatol 5(1):16-21 (2006 Jan).
  3. Rebora A. The management of rosacea. Am J Clin Dermatol 3(7):489-96 (2002).
  4. Bernstein J, Soltani K. Alcohol-induced rosacea flushing blocked by naloxone. Br J Dermatol 107(1):59-61 (1982 Jul).
  5. Wollina U. The response of erythematous rosacea to ondansetron. Br J Dermatol 140(3):561-2 (1999 Mar).
  6. Bikowski JB, Goldman MP. Rosacea: where are we now? J Drugs Dermatol 3(3):251-61 (2004 May-Jun).
  7. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad. Dermatol 51(4):499-512 (2004 Oct).
  8. Wilkin JK. Effect of subdepressor clonidine on flushing reactions in rosacea. Change in malar thermal circulation index during provoked flushing reactions. Arch Dermatol 119(3):211-4 (1983 Mar).
  9. Sneddon I. A clinical trail of tetracycline in rosacea. Br J Dermatol 78(12):649-52 (1966 Dec).
  10. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust 169(5):259-61 (1998 Sep).
  11. Ross J, Snelling A, Carnegie E, et al. Antibiotic resistant acne: lessons from Europe. Br J Dermatol 148(3):467-78 (2003 Mar).
  12. Espersen F. Resistance to antibiotics used in dermatological practice. Br J Dermatol 139 Suppl 53:4-8 (1998 Dec).
  13. Data on file, CollaGenex Pharmaceuticals.
  14. Pye RJ, Burton JL. Treatment of rosacea by metronidazole. Lancet 1(7971):1211-2 (1976 Jun 5).
  15. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Clin Pharmacol 102(4):443-5 (1980 Apr).
  16. Nikolowski J, Plewig G. [Oral treatment of rosacea with 13-cis-retinoic acid]. Hautarzt 32(11):575-84 (1981 Nov).
  17. Schmidt JB, Gebhart W, Raff M, Spona J. 13-cis-retinoic acid in rosacea. Clinical and laboratory findings. Acta Derm Venereol 64(1):15-21 (1984).
  18. Erdogan FG, Yurtsever P, Aksoy D, Eskioglu F. Efficacy of low-dose isotretinoin in patients with treatment-resistant rosacea. Arch Dermatol 134(7):884-5 (1998 Jul).

Editorial References

  1. Bruggemann H, Henne A, Hoster F, et al. The complete genome sequence of Propionibacterium acnes, a commensal of human skin. Science 305(5684):671-3 (2004 Jul 30).
  2. Bruggemann H. Insights in the pathogenic potential of Propionibacterium acnes from its complete genome. Semin Cutan Med Surg 24(2):67-72 (2005 Jun).
  3. Berman B, Zell D. Subantimicrobial dose doxycycline: a unique treatment for rosacea. Cutis 75(4 Suppl):19-24 (2005 Apr).
  4. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 54(2):258-65 (2006 Feb).
  5. Niren NM, Torok HM. The Nicomide Improvement in Clinical Outcomes Study (NICOS): results of an 8-week trial. Cutis 77(1 Suppl):17-28 (2006 Jan).
  6. Fivenson DP. The mechanisms of action of nicotinamide and zinc in inflammatory skin disease. Cutis 77(1 Suppl):5-10 (2006 Jan).
  7. Draelos ZD. Assessment of skin barrier function in rosacea patients with a novel 1% metronidazole gel. J Drugs Dermatol 4(5):557-62 (2005 Sep-Oct).
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