Chapter 206 Rosacea
Diagnostic Summary
• Chronic acneiform eruption on the face of middle-aged and older adults associated with facial flushing and telangiectasia.
• The acneiform component is characterized by papules, pustules, and seborrhea; the vascular component by erythema and telangiectasia; and the glandular component by hyperplasia of the soft tissue of the nose (rhinophyma).
• The primary involvement occurs over the flush areas of the cheeks and nose.
General Considerations
Rosacea is a common, chronic, progressive inflammatory skin disorder in which the nose and cheeks are abnormally red and may be covered with pimples similar to those seen in acne (see Chapter 141). Rosacea was originally called “acne rosacea” because its inflammatory papules and pustules so closely mimic those of acne vulgaris. Unlike acne vulgaris, whose etiology is based on the interaction of abnormal keratinization, increased sebum production, and bacterially induced inflammation, rosacea’s inflammation is vascular in nature. Rosacea generally occurs in patients between the ages of 25 and 70 years, and it is much more common in people with fair complexions. Women are three times more likely than men to have rosacea, although the disease is generally more severe in men. At least 13 million Americans are known to be affected.1,2
Rosacea is divided into three stages, but because progression does not necessarily occur, rosacea is also often divided into four specific subtypes (erythematous telangiectatic, papulopustular, phymatous, and ocular)1,3,4:
• Stage I: In this stage, or erythematous telangiectatic rosacea, erythema triggered by hot beverages, spicy foods, and alcohol may persist for hours; telangiectasias are noticeable on the central third of the face; and burning, stinging, and itching after the application of cosmetics, fragrances, and sunscreens become a major complaint.
• Stage II: In this stage, or papulopustular rosacea, the hallmarks are inflammatory papules and pustules. Flushing, telangiectasias, and seborrhea increase, and minimal enlargement of facial pores becomes obvious.
• Stage III: A small number of patients progress to this stage, or phymatous rosacea, which exhibits deep inflammatory nodules, large telangiectatic vessels, markedly dilated facial pores, sebaceous gland hyperplasia, and tissue hyperplasia, especially of the nose (rhinophyma).
It is important to point out that what differentiates the flushing that rosacea patients experience is its prolonged nature and intensity. Many people without rosacea experience evanescent flushing in response to embarrassment, exercise, or hot environments. However, although evanescent flushing episodes last from several seconds to few minutes, the flushing that the typical rosacea patient describes lasts longer than 10 minutes and is more red than pink, with an accompanying burning or stinging sensation. The stimuli that bring on such flushing in rosacea patients may be acutely felt emotional stress, hot drinks, alcohol, spicy foods, exercise, cold or hot weather, or hot baths or showers. However, many times the episodes are without known stimuli.
Etiology
There is also emerging evidence for a role for Helicobacter pylori in rosacea (discussed below as well). It is known that H. pylori infection increases several vasoactive substances, such as histamines, prostaglandins, and leukotrienes, and various cytokines. However, these vascular mediators are found only with H. pylori strains that also produce a specific cytotoxin, cytotoxin-associated gene A (CagA). The presence of H. pylori capable of producing this cytotoxin may be more important in the etiology of rosacea than other strains. When the presence of CagA was assessed in 60 rosacea patients and compared with age- and gender-matched control subjects with nonulcer dyspepsia, researchers found that when infected with H. pylori, 67% of rosacea patients versus only 32% of controls had positive findings for CagA. In addition, these patients had elevated systemic levels of tumor necrosis factor-α and interleukin 8. After the eradication of H. pylori infection in the rosacea patients, symptoms disappeared in almost all of them (51 of 53) and tumor necrosis factor-α and interleukin 8 levels normalized.7,8
Therapeutic Considerations
Hypochlorhydria
Gastric analysis of patients with rosacea has led to the postulate that it is the result of hypochlorhydria.1 Psychological factors—such as worry, depression, and stress—often reduce gastric acidity.2 Hydrochloric acid supplementation results in marked improvement in those patients with rosacea who have achlorhydria or hypochlorhydria.6,7 Patients with rosacea have also been shown to have diminished secretion of lipase (although bicarbonate and chymotrypsin secretion were normal) and to benefit from pancreatic supplementation.8
Helicobacter pylori
Given the high incidence of hypochlorhydria, it is perhaps not surprising that a high incidence of H. pylori infection in the stomach has also been found in patients with rosacea.9 In a pilot study, H. pylori was found in 46 of 94 patients with rosacea, 38 of 88 patients with other inflammatory diseases, and 5 of 14 patients without an inflammatory disease. The researchers believed that the flushing reaction in rosacea is caused by gastrin or vasoactive intestinal peptides. They also quoted an Irish study that found that 19 of 20 patients with acne rosacea tested positive for H. pylori.
Another study that evaluated histologic sections of the stomach mucosa found that 84% of 31 patients were H. pylori–positive.10 Interestingly, 20% of the patients who tested histologically positive also tested serologically negative for the organism. The consistency between clinical success in the treatment of rosacea with metronidazole and the abatement of H. pylori isolates and serologic results after treatment provides additional evidence suggesting an etiologic relationship between rosacea and H. pylori infection. However, it is also possible that H. pylori is simply associated with rosacea and is not a causative factor per se, because patients with rosacea may have rates of H. pylori infection similar to those in healthy subjects.11 Interestingly, patients with rosacea complain significantly more frequently of “indigestion” and use more antacids than the general population.11
A large number of studies have now confirmed a strong association between H. pylori and rosacea, with a 2003 study showing a correlation between the severity of rosacea and the level of infection.12
B Vitamins
The administration of large doses of B vitamins has been shown to be quite effective,13 with riboflavin appearing to be the key factor. For example, researchers on B vitamins were able to infect the skin of riboflavin-deficient rats with the mite Demodex folliculorum but not the skin of normal rats.14 This mite was once considered a causative factor in rosacea and may still be a factor in some patients, especially those with more granulomatous lesions. Evidence suggests that a delayed hypersensitivity reaction in follicles is triggered by D. folliculorum antigens, stimulating the progression of the affection to the papulopustular stage.15
Although B vitamins are important for patients with rosacea, care must be exercised because some patients’ rosacea may be aggravated by large doses of these common nutrients. There is a case report of a 53-year-old woman who presented to a dermatology clinic with a 9-month history of a facial eruption resembling acne rosacea. Treatment with oral hydroxychloroquine, ibuprofen, terfenadine, prednisone, erythromycin, and tetracycline had been tried during the 9 months without success. Topical desoximetasone, hydrocortisone, and cosmetic elimination also yielded no benefit. A patch test showed a positive reaction to nickel. The eruption began at the time of a personal stress as the patient was going through a marital separation. To help with her stress, the patient began taking 100 mg/day of pyridoxine and 100 mg/day of vitamin B12. Discontinuation of the vitamins resulted in a dramatic improvement; with rechallenge, the condition reappeared. The investigators noted that inflammation and exacerbations of acne related to vitamins B2, B6, and B12 have been reported in the European literature.16
Zinc
Zinc supplementation has been shown to be helpful in acne vulgaris and may also be effective in acne rosacea. To test this hypothesis, 25 patients with rosacea were evaluated and given a clinical score, then randomly allocated to receive either zinc (23 mg from zinc sulfate) or identical placebo capsules three times daily. After 3 months, the patients crossed over. A total of 19 patients completed the study. In the group started on zinc, the scores before therapy ranged from 5 to 11. The mean started to decrease directly after the first month of therapy with zinc sulfate to a significantly lower level. After shifting to placebo treatment, the mean started to rise gradually in the fifth month but remained significantly lower than the levels before therapy. In the group started on placebo, the score before therapy ranged from 5 to 9. The mean remained high in the first 3 months of therapy while the patients were on placebo. After shifting to zinc sulfate, the mean started to decrease after the fourth month to significantly low levels. No important side effects were reported apart from mild gastric upset in 3 (12%) patients on zinc sulfate. The authors concluded that zinc is a good option in the treatment of rosacea because it was found to be safe and effective and had no significant side effects.17
Topical Azelaic Acid
Topical application of azelaic acid (AzA) appears to be extremely effective in papulopustular rosacea. Initially, AzA was released in a 20% cream formulation and was shown in this vehicle to be effective in the treatment of mild to moderate rosacea. A 15% gel formulation of AzA vastly improved the delivery of AzA and has been proved to be superior in head-to-head studies to the 20% AzA cream. It is and equally as effective as metronidazole cream or gel.18–20 In a meta-analysis of five double-blind trials involving topical azelaic acid (cream or gel) for the treatment of rosacea compared with placebo or other topical treatments, four of five studies demonstrated significant decreases in mean inflammatory lesion count and erythema severity after treatment with AzA compared with placebo, and AzA was found to be equal to metronidazole in papulopustular rosacea. However, no significant decrease in the severity of telangiectasia occurred in any treatment group.19
Therapeutic Approach1. 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. 2002;46:584–587.
2. Blount B.W., Pelletier A.L. Rosacea: a common, yet commonly overlooked, condition. Am Fam Physician. 2002;66:435–440.
3. Buechner S.A. Rosacea: an update. Dermatology. 2005;210(2):100–108.
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5. Szlachcic A., Sliwowski Z., Karczewska E., et al. Helicobacter pylori and its eradication in rosacea. J Physiol Pharmacol. 1999;50:777–786.
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7. Poole W. Effect of vitamin B complex and S-factor on acne rosacea. S Med J. 1957;50:207–210.
8. Barba A., Rosa B., Angelini G., et al. Pancreatic exocrine function in rosacea. Dermatologica. 1982;165:601–606.
9. Baker B. Helicobacter pylori strikes again: this time it’s rosacea. Family Practice News. 6, 1994; Sept 1.
10. Rebora A., Drago F., Parodi A. May Helicobacter pylori be important for dermatologists? Dermatology. 1995;191:6–8.
11. Sharma V.K., Lynn A., Kaminski M., et al. A study of the preva-lence of Helicobacter pylori infection and other markers of upper gastrointestinal tract disease in patients with rosacea. Am J Gastroenterol. 1998;93:220–222.
12. Diaz C., O’Callaghan C.J., Khan A., et al. Rosacea: a cutaneous marker of Helicobacter pylori infection? Results of a pilot study. Acta Derm Venereol. 2003;83:282–286.
13. Tulipan L. Acne rosacea: a vitamin B complex deficiency. N Y State J Med. 1929;29:1063–1064.
14. Johnson L., Eckardt R. Rosacea keratitis and conditions with vascularization of the cornea treated with riboflavin. Arch Ophth. 1940;23:899.
15. Georgala S., Katoulis A.C., Kylafis G.D., et al. Increased density of Demodex folliculorum and evidence of delayed hypersensitivity reaction in subjects with papulopustular rosacea. J Eur Acad Dermatol Venereol. 2001;15:441–444.
16. Sherertz E. Acneiform eruption due to ‘megadose’ vitamins B6 and B12. Cutis. 1991;48:119–120.
17. Sharquie K.E., Najim R.A., Al-Salman H.N. Oral zinc sulfate in the treatment of rosacea: a double-blind, placebo-controlled study. Int J Dermatol. 2006;45(7):857–861.
18. Elewski B., Thiboutot D. A clinical overview of azelaic acid. Cutis. 2006;77(suppl 2):12–16.
19. Liu R.H., Smith M.K., Basta S.A., et al. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. Arch Dermatol. 2006;142(8):1047–1052.
20. Czernielewski J., Liu Y. Comparison of 15% azelaic acid gel and 0.75% metronidazole gel for the topical reatment of papulopustular rosacea. Arch Dermatol. 2004;140(10):1282–1283.
