[8] Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009; 91(2):456–88. Doi:

[9] Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R. Diagnosis and treatment of polycystic ovary syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013; 98(12):4565–92. Doi: 10.1210/jc.2013-2350. [10] Housman E, Reynolds RV. Polycystic ovary syndrome: a review for dermatologists: Part I. Diagnosis and manifestations. J Am Acad Dermatol. 2014; 71(5):847. Doi: 10.1016/j.

[11] Schmidt TH, Shinkai K. Evidence-based approach to cutaneous hyperandrogenism in women. J Am Acad Dermatol. 2015; 73(4):672–90. Doi: 10.1016/j.jaad.2015.05.026.

[12] Lee AT, Zane LT. Dermatologic manifestations of polycystic ovary syndrome. Am J Clin

[13] Schmidt TH, Khanijow K, Cedars MI, Huddleston H, Pasch L, Wang ET, et al. Findings and systemic associations in women with polycystic ovary syndrome. JAMA Dermatol.

[14] Buzney E, Sheu J, Buzney C, Reynolds RV. Polycystic ovary syndrome: a review for dermatologists: Part II. Treatment. J Am Acad Dermatol. 2014; 71(5):859. Doi: 10.1016/j.

[15] Dédjan AH, Chadli A, El Aziz S, Farouqi A. Hyperandrogenism-Insulin resistance-acanthosis nigricans syndrome. Case Rep Endocrinol. 2015; 193097. Doi: 10.1155/2015/193097.

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[42] Calderón-Castrat X, Bancalari-Diaz D, Román-Curto C, Romo-Melgar A, Amorós-Cerdán D2, A Alcaraz-Mas L2, et al. PSTPIP1 Gene mutation in a pyoderma gangrenosum, acne and suppurative hidradenitis (PASH) Syndrome. Br J Dermatol. 2016; 175(1):194–8. Doi: 10.1111/bjd.14383.

[31] Yamamoto T. Pustulotic arthro-osteitis associated with palmoplantar pustulosis. J

[32] Hurtado-Nedelec M, Chollet-Martin S, Nicaise-Roland P, Grootenboer-Mignot S, Ruimy R, Meyer O, et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford). 2008;

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[35] Firinu D, Murgia G, Lorrai MM, Barca MP, Peralta MM, Manconi PE, et al. Biological treatments for SAPHO syndrome: an update. inflamm allergy drug targets. 2014;

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**Chapter 12 Provisional chapter**

#### **Acne Conglobata Acne Conglobata**

Fatma Pelin Cengiz and Funda Kemeriz Fatma Pelin Cengiz and Funda Kemeriz

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67044

### **Abstract**

Acne conglobata is the severe form of acne, located on the face, back, and chest with large, painful, pus-filled cysts deep in the skin. The abscesses and sinuses result in pain, inflammation, and hypertrophic and atrophic scars. In this chapter, we aimed to clarify the pathways of acne conglobata and review the treatment options based on the literature.

**Keywords:** acne, nodule, severe, scar, treatment

### **1. Introduction**

Acne conglobata (AC) is a severe chronic inflammatory disorder characterized by the presence of comedones, cysts, and scars on the face, back, and chest. It affects deep skin tissue and can result in swelling, bleeding, pain, and scarring. The clinical effects of treatment options for acne conglobata are often unsatisfactory because of a long course of therapy, side effects, the high rate of recurrence, and failure to prevent scar formation. Therefore, we aim to discuss the treatment options based on the literature in this chapter.

### **2. Clinical presentation**

Acne conglobata (AC) is the uncommon and severe form of acne, characterized by large, tender nodules; draining sinuses; and interconnecting abscesses with seropurulent discharge. These lesions are generally located on the back, chest, and face. Healing of the nodules, abscesses usually causes hypertrophic and atrophic scars. Besides, chronic scars of AC may result in squamous cell carcinoma [1]. This disease is common in males more than females. The disease affects young adults and adolescents more frequently than elder people.

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acne conglobata may develop owing to acute flare of existing acne, or it may occur as the rebound of acne that has been latent for a long time.

Synovitis, pustulosis, acne conglobata, hyperostosis, and osteitis are clinically specific inflammatory disorders that may be seen barely in the same patient in a syndrome known as SAPHO syndrome [2].

Acne conglobata may also be associated with the PAPA syndrome, which consists of pyogenic arthritis, acne conglobata, and pyoderma gangrenosum [3].

The primary causes of acne conglobata are still unknown. The HLA-A and HLA-B phenotypes were evaluated in six patients with acne conglobata and hidradenitis suppurativa, in four of whom had HLA-B7 cross-reacting antigens and all had HLA-DRw4 [4]. Other causes include using anabolic steroids, withdrawal of testosterone therapy, nutrition or medications that contain bromine or iodine, aromatic hydrocarbons, and adrenal gland tumors which release large amount of androgens [5].

Acne conglobata can be malodorous, and patients may eliminate themselves from community. Severe scarring can lead to psychological problems, such as anxiety, depression, and low self-esteem in many patients.

### **3. Treatment**

Isotretinoin (13-cis retinoic acid) is an oral pharmaceutical drug primarily preferred in the treatment of severe nodular acne. The adverse effects are the flare of acne, cheilitis, xerosis, an increased susceptibility to sunburn, muscle aches, myalgias, and headaches. The patients need to be monitored for blood lipids and liver enzymes especially closely. It has an X category for pregnancy.

Isotretinoin, generally combined with prednisone, is the approved therapy for severe acne conglobata. The recommended dosage of isotretinoin is 0.5–1.0 mg/kg/day for at least 4–5 months [6].

Gollnick et al. compared the effectiveness and safety profile of combined azelaic acid cream plus oral minocycline with oral isotretinoin in severe acne. Their study involved 85 patients with nodular papulopustular acne or acne conglobata who were treated for 6 months. AA cream was applied twice daily, and minocycline was taken twice daily in a dose of 50 mg (daily 100 mg). The doses of isotretinoin were 0.8 mg/kg for the first month, 0.7 mg/kg for the second month, 0.5–0.7 mg/kg for the third month, and 0.5 mg/kg for the fourth to sixth months per day [7].

In the 6-month course, 50 patients in the combined therapy group achieved median reduction of facial comedones, 70%; of papules and pustules, 88%; and of deep inflammatory acne lesions, 100%, while 35 patients in the oral isotretinoin group achieved reduction of comedones, 83%; of papules and pustules, 97%; and of deep inflammatory acne lesions, 100%. Overall, oral isotretinoin was more effective than the combined treatment. The local side effects observed under the combination of AA and minocycline were significantly lower than that seen with isotretinoin (36.5% versus 65.7%). The incidence of systemic side effects was lower under the combined therapy than under isotretinoin (8% versus 14.3%). They suggested that the combination of topical 20% AA cream and oral minocycline is a highly effective treatment in severe forms of acne, and it is better tolerated and associated with fewer risks than oral isotretinoin [7].

Acne conglobata may develop owing to acute flare of existing acne, or it may occur as the

Synovitis, pustulosis, acne conglobata, hyperostosis, and osteitis are clinically specific inflammatory disorders that may be seen barely in the same patient in a syndrome known as SAPHO

Acne conglobata may also be associated with the PAPA syndrome, which consists of pyogenic

The primary causes of acne conglobata are still unknown. The HLA-A and HLA-B phenotypes were evaluated in six patients with acne conglobata and hidradenitis suppurativa, in four of whom had HLA-B7 cross-reacting antigens and all had HLA-DRw4 [4]. Other causes include using anabolic steroids, withdrawal of testosterone therapy, nutrition or medications that contain bromine or iodine, aromatic hydrocarbons, and adrenal gland tumors which

Acne conglobata can be malodorous, and patients may eliminate themselves from community. Severe scarring can lead to psychological problems, such as anxiety, depression, and low

Isotretinoin (13-cis retinoic acid) is an oral pharmaceutical drug primarily preferred in the treatment of severe nodular acne. The adverse effects are the flare of acne, cheilitis, xerosis, an increased susceptibility to sunburn, muscle aches, myalgias, and headaches. The patients need to be monitored for blood lipids and liver enzymes especially closely. It has an X category for

Isotretinoin, generally combined with prednisone, is the approved therapy for severe acne conglobata. The recommended dosage of isotretinoin is 0.5–1.0 mg/kg/day for at least 4–5 months [6].

Gollnick et al. compared the effectiveness and safety profile of combined azelaic acid cream plus oral minocycline with oral isotretinoin in severe acne. Their study involved 85 patients with nodular papulopustular acne or acne conglobata who were treated for 6 months. AA cream was applied twice daily, and minocycline was taken twice daily in a dose of 50 mg (daily 100 mg). The doses of isotretinoin were 0.8 mg/kg for the first month, 0.7 mg/kg for the second month, 0.5–0.7 mg/kg for the third month, and 0.5 mg/kg for the fourth to sixth months

In the 6-month course, 50 patients in the combined therapy group achieved median reduction of facial comedones, 70%; of papules and pustules, 88%; and of deep inflammatory acne lesions, 100%, while 35 patients in the oral isotretinoin group achieved reduction of comedones, 83%; of papules and pustules, 97%; and of deep inflammatory acne lesions, 100%. Overall, oral isotretinoin was more effective than the combined treatment. The local side effects observed under the combination of AA and minocycline were significantly lower than that seen with

rebound of acne that has been latent for a long time.

arthritis, acne conglobata, and pyoderma gangrenosum [3].

release large amount of androgens [5].

self-esteem in many patients.

**3. Treatment**

pregnancy.

per day [7].

syndrome [2].

176 Acne and Acneiform Eruptions

TNF-α is one of the important cytokines involved in the pathogenesis of acne conglobata. Graham et al. found that *Propionibacterium acnes* stimulated keratinocytes to produce interleukin (IL)-1α, IL-8, and TNF-α [8]. Caillon et al. showed that levels of TNF-α and IL-8 secretion in peripheral blood mononuclear cells were significantly higher than in patients with acne vulgaris than controls [9].

As a result of the role of the TNF-α in proliferation of the immune response with the inflammatory infiltrate including neutrophils, lymphocytes, and histiocytes, it was hypothesized that acne conglobata might benefit from anti-inflammatory therapy. Notable results with adalimumab have been reported for the treatment of dissecting cellulitis of the scalp and hidradenitis suppurativa [10, 11].

On the other hand, anti-TNF therapy can stimulate paradoxical inflammatory skin conditions, of which the most frequent is a psoriasiform eruption. There have been three patients with Crohn's disease, psoriasis vulgaris, and rheumatoid arthritis who were treated with adalimumab in the literature. As a result of adalimumab therapy, acneiform eruptions were occurred in these cases [12]. It was suggested that genetic predisposition and overlap with the primary inflammatory disease and autoimmune sensitivity induced interferon-α and cytokine imbalance [13].

Given the previous success reported with hidradenitis suppurativa, Shirakawa et al. considered infliximab therapy in a patient with acne conglobata and rheumatoid arthritis. The patient had experienced flares of the acne conglobata and side effects of oral isotretinoin. The patient was started on the 300 mg (3 mg/kg) of infliximab for the treatment of rheumatoid arthritis. The same dose was repeated at weeks 2 and 6. They observed a significant improvement in the size and number of his cystic lesions after the third dose. Subsequently, the same doses were repeated every 8 weeks and continued for at least 6 months. The patient had achieved a decrease in the number of lesions and pain symptoms [14].

Yiu et al. reported a patient with recalcitrant acne conglobata, who was commenced on subcutaneous adalimumab at 80 mg loading dose, followed by 40 mg every other week, in combination with 15 mg prednisolone. Most of the inflammatory nodules resolved within 4 weeks of commencing treatment with adalimumab, and this response was maintained at the 12-week follow-up [15].

Sand et al. reported another unresponsive patient to doxycycline, oral isotretinoin, combination of prednisolone and isotretinoin, and combination of isotretinoin and dapsone. They initiated monotherapy with adalimumab using an initial loading dose of 80 mg, followed by 40 mg monthly twice. They observed a significant decrease in the size and degree of inflammation of the nodular lesions 4 weeks after initial treatment and disappearance of all nodular lesions after 12 weeks of therapy. The patient had received continuous monotherapy with adalimumab, 40 mg, twice monthly for a total of 12 months, and no recurrence of acne lesions had appeared [16].

Vega et al. reported a 14-year-old adolescent with recalcitrant acne conglobata on the face, neck, and upper chest. That patient had experienced acne fulminans and flares of severe acne while on the isotretinoin and prednisone therapies. Then, twice weekly injections of etanercept 50 mg combined with oral isotretinoin 40 mg/d were started. They observed a clear improvement after 2 months of treatment. The patient had completed the isotretinoin cycle of 9600 mg over 8 months. They continued etanercept (50 mg/wk) 3 months more, and the treatment was completed after 1 year. The patient had experienced no relapse [17].

Schuttelaar et al. reported another young patient with severe acne unresponsive to other treatments. They started him on infliximab 5 mg/kg intravenously at 8-week interval. A total of eight infusions were administered. After three infusions, they did not observe neither new lesions nor activation of the old lesions. After 4 months, they successfully treated negligible relapse of the acne with intralesional corticosteroids. No relapse was occurred at 1-year follow-up [18].

Electron beam processing has the ability to break the chains of DNA in living organisms and results in local destruction of cells. [19, 20]. The electron beam therapy delivers radiation primarily to the superficial skin lesions and spares the deeper tissues from radiation. Electron beam radiation has been used in the treatment of mycosis fungoides, basal cell carcinoma, squamous cell carcinoma, and AIDS-related molluscum contagiosum lesions and Kaposi's sarcoma [19–23]. The acute side effects of electron beam radiation are fatigue, itching, tanning, and burns. Long-term side effects include dry skin, decreased sweating, skin color changes, loss of scalp hair, and the development of dilated blood vessels [24].

Myers et al. reported a 53-year-old patient with acne conglobata and hidradenitis suppurativa who is unresponsive to oral doxycycline, oral ampicillin, triamcinolone intralesional injections, topical benzoyl peroxide 5% wash, clindamycin phosphate, 1% topical solution, betamethasone valerate 0.1% cream, and cyclosporine 5 mg/kg per day. After these therapies, the patient was started a total of eight treatments of modern external beam radiation over 2 weeks localized to the bilateral mandibular cheeks. Electron energies were 9 MeV. Daily fraction sizes were 2.5 Gy for a total of 20 Gy to each side of the face. Three weeks after radiation, the patient reported subjective improvement in cyst size, cyst drainage, pain, and self-esteem. He had no significant xerosis or pigmentary abnormalities status after radiation. The patient had experienced no relapse at 5-month follow-up [25].

Photodynamic therapy (PDT) is a kind of phototherapy that induces selective cytotoxic destruction by the activation of a nontoxic light-sensitive compound with light. Up-to-date PDT has been used for several dermatologic diseases, such as psoriasis, cutaneous T-cell lymphoma, and warts [26]. PDT with topical 5-ALA damages sebaceous glands, inhibits sebum production, kills *Propionibacterium acnes*, and obstructs the follicular openings [27]. The advantages of PDT include rapid efficacy, short recovery time, less destruction, and pain. Despite of these advantages, the local side effects of PDT are erythema, skin peeling, pain, burning, stinging, exfoliation, and post-inflammatory hyperpigmentation [27, 28]. It is obligatory to photoprotect after treatment for phototoxicity [29].

Yang et al. investigated the clinical effects of photodynamic therapy with topical 5-aminolevulinic acid for facial acne conglobata. They included 75 patients with facial acne conglobata. They divided the patients into photodynamic therapy (PDT) group with topical 5% aminolevulinic acid and red light for three times in a month and control group (n = 40) with the Chinese herbal medicine mask plus red light once a week. The patients were also administered topical metronidazole, oral doxycycline, viaminate, and zinc gluconate. Efficacy was assessed according to symptom score, cure rate, and response rate, 2 weeks after the final therapy course, and time points for assessment were selected as day 0, day 10, and day 20; day 34 for the treatment group; and day 7, day 14, day 21, and day 35 for the control group. They observed that PDT was more effective for pustules and papules than control group. The PDT group was associated with a higher cure rate, a lower symptom score, and response rate than the control group. They didn't observe systemic side effects. The erythematous swelling, increased number of cysts, pigmentation, and severe pain were the local side effects which they observed in the treatment group with PDT. They demonstrated that the treatment of acne conglobata with PDT is associated with a high cure rate, short treatment period, few side effects, and reduced scar formation [30].

Hasegawa et al. achieved to treat a case of acne conglobata by CO(2) laser ablation to remove the top of the sinuses and their tracts. After laser ablation, topical tretinoin therapy was also started simultaneously to prevent the appearance of new acne lesions. They proposed the CO(2) laser ablation with topical tretinoin as a powerful treatment option for acne conglobata [31]. They also reported another acne conglobata case, which they successfully treated by fractional laser after CO laser abrasion of cysts combined with topical tretinoin [32].

Liu et al. compared the effectiveness of encircling acupuncture combined with venesection and cupping and oral isotretinoin. A total of 26 acupuncture patients had their acupuncture courses once daily; venesection and cupping were applied twice a week. Patients of isotretinoin group were treated with oral isotretinoin 20 mg/d. The duration of study was 4 weeks. After 4 weeks, in acupuncture group and Western medicine group, 3 (11.5%) and 4 (15.4%) cases experienced remarkable relief in their signs, 14 (53.8%) and 11 (42.3%) had marked improvement, 6 (23.1%) and 7 (26.9%) had improvement, and 3 (11.5%) and 4 (15.4%) failed, with the effective rates being 88.5% and 84.6%, respectively. Overall, they didn't observe any significant difference between acupuncture and oral isotretinoin (*P* > 0.05). In terms of lowering serum IL-6 content, acupuncture was found superior than oral isotretinoin (*P* < 0.05) [33].

### **Author details**

Vega et al. reported a 14-year-old adolescent with recalcitrant acne conglobata on the face, neck, and upper chest. That patient had experienced acne fulminans and flares of severe acne while on the isotretinoin and prednisone therapies. Then, twice weekly injections of etanercept 50 mg combined with oral isotretinoin 40 mg/d were started. They observed a clear improvement after 2 months of treatment. The patient had completed the isotretinoin cycle of 9600 mg over 8 months. They continued etanercept (50 mg/wk) 3 months more, and the

Schuttelaar et al. reported another young patient with severe acne unresponsive to other treatments. They started him on infliximab 5 mg/kg intravenously at 8-week interval. A total of eight infusions were administered. After three infusions, they did not observe neither new lesions nor activation of the old lesions. After 4 months, they successfully treated negligible relapse of the acne with intralesional corticosteroids. No relapse was occurred at 1-year

Electron beam processing has the ability to break the chains of DNA in living organisms and results in local destruction of cells. [19, 20]. The electron beam therapy delivers radiation primarily to the superficial skin lesions and spares the deeper tissues from radiation. Electron beam radiation has been used in the treatment of mycosis fungoides, basal cell carcinoma, squamous cell carcinoma, and AIDS-related molluscum contagiosum lesions and Kaposi's sarcoma [19–23]. The acute side effects of electron beam radiation are fatigue, itching, tanning, and burns. Long-term side effects include dry skin, decreased sweating, skin color changes,

Myers et al. reported a 53-year-old patient with acne conglobata and hidradenitis suppurativa who is unresponsive to oral doxycycline, oral ampicillin, triamcinolone intralesional injections, topical benzoyl peroxide 5% wash, clindamycin phosphate, 1% topical solution, betamethasone valerate 0.1% cream, and cyclosporine 5 mg/kg per day. After these therapies, the patient was started a total of eight treatments of modern external beam radiation over 2 weeks localized to the bilateral mandibular cheeks. Electron energies were 9 MeV. Daily fraction sizes were 2.5 Gy for a total of 20 Gy to each side of the face. Three weeks after radiation, the patient reported subjective improvement in cyst size, cyst drainage, pain, and self-esteem. He had no significant xerosis or pigmentary abnormalities status after radiation. The patient

Photodynamic therapy (PDT) is a kind of phototherapy that induces selective cytotoxic destruction by the activation of a nontoxic light-sensitive compound with light. Up-to-date PDT has been used for several dermatologic diseases, such as psoriasis, cutaneous T-cell lymphoma, and warts [26]. PDT with topical 5-ALA damages sebaceous glands, inhibits sebum production, kills *Propionibacterium acnes*, and obstructs the follicular openings [27]. The advantages of PDT include rapid efficacy, short recovery time, less destruction, and pain. Despite of these advantages, the local side effects of PDT are erythema, skin peeling, pain, burning, stinging, exfoliation, and post-inflammatory hyperpigmentation [27, 28]. It is obligatory to

treatment was completed after 1 year. The patient had experienced no relapse [17].

loss of scalp hair, and the development of dilated blood vessels [24].

had experienced no relapse at 5-month follow-up [25].

photoprotect after treatment for phototoxicity [29].

follow-up [18].

178 Acne and Acneiform Eruptions

Fatma Pelin Cengiz<sup>1</sup> \* and Funda Kemeriz<sup>2</sup>

### **References**

[16] Sand FL, Thomsen SF. Adalimumab for the treatment of refractory acne conglobata. JAMA Dermatol 2013;149:1306–1307.

**References**

180 Acne and Acneiform Eruptions

[1] Whipp MJ, Harrington CI, Dundas S. Fatal squamous cell carcinoma associated with

[2] Zuo RC, Schwartz DM, Lee CC, Anadkat MJ, Cowen EW, Naik HB. Palmoplantar pustules and osteoarticular pain in a 42-year-old woman. J Am Acad Dermatol 2015;72:550–553. [3] Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)-a new autoinflammatory syndrome distinct from

[4] Schackert K, Scholz S, Steinbauer-Rosenthal I, Albert ED, Wank R, Plewig G. Letter: HL-A antigens in acne conglobata: a negative study. Arch Dermatol 1974;110:468. [5] Rapini, Ronald P, Bolognia, Jean L, Jorizzo, Joseph L. (2007). Dermatology: 2-Volume

[6] Jeong S, Lee CW. Acne conglobata: treatment with isotretinoin, colchicine, and cyclosporin as compared with surgical intervention. Clin Exp Dermatol 1996;21:462–463.

[7] Gollnick HP, Graupe K, Zaumseil RP. Comparison of combined azelaic acid cream plus oral minocycline with oral isotretinoin in severe acne. Eur J Dermatol 2001;11:538–544. [8] Graham GM, Farrar MD, Cruse-Sawyer JE. Proinflammatory cytokine production by human keratinocytes stimulated with Propionibacterium acnes and P. acnes GroEL.

[9] Caillon F, O'Connell M, Eady EA. Interleukin-10 secretion from CD14+ peripheral blood mononuclear cells is downregulated in patients with acne vulgaris. Br J Dermatol

[10] Kimball AB, Kerdel F, Adams D. Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157:846–855.

[11] Navarini AA, Trueb RM. 3 cases of dissecting cellulitis of the scalp treated with adalimumab: control of inflammation within residual structural disease. Arch Dermatol

[12] Fernandez-Crehuet P, Ruiz-Villaverde R. Acneiform eruption as a probable paradoxical

[13] Cleynen I, Verimeire S. Paradoxical inflammation induced by anti-TNF agents in patients

[14] Shirakawa M, Uramoto K, Harada FA. Treatment of acne conglobata with infliximab.

[15] Yiu ZZ, Madan V, Griffiths CE. Acne conglobata and adalimumab: use of tumour necrosis factor-α antagonists in treatment-resistant acne conglobata, and review of the literature.

reaction to adalimumab. Int J Dermatol 2015;54(8):e306–e308.

with IBD. Nat Rev Gastroenterol Hepatol 2012;9:496–503.

J Am Acad Dermatol 2006;55:344–346.

Clin Exp Dermatol 2015;40:383–386.

acne conglobata in a father and daughter. Br J Dermatol 1987;117:389–392.

PAPA syndrome. J Am Acad Dermatol 2012;66:409–415.

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acne conglobata: an open, prospective, parallel-arm trial. Photodermatol Photoimmunol Photomed 2013;29 :233–238.

#### **Chapter 13 Provisional chapter**

#### **Acne Rosacea Acne Rosacea**

acne conglobata: an open, prospective, parallel-arm trial. Photodermatol Photoimmunol

[31] Hasegawa T, Matsukura T, Suga Y, Muramatsu S, Mizuno Y, Tsuchihashi H, Haruna K, Ogawa H, Ikeda S. Case of acne conglobata successfully treated by CO(2) laser combined

[32] Hasegawa T, Matsukura T, Hirasawa Y, Otsuki A, Tsuchihashi H, Niwa Y, Okuma K, Ogawa H, Ikeda S. Acne conglobata successfully treated by fractional laser after CO laser abrasion of cysts combined with topical tretinoin. J Dermatol 2009;36:118–119. [33] Liu CZ, Lei B, Zheng JF. Randomized control study on the treatment of 26 cases of acne conglobata with encircling acupuncture combined with venesection and cupping. Zhen

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Photomed 2013;29 :233–238.

182 Acne and Acneiform Eruptions

Ci Yan Jiu 2008;33:406–408.

Burhan Engin, Muazzez Çiğdem Oba, Zekayi Kutlubay, Server Serdaroğlu and Yalçın Tüzün Burhan Engin, Muazzez Çiğdem Oba, Zekayi Kutlubay, Server Serdaroğlu and Yalçın Tüzün Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65636

#### **Abstract**

Rosacea is a common chronic inflammatory cutaneous disorder with variable presen‐ tation and severity. Disease usually occurs between the ages of 30 and 50 years. Women are more commonly affected than men. Rosacea is divided into four subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular, and one variant: lupoid or granulomatous rosacea. Erythematotelangiectatic rosacea is manifested as flushing and persistent centrofacial erythema, and papulopustular rosacea as papules and pustules in a centrofacial distribution. With disease progression, phymas consisting of sebaceous gland hypertrophy can develop. Ocular rosacea can result in blepharitis and conjunctivitis. Diagnosis is made clinically. Management of rosacea consists of protective measures such as sun protection and gentle skin care and topical and systemic treatments to suppress inflammation and erythema.

**Keywords:** rosacea, acne, perioral dermatitis, rhinophyma, ocular rosacea

### **1. Introduction**

Rosacea is a common chronic inflammatory cutaneous disorder with variable presentation and severity. Facial flushing, telangiectasia, papules, and pustules are the main features of cutaneous rosacea.

### **2. Epidemiology**

Rosacea can be seen in any age, but the onset usually occurs between the ages of 30 and 50 years. Women are more commonly affected than men; however, the development of

phymatous skin changes is more commonly observed in men. Although the disease is more common in fair‐skinned people of Celtic origin, patients of any ethnic group can be affected [1]. Up to 1/3 of the patients report a family history [2]. Rhinophyma, bulbous nose due to increased connective tissue and hyperplastic sebaceous glands, is almost ex‐ clusively seen in men over 40 years of age [3]. The prevalence is highly variable as the methods used and the populations studied vary greatly from one study to another [4]. A Swedish study reported a prevalence of 10% with a female‐to‐male ratio of 3:1 [5]. Eye involvement may be observed in more than 50% of patients [1].

### **3. Pathogenesis**

Pathogenesis of rosacea is not well understood. Abnormalities in innate immunity, role of cutaneous microorganisms, and UV damage and vascular dysfunction may play a role in pathogenesis of rosacea.

Recent studies have shown the dysregulation of innate immune response in rosacea. Due to an exacerbated innate immune response, patients develop inflammatory reactions to stimuli that do not affect normal individuals. Patients with rosacea have high levels of cathelicidin, an antimicrobial peptide with vasoactive and proinflammatory properties and local protease kallikrein 5 (KLK5), which controls the production of cathelicidin peptides in epidermis. Injection of mouse skin with cathelicidin peptides from patients with rosacea led to skin changes similar to those observed in rosacea confirming the hypothesis [6]. Toll‐like receptors (TLRs) work by triggering inflammation in response to recognized microbial patterns and elevated TLR2 activity, leading to an increase in KLK5 level which may also contribute to enhanced inflammatory responses responsible for rosacea signs [7].

Some microorganisms have been proposed to stimulate inflammatory reaction in cutaneous rosacea. *Demodex folliculorum* is an obligatory parasite found in pilosebaceous unit. Although almost all adults are infested with *Demodex*, patients with rosacea have increased density of *Demodex* mites supporting a significant association between *Demodex* infestation and the development of rosacea [8]. Correlation of gastrointestinal *Helicobacter pylori* infection and rosacea is controversial. The prevalence of *H. pylori* infection is shown to be increased or not different in patients with rosacea compared to control subjects. Treatment of *H. pylori* infection with antibiotics has been shown to improve rosacea, but this may be the benefit of anti‐ inflammatory effects of the antibiotics used for treatment [9].

UV and sun exposure are among the exacerbating factors for rosacea. UV‐B has been shown to induce cutaneous angiogenesis in mice. In skin, UV‐B increases vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) secretion from human keratinocytes promoting angiogenesis. UV irradiation also produces reactive oxygen species, causing a damage in dermal matrix and thus leading to inflammation [6].

Vascular hyperreactivity may also play a role in disease pathogenesis. Dermal expression of VEGF, CD31, and lymphatic endothelium marker D2‐40 has been shown to be elevated in rosacea, leading to stimulation of vascular and lymphatic endothelial cells [10].

### **4. Classification and clinical features**

phymatous skin changes is more commonly observed in men. Although the disease is more common in fair‐skinned people of Celtic origin, patients of any ethnic group can be affected [1]. Up to 1/3 of the patients report a family history [2]. Rhinophyma, bulbous nose due to increased connective tissue and hyperplastic sebaceous glands, is almost ex‐ clusively seen in men over 40 years of age [3]. The prevalence is highly variable as the methods used and the populations studied vary greatly from one study to another [4]. A Swedish study reported a prevalence of 10% with a female‐to‐male ratio of 3:1 [5]. Eye

Pathogenesis of rosacea is not well understood. Abnormalities in innate immunity, role of cutaneous microorganisms, and UV damage and vascular dysfunction may play a role in

Recent studies have shown the dysregulation of innate immune response in rosacea. Due to an exacerbated innate immune response, patients develop inflammatory reactions to stimuli that do not affect normal individuals. Patients with rosacea have high levels of cathelicidin, an antimicrobial peptide with vasoactive and proinflammatory properties and local protease kallikrein 5 (KLK5), which controls the production of cathelicidin peptides in epidermis. Injection of mouse skin with cathelicidin peptides from patients with rosacea led to skin changes similar to those observed in rosacea confirming the hypothesis [6]. Toll‐like receptors (TLRs) work by triggering inflammation in response to recognized microbial patterns and elevated TLR2 activity, leading to an increase in KLK5 level which may also contribute to

Some microorganisms have been proposed to stimulate inflammatory reaction in cutaneous rosacea. *Demodex folliculorum* is an obligatory parasite found in pilosebaceous unit. Although almost all adults are infested with *Demodex*, patients with rosacea have increased density of *Demodex* mites supporting a significant association between *Demodex* infestation and the development of rosacea [8]. Correlation of gastrointestinal *Helicobacter pylori* infection and rosacea is controversial. The prevalence of *H. pylori* infection is shown to be increased or not different in patients with rosacea compared to control subjects. Treatment of *H. pylori* infection with antibiotics has been shown to improve rosacea, but this may be the benefit of anti‐

UV and sun exposure are among the exacerbating factors for rosacea. UV‐B has been shown to induce cutaneous angiogenesis in mice. In skin, UV‐B increases vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) secretion from human keratinocytes promoting angiogenesis. UV irradiation also produces reactive oxygen species, causing a

Vascular hyperreactivity may also play a role in disease pathogenesis. Dermal expression of VEGF, CD31, and lymphatic endothelium marker D2‐40 has been shown to be elevated in

rosacea, leading to stimulation of vascular and lymphatic endothelial cells [10].

involvement may be observed in more than 50% of patients [1].

enhanced inflammatory responses responsible for rosacea signs [7].

inflammatory effects of the antibiotics used for treatment [9].

damage in dermal matrix and thus leading to inflammation [6].

**3. Pathogenesis**

184 Acne and Acneiform Eruptions

pathogenesis of rosacea.

Rosacea is manifested as erythematous flushing, papules, and pustules in a centrofacial distribution. Intermittent or chronic facial edema may also occur. With disease progression, some patients may develop yellow‐orange plaques called phymas consisting of sebaceous gland hypertrophy [11].

There are four stages: pre‐rosacea and stages I through III. Patients with frequent flushing are considered in pre‐rosacea group. In stage I, there is erythema that lasts from hours to days and telangiectasias. In stage II, persistent erythema is accompanied by multiple inflammatory papules and pustules. In stage III, large inflammatory nodules and connective tissue hyper‐ plasia occur [4] (**Table 1**).

**Table 1.** Stage symptoms and signs [11].

The National Rosacea Society (NRS) has classified rosacea into four subtypes: erythematote‐ langiectatic, papulopustular, phymatous, and ocular, and one variant: lupoid or granuloma‐ tous rosacea.

### **4.1. Erythematotelangiectatic type**

The erythematotelangiectatic type is the most common subtype of rosacea (**Figure 1**). It is characterized by flushing and persistent central facial erythema with sparing of periocular skin. The flushing of rosacea lasts longer than 10 min differentiating it from physiological flushing episodes. Telangiectasias are common but not essential for the diagnosis of this subtype. Stinging or burning sensations may be present [4].

### **4.2. Papulopustular type**

Papulopustular rosacea is characterized by persistent central facial erythema: small, dome‐ shaped erythematous papules and surmounting pustules on the central face [4] (**Figure 2**). However, papules and pustules may also occur periorificially. The inflammation seen in papulopustular rosacea is similar to acne vulgaris, but comedones typical for acne vulgaris are absent in rosacea [12].

In a study, 15 patients with pustular rosacea and 15 age‐ and sex‐matched control subjects were compared. A significantly increased growth of *S. epidermidis* was found in rosacea pustules and eyelid margins of rosacea patients suggesting a role of *S. epidermidis* in pathogenesis of pustular and ocular rosacea [13].

**Figure 1.** Erythematotelangiectatic type of rosacea. Prominent telangiectatic vessels and erythema on the cheek with characteristic sparing of periocular skin.

#### **4.3. Ocular rosacea**

Ocular rosacea occurs in more than 50% of patients with rosacea. Eye involvement may follow, as seen in half of the patients, may precede as in 20%, or occur simultaneously with skin changes [12].

Patients with ocular rosacea may complain of foreign body sensation, dryness, itching, photophobia, and tearing. If the cornea is involved by the disease, the visual acuity may be decreased [14]. Blepharitis and conjunctivitis are the most common findings. Blepharitis is characterized by the eyelid margin erythema, scale, and staphylococcal infections. Hypopyon, scleritis, keratitis, and iritis can also occur. Rosacea keratitis is a severe condition and has a poor prognosis. It can lead to corneal opacity, scarring, and loss of vision. The severity of ocular rosacea symptoms is often not related to the severity of cutaneous manifestations [4].

### **4.4. Phymatous rosacea**

In a study, 15 patients with pustular rosacea and 15 age‐ and sex‐matched control subjects were compared. A significantly increased growth of *S. epidermidis* was found in rosacea pustules and eyelid margins of rosacea patients suggesting a role of *S. epidermidis* in pathogenesis of

**Figure 1.** Erythematotelangiectatic type of rosacea. Prominent telangiectatic vessels and erythema on the cheek with

**Figure 2.** Papulopustular type of rosacea. Extensive papules and pustules on a background of persistent erythema.

Ocular rosacea occurs in more than 50% of patients with rosacea. Eye involvement may follow, as seen in half of the patients, may precede as in 20%, or occur simultaneously with skin

pustular and ocular rosacea [13].

186 Acne and Acneiform Eruptions

characteristic sparing of periocular skin.

**4.3. Ocular rosacea**

changes [12].

Phymatous rosacea shows tissue hypertrophy manifesting as thickened skin with irregular contours and prominent pores. Involvement most commonly occurs on the nose (rhinophyma), but the chin (gnathophyma), forehead (metophyma), and ears (otophyma) may also be affected [4]. Rhinophyma occurs mostly in men with a male/female ratio of 20:1. Although rhinophyma is often accepted as a presentation of last stage of rosacea, it may occur in patients with few or no other features of rosacea. One diagnosis is a clinical one, and biopsy is only indicated to rule out alternative diagnoses or in suspicion of a malignancy such as basal cell carcinoma or squamous cell carcinoma [15].

### **4.5. Granulomatous rosacea**

Granulomatous rosacea was classified by the expert committee as a disease variant charac‐ terized by discrete yellow, brown, red papules, or nodules on periorificial facial skin [12] (**Figure 3**). Patients do not often have persistent erythema or flushing of the face and may not have their disease distributed to convexities of the face [16].

**Figure 3.** Granulomatous rosacea. Discrete yellow papules clustered periorficially.

### **5. Histopathology**

In mild forms of rosacea, histologic findings are often limited to vascular ectasia and mild edema. A lymphohistiocytic infiltrate with perivascular and perifollicular distribution is observed in papulopustular form [17]. Solar elastosis is invariably found in histopathologic examination of biopsy specimens. In granulomatous variant, non‐caseating epithelioid granulomas are seen within the dermis [18].

### **6. Diagnosis and differential diagnosis**

Diagnosis of rosacea is made clinically; there is no laboratory test to confirm the diagnosis. A biopsy is only indicated to rule out alternative diagnoses [1] (**Table 2**).

**Table 2.** Differential diagnosis of facial rosacea [17, 19].

Acne vulgaris is the disease most commonly confused with rosacea, especially in middle‐aged adults. Key distinguishing feature between acne vulgaris and rosacea is the absence of comedones in rosacea [4]. Patients with acne vulgaris are often younger patients, having oily skin with comedones, larger pustules, and less erythema with scarring [1].

Perioral dermatitis presents with micropustules and vesicles with scaling around the mouth. Seborrheic dermatitis often coexists with rosacea [17]. Scaling and erythema of the scalp, eyebrows, external auditory canals, and retroauricular folds serve as clues to the presence of seborrheic dermatitis [4].

The malar erythema of systemic lupus erythematosus can be difficult to distinguish from rosacea. Clinically, papules pustules and ocular symptoms are mostly absent in lupus [17]. Severe Demodex infection (demodicosis) may present with rosacea‐like features, but flushing and telangiectasia are absent [4]. And also, photodermatitis is triggered by sun exposure and has similar skin manifestations to rosacea [4].

### **7. Associated diseases**

**5. Histopathology**

188 Acne and Acneiform Eruptions

Acne vulgaris

Photodermatitis Sarcoidosis Demodicosis Haber syndrome Basal cell carcinoma

Seborrheic dermatitis Keratosis pilaris Dermatomyositis

Systemic lupus erythematosus

seborrheic dermatitis [4].

granulomas are seen within the dermis [18].

**Table 2.** Differential diagnosis of facial rosacea [17, 19].

has similar skin manifestations to rosacea [4].

**6. Diagnosis and differential diagnosis**

In mild forms of rosacea, histologic findings are often limited to vascular ectasia and mild edema. A lymphohistiocytic infiltrate with perivascular and perifollicular distribution is observed in papulopustular form [17]. Solar elastosis is invariably found in histopathologic examination of biopsy specimens. In granulomatous variant, non‐caseating epithelioid

Diagnosis of rosacea is made clinically; there is no laboratory test to confirm the diagnosis. A

Acne vulgaris is the disease most commonly confused with rosacea, especially in middle‐aged adults. Key distinguishing feature between acne vulgaris and rosacea is the absence of comedones in rosacea [4]. Patients with acne vulgaris are often younger patients, having oily

Perioral dermatitis presents with micropustules and vesicles with scaling around the mouth. Seborrheic dermatitis often coexists with rosacea [17]. Scaling and erythema of the scalp, eyebrows, external auditory canals, and retroauricular folds serve as clues to the presence of

The malar erythema of systemic lupus erythematosus can be difficult to distinguish from rosacea. Clinically, papules pustules and ocular symptoms are mostly absent in lupus [17]. Severe Demodex infection (demodicosis) may present with rosacea‐like features, but flushing and telangiectasia are absent [4]. And also, photodermatitis is triggered by sun exposure and

skin with comedones, larger pustules, and less erythema with scarring [1].

biopsy is only indicated to rule out alternative diagnoses [1] (**Table 2**).

Rosacea patients may have increased risk of developing certain diseases as evidenced by case‐ controlled studies. Further studies are necessary to confirm these associations.

Patients with rosacea are more likely to have dyslipidemia and hypertension. They are also at increased risk of coronary artery disease after adjustment for cardiovascular disease risk factors [20]. There is a possible association between rosacea and an increased risk of thyroid cancer and basal cell carcinoma [21].

Rosacea was associated with a significantly increased risk of glioma in a Danish nationwide cohort [22]. In the same Danish cohort, patients with rosacea had an increased risk of autoim‐ mune diseases, including type 1 diabetes mellitus, celiac disease, multiple sclerosis, and rheumatoid arthritis [23].

### **8. Treatment**

#### **8.1. Protective measures**

Protective measures are of utmost importance in management of rosacea patients of all subtypes. These include avoidance of triggers of flushing, gentle skin care, and sun protection.

Most sufferers report worsening of the disease by factors such as hot or cold temperature, wind, hot drinks, exercise, spicy food, alcohol, emotions, and menopause [24]. A variety of medica‐ tions may exacerbate flushing such as vasodilative drugs, nicotinic acid and amyl nitrite, calcium channel blockers, and opiates [1].

Cleansers containing acetone or alcohol should be avoided. Usage of abrasive or exfoliant preparations and vigorous rubbing of the skin should also be discontinued [1].

Daily application of combined ultraviolet‐A and ultraviolet‐B protective sunscreen with a sun protection factor of 15 or greater should be advised to every patient. Sun‐blocking creams containing titanium dioxide and zinc oxide are usually well tolerated [1].

### **8.2. Erythematotelangiectatic rosacea**

Erythematotelangiectatic rosacea is the most treatment‐resistant subtype of rosacea. Flushing and burning are the most difficult features to treat. Non‐cardioselective β‐blockers such as propranolol 40 mg twice daily or nadolol 40 mg daily can be tried, but provide rather limited benefit [25].

Topical or oral medications described below for papulopustular rosacea are often used, but evidence supporting their role in erythematotelangiectatic rosacea is lacking [1].

Treatment of erythema and telangiectasia with vascular lasers or intense pulse light can help in improving flushing and burning [4].

#### **8.3. Papulopustular rosacea**

Systemic and topical antibiotics are effective in treatment of papulopustular rosacea. Patients with moderate‐to‐severe papulopustular rosacea at initial presentation may require systemic therapy to achieve clearance of inflammatory skin lesions followed by topical treatment to avoid relapses. Topical medications alone can be used to control milder disease.

Main topical agents utilized for the treatment of rosacea include metronidazole, sulfacetamide‐ sulfur, azelaic acid, and topical antibiotics (clindamycin, erythromycin) [26]. Three varieties of 0.75% metronidazole and 1% metronidazole and several brands of 10% sodium sulfacetamide with 5% sulfur and 15% azelaic acid gel are medications that have been approved by the Food and Drug Administration (FDA) for rosacea. All are indicated for the papules, pustules, and erythema [4].

Topical metronidazole used once or twice daily is effective in treatment of inflammatory papules and pustules and improving erythema of papulopustular rosacea. Azelaic acid is a well‐tolerated preparation that also reduces papules and pustules. It is available in 15% gel and 20% cream forms, applied twice a day; 10% sodium sulfacetamide with 5% sulfur is used to treat acne, rosacea, and seborrheic dermatitis. It has beneficial effects in reducing both inflammatory lesion counts and erythema scores in papulopustular rosacea [27]. Topical erythromycin used for acne vulgaris can help in reducing symptoms but may prove irritant on skin affected by rosacea [24]. Clindamycin gel, also developed for treatment of acne, may be better tolerated. A combined formulation containing 5% benzoyl peroxide and 1% clinda‐ mycin has proved effective and well tolerated in a placebo‐controlled trial [4].

Topical retinoids have been used to treat rosacea, but the true efficacy has not been established. Adapalen, a relatively well‐tolerated retinoid, has been shown to be an alternative treatment agent in management of papulopustular rosacea [28].

Effective systemic antibiotics include tetracyclines (e.g., tetracycline or oxytetracycline 250 mg twice daily) and erythromycin 250 mg twice daily. Second‐generation tetracyclines, such as minocycline and doxycycline, are also effective and offer the advantages of once daily administration and less gastrointestinal side effects [24]. Doxycycline shows anti‐inflamma‐ tory effects at doses as low as 40 mg daily [29]. Azithromycin was proven to be as effective as doxycycline in a number of studies [4]. In one series, azithromycin proved beneficial after 4 weeks at 250 mg/day, for 3 days each week (Monday, Wednesday, and Friday) [30].

Oral metronidazole is an effective alternative treatment for rosacea. Metronidazole (200 mg) taken twice daily for 12 weeks has been proved to be as effective in improving the inflammatory lesions of rosacea as 250 mg oxytetracycline taken twice daily [4]. Abstinence from alcohol during metronidazole therapy is necessary to avoid disulfiram‐like reactions. Although relatively safe, metronidazole has been associated with potential side effects such as neuro‐ pathy and seizures [24].

Oral isotretinoin is a treatment option for severe rosacea. The onset of action of systemic retinoids is slow when compared with the oral antibiotics. It is effective both in eryth‐ ematotelangiectatic and papulopustular rosacea. Oral istotretinoin can also be used for granulomatous rosacea and rhinophyma. It has been shown that treatment‐resistant patients taking isotretinoin experienced fewer papules and pustules, a reduction in erythema, and decreased nasal volume [31]. Daily doses of isotretinoin range from 0.2 to 1 mg/kg. It is usually given for 6 months. With low dose therapy, the common mucosal side effects of the drug are minimal and tolerable. However, due to its tera‐ togenic effects, it is contraindicated in women of childbearing potential [4].

#### **8.4. Ocular rosacea**

**8.3. Papulopustular rosacea**

190 Acne and Acneiform Eruptions

erythema [4].

pathy and seizures [24].

Systemic and topical antibiotics are effective in treatment of papulopustular rosacea. Patients with moderate‐to‐severe papulopustular rosacea at initial presentation may require systemic therapy to achieve clearance of inflammatory skin lesions followed by topical treatment to

Main topical agents utilized for the treatment of rosacea include metronidazole, sulfacetamide‐ sulfur, azelaic acid, and topical antibiotics (clindamycin, erythromycin) [26]. Three varieties of 0.75% metronidazole and 1% metronidazole and several brands of 10% sodium sulfacetamide with 5% sulfur and 15% azelaic acid gel are medications that have been approved by the Food and Drug Administration (FDA) for rosacea. All are indicated for the papules, pustules, and

Topical metronidazole used once or twice daily is effective in treatment of inflammatory papules and pustules and improving erythema of papulopustular rosacea. Azelaic acid is a well‐tolerated preparation that also reduces papules and pustules. It is available in 15% gel and 20% cream forms, applied twice a day; 10% sodium sulfacetamide with 5% sulfur is used to treat acne, rosacea, and seborrheic dermatitis. It has beneficial effects in reducing both inflammatory lesion counts and erythema scores in papulopustular rosacea [27]. Topical erythromycin used for acne vulgaris can help in reducing symptoms but may prove irritant on skin affected by rosacea [24]. Clindamycin gel, also developed for treatment of acne, may be better tolerated. A combined formulation containing 5% benzoyl peroxide and 1% clinda‐

Topical retinoids have been used to treat rosacea, but the true efficacy has not been established. Adapalen, a relatively well‐tolerated retinoid, has been shown to be an alternative treatment

Effective systemic antibiotics include tetracyclines (e.g., tetracycline or oxytetracycline 250 mg twice daily) and erythromycin 250 mg twice daily. Second‐generation tetracyclines, such as minocycline and doxycycline, are also effective and offer the advantages of once daily administration and less gastrointestinal side effects [24]. Doxycycline shows anti‐inflamma‐ tory effects at doses as low as 40 mg daily [29]. Azithromycin was proven to be as effective as doxycycline in a number of studies [4]. In one series, azithromycin proved beneficial after 4

Oral metronidazole is an effective alternative treatment for rosacea. Metronidazole (200 mg) taken twice daily for 12 weeks has been proved to be as effective in improving the inflammatory lesions of rosacea as 250 mg oxytetracycline taken twice daily [4]. Abstinence from alcohol during metronidazole therapy is necessary to avoid disulfiram‐like reactions. Although relatively safe, metronidazole has been associated with potential side effects such as neuro‐

Oral isotretinoin is a treatment option for severe rosacea. The onset of action of systemic retinoids is slow when compared with the oral antibiotics. It is effective both in eryth‐ ematotelangiectatic and papulopustular rosacea. Oral istotretinoin can also be used for

weeks at 250 mg/day, for 3 days each week (Monday, Wednesday, and Friday) [30].

avoid relapses. Topical medications alone can be used to control milder disease.

mycin has proved effective and well tolerated in a placebo‐controlled trial [4].

agent in management of papulopustular rosacea [28].

Treatment of ocular rosacea depends on disease severity. Lid hygiene and warm compresses are the baseline treatment for all patients. For mild ocular rosacea, fucidic acid preparations and metronidazole gel are frequently used [4]. Systemic antibiotics such as oral tetracyclin or doxycyclin may be used in patients with a more severe involvement [32]. The keratitis associated with rosacea can be severe, and patients with potentially serious ocular symptoms should be referred to an ophthalmologist.

### **8.5. Rhinophyma**

In patients with early rhinophyma, medical treatment with systemic isotretinoin may prove beneficial. In advanced cases, surgery is performed. Surgery can be done either as a complete excision or an incomplete excision made by cryosurgery, dermabrasion, electrosurgery, sharp blade excision, shaving with a razor, or laser surgery [32].

### **Author details**

Burhan Engin\* , Muazzez Çiğdem Oba, Zekayi Kutlubay, Server Serdaroğlu and Yalçın Tüzün

\*Address all correspondence to<EMAIL_ADDRESS>
Cerrahpaşa Medical Faculty, Dermatology Department, Istanbul University, Istanbul, Turkey

### **References**

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[10] Gomaa AH, Yaar M, Eyada MM, Bhawan J: Lymphangiogenesis and angiogenesis in non‐phymatous rosacea. J Cutan Pathol. 2007;34:748–753. doi:10.1111/j.1600‐0560.2006.

[12] 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

[13] Whitfeld M, Gunasingam N, Leow LJ, Shirato K, Preda V: Staphylococcus epidermidis: a possible role in the pustules of rosacea. J Am Acad Dermatol. 2011;64:49–52. doi:

[14] Vieira AC, Höfling‐Lima AL, Mannis MJ: Ocular rosacea—a review. Arq Bras Oftalmol.

[15] Lazeri D, Colizzi L, Licata G, et al: Malignancies within rhinophyma: report of three new cases and review of the literature. Aesthetic Plast Surg. 2012;36:396–405. doi:

[16] Crawford GH, Pelle MT, James WD: Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004;51:327–341. doi:10.1016/j.jaad.2004.03.030

[17] Webster GF: Rosacea. Med Clin North Am. 2009;93:1183–1194. doi:10.1016/j.mcna.

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#### **Chapter 14 Provisional chapter**

### **Ocular Rosacea Ocular Rosacea**

### Aysun Sanal Dogan Aysun Sanal Dogan

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66470

#### **Abstract**

Acne rosacea (AR) is a chronic cutaneous inflammatory disease of the midface. Ocular involvement occurs in 30–70% of patients. Although the incidence of this disease is seen highest between the ages of 30 and 50 years, it can also develop during childhood. The diagnosis depends on clinical findings such as meibomian gland dysfunction (MGD), conjunctival hyperemia, and corneal vascularization, and untreated cases can progress and lead to vision loss. Pathogenetic factors can be the altered the immune system, colonization of microorganisms, inflammation, abnormalities of sebaceous, and meibomian glands, environmental factors, and vascular dysregulation. Differential diagnosis from other ophthalmologic and dermatologic diseases is important. Management requires an interdisciplinary approach with a step‐wise treatment algorithm. Patients should be informed about the chronic course of the disease and avoid the exacerbating factors. Caring about the lid hygiene and use of non‐preserved artificial eye tears, topical ointments including antibiotics, anti‐inflammatory agents are used when necessary. However, the mainstay of the therapy is the use of oral antibiotics for a long period. Surgical interventions may be needed in cases with a vision‐threatening condition. During the long‐term treatment period and disease course, the complications of medications should also be considered cautiously and patient should be followed up routinely.

**Keywords:** ocular rosacea, dry eye, meibomian gland, meibomian gland dysfunction, treatment

### **1. Introduction**

Acne rosacea (AR) is the chronic inflammatory disease of skin typically involving the cheeks, nose, chin, and central forehead. The dermatological findings are transient or persistent erythema, papules, pustules, and telangiectasia. During the chronic course, these findings show exacerbations and remissions that may end up with progression. This dermatologic condition has been classified by National Rosacea Society into four subtypes based on the clinical fea-

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

tures: (1) erythematotelangiectatic rosacea, (2) papulopustular rosacea, (3) phymatous rosacea, and (4) ocular rosacea [1]. Flushing, chronic inflammation, and fibrosis are present in dermatologic course. The presence of one of the findings: flushing, non‐transient erythema, plaque, dry appearance, edema, papules‐pustules, and telangiectasia on the face with burning sensation, ocular manifestations, and phymatous changes is indicative of rosacea, and these symptoms are graded as mild, moderate, and severe [2]. Ocular manifestations are defined as one of the secondary criteria [1].

Under the circumstances of existing acne rosacea, the diagnosis of ocular rosacea (OR) is made by the presence of inflammation of the ocular surface, accompanying redness, burning, and itching symptoms of the eye. The diagnosis is confirmed by the presence of corneal infiltration with meibomian gland inflammation, and accompanying skin findings of rosacea [3].

### **2. Epidemiology**

AR is usually seen between ages of 30 and 50 years [4, 5]. The prevalence is reported from 4 to 22% that is more frequent in fair‐skinned people [5–8]. The OR starts to be detected approximately 10 years after the diagnosis of AR, with an increasing incidence between ages of 40 and 50 years [5]. The ocular involvement occurs in 58–72% and interestingly the ocular signs may precede in 20% of rosacea patients [9, 10]. Because of mild cutaneous manifestations, the ocular findings may be underestimated in children. Therefore, the diagnosis is delayed with more ocular complications. In a case series, it was shown that only two of six children with ocular rosacea demonstrated cutaneous rosacea findings [11].

Although AR affects women more than men, ocular involvement is to be seen in both sexes equally [5, 12]. There is a family history in 15–30% of cases [13, 14]. Hence, with a suspicion of family history, the children should be followed up closely and should be kept in mind that the condition tends to progress in adulthood [15].

### **3. Pathogenesis**

Although AR has no proven cause, scientific studies showed that there is dysregulation of vascular, immunologic, and nervous systems [16, 17]. Ocular surface is the mainly affected area with OR. Ocular surface compromises cellular components of the palpebral and bulbar conjunctiva such as corneoscleral limbus, cornea, eyelid margins, eyelashes, and tear film [18].

### **3.1. Altered immune system**

Altered immune system may be one of the factors. It was postulated that a type IV hypersensitivity reaction may be responsible for the conjunctival inflammation in OR in which the reactant is unknown [19, 20].

### **3.2. Colonization of microorganism**

tures: (1) erythematotelangiectatic rosacea, (2) papulopustular rosacea, (3) phymatous rosacea, and (4) ocular rosacea [1]. Flushing, chronic inflammation, and fibrosis are present in dermatologic course. The presence of one of the findings: flushing, non‐transient erythema, plaque, dry appearance, edema, papules‐pustules, and telangiectasia on the face with burning sensation, ocular manifestations, and phymatous changes is indicative of rosacea, and these symptoms are graded as mild, moderate, and severe [2]. Ocular manifestations are defined as one of the

Under the circumstances of existing acne rosacea, the diagnosis of ocular rosacea (OR) is made by the presence of inflammation of the ocular surface, accompanying redness, burning, and itching symptoms of the eye. The diagnosis is confirmed by the presence of corneal infiltration with meibomian gland inflammation, and accompanying skin findings of rosa-

AR is usually seen between ages of 30 and 50 years [4, 5]. The prevalence is reported from 4 to 22% that is more frequent in fair‐skinned people [5–8]. The OR starts to be detected approximately 10 years after the diagnosis of AR, with an increasing incidence between ages of 40 and 50 years [5]. The ocular involvement occurs in 58–72% and interestingly the ocular signs may precede in 20% of rosacea patients [9, 10]. Because of mild cutaneous manifestations, the ocular findings may be underestimated in children. Therefore, the diagnosis is delayed with more ocular complications. In a case series, it was shown that only two of six children with

Although AR affects women more than men, ocular involvement is to be seen in both sexes equally [5, 12]. There is a family history in 15–30% of cases [13, 14]. Hence, with a suspicion of family history, the children should be followed up closely and should be kept in mind that

Although AR has no proven cause, scientific studies showed that there is dysregulation of vascular, immunologic, and nervous systems [16, 17]. Ocular surface is the mainly affected area with OR. Ocular surface compromises cellular components of the palpebral and bulbar conjunctiva such as corneoscleral limbus, cornea, eyelid margins, eyelashes, and tear film [18].

Altered immune system may be one of the factors. It was postulated that a type IV hypersensitivity reaction may be responsible for the conjunctival inflammation in OR in which the

ocular rosacea demonstrated cutaneous rosacea findings [11].

the condition tends to progress in adulthood [15].

secondary criteria [1].

196 Acne and Acneiform Eruptions

**2. Epidemiology**

**3. Pathogenesis**

**3.1. Altered immune system**

reactant is unknown [19, 20].

cea [3].

*Demodex folliculorum* is a saprophytic mite that is found in normal flora of the skin. There are studies demonstrating that the Demodex density increased in rosacea patients [21, 22].

*Bacillus olenorium* serum immunoreactivity was detected in ocular rosacea patients. Its proteins cause high immune reactions [22, 23].

*Staphylococcus epidermidis* and *Propionibacterium acnes* that are found commonly in lid flora are accused microorganisms for their production of high levels of bacterial lipases [24].

In a study, *Chlamydia pneumoniae* antigen was detected in 40% of skin biopsies patient with rosacea [25].

Moreover, *Helicobacter pylori* IgG antibodies were found in 81% of the acne rosacea patients with dyspepsia, but there is a debate whether this is a coincidence or not [26]. The proteins produced by these pathogens might be responsible for the some aspects of rosacea.

The increased amount of free fatty acids produced by meibomian glands causes tear film instability and irritates the ocular tissues [27]. This increase may be due to biochemical abnormality of the meibomian gland secretions or lipolytic exoenzymes of bacteria which degrade lipids into free fatty acids [28].

### **3.3. Inflammation**

OR was found to be associated with the increased tear fluid levels of several inflammatory mediators such as interleukin‐1 (IL‐1) and gelatinase B activity [29]. Matrix metalloproteinases (MMP), interferon‐alpha (IFN‐α), and inflammatory cytokines seem to be an important component of pathophysiology [30].

The meibomian glands of rosacea patients cause keratinization of epithelial cells, end up with thickening of secretions, plugging of the orifices, and trapping of the secretions [31].

### **3.4. Environmental factors**

Many rosacea patients are aware of some factors that exacerbate their symptoms. Although these triggering factors differ for each patient: alcohol, sunlight, wind, temperature extremes, hot, and spicy foods, vigorous exercise, hot baths, medications that dilate blood vessels, menopause, and emotional factors (stress, anger, and embarrassment) can also play role in the pathogenesis [32–34].

### **3.5. Genetics**

Rosacea is associated with familial predisposition [35]. In a study conducted in twin pairs, rosacea contribution has been reported equally by genetic and environmental factors [36]. The genetic predisposition showed single nucleotide polymorphisms in HLA‐DRA and BTNL2 genes that support the concept of a genetic component for rosacea [37].

### **3.6. Vascular dysregulation and neurologic system**

There is vascular dilatation and telangiectatic vessels and increased blood flow, causing erythema, flushing, and neovascularization [5, 34, 38], which is probably under control of the sympathetic system [39].

### **4. Diagnosis**

The diagnosis of both dermatological rosacea and ocular rosacea is clinical. There is no single‐ specific test—even skin biopsy—to confirm the diagnosis.

Ocular involvement is varied and non‐specific. Most of the patients refer to ophthalmologist with dry eye symptoms (**Table 1**). No correlation exists between the severity of the ocular manifestations and that of the skin lesions. However, in patients with increased flushing, ocular rosacea prevalence is higher [40].

Although rosacea is uncommon in pediatric cases, it deserves attention due to undiagnosed ocular rosacea that is common with severe ocular complication [41]. History of triggering factors should be investigated and dermatologist consultation is required.

### **4.1. Clinical feature**

Both eyes are usually affected simultaneously, but unilateral or sequential involvements can also occur.

The primary and the starter of the ocular involvement is the meibomian gland dysfunction (MGD) [42]. Ghanem et al. reported that the most common ocular signs in patients with rosacea from the ophthalmologic clinic were meibomian gland dysfunction (MGD) in 85.2%, lid margin telangiectasias in 53.4%, blepharitis in 44.3%, and interpalpebral hyperemia in 40.9%. Accordingly, patients from the dermatology clinic were reported to exhibit MGD in 27.3%, chalazion/hordeolum, lid margin telangiectasia in 18.2%, anterior blepharitis in 13.6%, and pinguecula in 13.6% [9] Vision loss is a rare but devastating complication [43]. OR has been graded as mild, moderate, and severe (**Table 2**) [2].

**Table 1.** Ocular symptoms of the ocular rosacea patient.

**Table 2.** Grading of ocular rosacea [2].

#### **4.2. Symptoms**

**3.6. Vascular dysregulation and neurologic system**

specific test—even skin biopsy—to confirm the diagnosis.

tors should be investigated and dermatologist consultation is required.

– dryness sensations (burning and stinging, feeling of a having foreign body sensation in the eye)

ocular rosacea prevalence is higher [40].

graded as mild, moderate, and severe (**Table 2**) [2].

sympathetic system [39].

198 Acne and Acneiform Eruptions

**4. Diagnosis**

**4.1. Clinical feature**

also occur.

**Ocular symptoms**

– sensitivity to light (photophobia)

**Table 1.** Ocular symptoms of the ocular rosacea patient.

– red and swollen eyelids – blurry or decreased vision

– irritation – itching – redness

– tearing

There is vascular dilatation and telangiectatic vessels and increased blood flow, causing erythema, flushing, and neovascularization [5, 34, 38], which is probably under control of the

The diagnosis of both dermatological rosacea and ocular rosacea is clinical. There is no single‐

Ocular involvement is varied and non‐specific. Most of the patients refer to ophthalmologist with dry eye symptoms (**Table 1**). No correlation exists between the severity of the ocular manifestations and that of the skin lesions. However, in patients with increased flushing,

Although rosacea is uncommon in pediatric cases, it deserves attention due to undiagnosed ocular rosacea that is common with severe ocular complication [41]. History of triggering fac-

Both eyes are usually affected simultaneously, but unilateral or sequential involvements can

The primary and the starter of the ocular involvement is the meibomian gland dysfunction (MGD) [42]. Ghanem et al. reported that the most common ocular signs in patients with rosacea from the ophthalmologic clinic were meibomian gland dysfunction (MGD) in 85.2%, lid margin telangiectasias in 53.4%, blepharitis in 44.3%, and interpalpebral hyperemia in 40.9%. Accordingly, patients from the dermatology clinic were reported to exhibit MGD in 27.3%, chalazion/hordeolum, lid margin telangiectasia in 18.2%, anterior blepharitis in 13.6%, and pinguecula in 13.6% [9] Vision loss is a rare but devastating complication [43]. OR has been Feeling of dryness, irritation symptoms with burning and stinging and feeling of having foreign body sensation in the eye are common. Blurry vision, redness, sensitivity to light (photophobia), tearing, itching, red, and swollen eyelids are the other encountered symptoms.

#### **4.3. Signs**

It is not rare that the symptoms of the patient are not proportional with the ocular findings. Reduced fluorescein tear breakup time, punctate staining on the cornea, and bulbar conjunctiva (**Figure 1**). Superficial punctate keratopathy (due to tear film instability), dry eye disease, blepharitis, styes, MGD, eyelid inflammation‐collaretes, telangiectasis, conjunctival hyperemia, conjunctival scarring, punctate epithelial keratitis, corneal infiltrate/vascularization, corneal thinning, corneal astigmatism, corneal ulceration, phlyctenules, phlyctenular keratitis, limbal pannus, episcleritis, scleritis, corneal melting, and perforation, iritis, periorbital edema, recurrent chalazia, pannus, neovascularization, trichiasis (**Figures 1**–**5**) [43–46].

#### *4.3.1. Eyelid*

The lipid layer produced by meibomian glands stabilizes the tear film and prevents evaporation. Abnormality of this function is the primary cause of the blepharitis and evaporative‐type dry eye. Dry eye can be detected by decreased tear breakup times. There is inflammation, dilatation, and occlusion of the meibomian glands [31]. With pressure to eyelid margins, there is hardness to express the secretion, and usually occluded by toothpaste‐like material namely meibomana. Hordeolum and chalazion are the signs of focal inflamed obstructive MGD. In chronic course, there will be telangiectatic vessels around the orifices of the meibomian glands. At the end, the ducts are fully keratinized and disappears leading the meibomian gland dropout.

**Figure 1.** Ocular rosacea patient with irregular ocular margin, conjunctival hyperemia and trichiasis.

#### *4.3.2. conjunctiva*

Conjunctival hyperemia is the common finding. Hyperemia is mostly obvious in interpalpebral area. In 9% of OR, there is also conjunctival scarring [47].

#### *4.3.3. cornea*

Disease starts with inferior punctate epitheliopathy. Superficial vascularization of the peripheral cornea (especially triangular in shape and extending from inferior cornea) develops in

**Figure 2.** Ocular rosacea with sterile corneal infiltrate, lid telangiectasia, meibomian gland occlusion and foamy secretion.

**Figure 3.** Bulbar interpalpebral conjunctival hyperemia with fine corneal vascularization.

untreated cases. In case of recurrent epithelium defects, one should be suspicious of OR also. Inflammatory episodes will end up with devastating problems, such as corneal scarring, thinning even perforation and sight threatening keratitis [48–51].

#### **4.4. Ocular tests and imaging**

*4.3.2. conjunctiva*

200 Acne and Acneiform Eruptions

*4.3.3. cornea*

Conjunctival hyperemia is the common finding. Hyperemia is mostly obvious in interpalpe-

**Figure 1.** Ocular rosacea patient with irregular ocular margin, conjunctival hyperemia and trichiasis.

Disease starts with inferior punctate epitheliopathy. Superficial vascularization of the peripheral cornea (especially triangular in shape and extending from inferior cornea) develops in

**Figure 2.** Ocular rosacea with sterile corneal infiltrate, lid telangiectasia, meibomian gland occlusion and foamy secretion.

bral area. In 9% of OR, there is also conjunctival scarring [47].

Tests of evaporative dry eye are altered in OR. Tear osmolarity values, Ocular surface disease index (OSDI) questionnaire and corneal staining scores were significantly higher, and

**Figure 4.** Ocular rosacea with severe dry eye symptoms and inferior punctate epitheliopathy.

**Figure 5.** Corneal haze inferotemporally signifying healed corneal involvement of ocular rosacea.

Schirmer‐I test and fluorescein tear breakup time were significantly lower, which all confirms tear hyperosmolarity and tear film dysfunction [52].

Dry eye in rosacea patients can also be diagnosed by tear meniscus measurement with optical coherence tomography (OCT) with considerable sensitivity and specificity [53]. Central corneal thickness, corneal hysteresis and corneal resistance factors were all significantly decreased in OR patients when compared to healthy controls [54]. Patients with OR show significant meibomian gland dropout which can be demonstrated by meibography (**Figure 6**)

**Figure 6.** Ocular rosacea. Meibography, meibomian dropout.

[31, 42]. *In vivo* confocal microscopy findings revealed inflammatory changes of ocular surface and even Demodex infestations on eyelids [55, 56].

### **5. Differential diagnosis**

### **5.1. From dermatological diseases**

In patients with suspicion of OR, if facial dermatologic inflammatory changes exist, clinician would be aware of three main differential diagnosis [57]. These are as follows:

Acne vulgaris: The presence of comedones—which does not exist in rosacea—in young patients direct the clinician to diagnosis of acne vulgaris.

Seborrheic dermatitis: In seborrheic dermatitis, facial erythema is accompanied by yellowish scaling and prominent dandruff.

Perioral dermatitis: There is perioral involvement without flushing or telangiectasia.

#### **5.2. From ophthalmological diseases**

Ocular findings must be differentiated from the other causes of dry eye.

Corneal involvements must be differentiated from herpetic or bacterial keratitis and recurrent epithelial defects [48, 58, 59].

All forms of conjunctivitis are in differential diagnosis. Due to chronic course and leading to conjunctival scarring, chlamydial conjunctivitis deserves attention.

In severe OR, which ends up with inferior thinning and irregular astigmatism, it may resemble to keratoconus [51].

### **6. Management**

Schirmer‐I test and fluorescein tear breakup time were significantly lower, which all confirms

**Figure 5.** Corneal haze inferotemporally signifying healed corneal involvement of ocular rosacea.

Dry eye in rosacea patients can also be diagnosed by tear meniscus measurement with optical coherence tomography (OCT) with considerable sensitivity and specificity [53]. Central corneal thickness, corneal hysteresis and corneal resistance factors were all significantly decreased in OR patients when compared to healthy controls [54]. Patients with OR show significant meibomian gland dropout which can be demonstrated by meibography (**Figure 6**)

tear hyperosmolarity and tear film dysfunction [52].

202 Acne and Acneiform Eruptions

**Figure 6.** Ocular rosacea. Meibography, meibomian dropout.

For an effective therapeutic strategy, an interdisciplinary collaboration is needed between ophthalmologist and dermatologist. The stepwise approach is recommended.

	- Systemic tetracycline/doxycycline/minocycline shows the therapeutic effects by decreasing lid flora, inhibiting collagenase activity which prevents corneal thinning, inhibiting inflammatory mediators (i.e. MMP), decreasing concentration of free fatty acids [64–66].
	- Clarithromycin are also effective to *H. pylori* [67].
	- Metronidazole has anti‐inflammatory, anti‐microbic, anti‐parasitic, and immunosuppressive effects [68].
	- Azithromycin 3 times per week for 4 weeks [69].
	- Erythromycin is appropriate for children <8 years old to avoid the untoward effects of tetracycline [70].

In cases of severe corneal involvement, surgical options are indicated [49]. Progressive epitheliopathy unresponsive to topical treatment with hazy epithelium extending centrally, indicating limbal stem cell insufficiency, is treated with limbal stem cell transplantation [75]. Thinning of the cornea and threatening perforation are treated with conjunctival flaps or amniotic membranes [43]. Little corneal perforations may benefit from cyanoacrylate glues. Minority people with untreated or resistant to treatment may need keratoplasty at the end of long‐term OR [49].

Rosacea naturally waxes and wanes. However, because the damage from rosacea can be progressive, the long‐lasting use of therapy has advantages. Due to the lack of prospective controlled studies, the optimum modality and duration for treatment and prevention of OR recurrence remain unclear. The duration of the treatment depends on the ophthalmologist's decision and the severity of the ocular involvement. There is a consensus to give treatment for several months, and tapering the doses within follow‐ups.

### **7. Complications**

⁻ Lubricants: Lubricants are used to decrease inflammatory mediators, and to provide symptomatic relief. Non‐preserved artificial tears are recommended with a patient‐ individualized dosage [61]. The initial high dosages might be tapered gradually. OR is usually mild and responds well to lid hygiene and lubricants, but must be advised to do

⁻ Topical antibiotics: Azithromycin 1.5% eye drops are effective for MGD treatment even with phlyctenular keratoconjunctivitis complicating OR [62, 63]. It has an anti‐inflammatory effect as well as an antimicrobial effect. Topical antibiotic ointments (fucidic acid and metronidazole gel applied to lid margins), especially in the nighttime, are also effective to

⁻ Mainstay of the treatment is the use of systemic antibiotics. Due to relapses, maintenance treatment may be 6 months. Low doses with longer duration of the antibiotic usage must be preferred to benefit from the anti‐inflammatory effect without inducing resistance and

◦ Systemic tetracycline/doxycycline/minocycline shows the therapeutic effects by decreasing lid flora, inhibiting collagenase activity which prevents corneal thinning, inhibiting inflammatory mediators (i.e. MMP), decreasing concentration of free fatty acids [64–66].

◦ Metronidazole has anti‐inflammatory, anti‐microbic, anti‐parasitic, and immunosup-

◦ Erythromycin is appropriate for children <8 years old to avoid the untoward effects of

⁻ Topical anti‐inflammatory agents: Topical corticosteroids suppress the exacerbation episodes and are effective in prevention of the recurrent corneal erosions when used in combination with systemic doxycycline [71]. The application would be tapered and stopped after the symptomatic relief. Topical steroids should be used cautiously, minimal dose with minimal duration, under the supervision of the ophthalmologist. Instead of steroids, topical cyclosporine (with 0.05% concentration) might be the choice for a longer period of

⁻ Dietary intervention with omega‐3 fatty acids for 6 months is effective in decreasing the

⁻ Surgical: Intraductal meibomian gland probing is shown to be a promising technique to improve dry eye symptoms related with OR [74]. Epilation of trichiatic lashes will elimi-

In cases of severe corneal involvement, surgical options are indicated [49]. Progressive epitheliopathy unresponsive to topical treatment with hazy epithelium extending centrally,

regularly to avoid exacerbations of symptoms.

◦ Clarithromycin are also effective to *H. pylori* [67].

◦ Azithromycin 3 times per week for 4 weeks [69].

dry eye symptoms and signs in ocular rosacea [73].

nate the mechanical insult to ocular surface.

restore the flora.

204 Acne and Acneiform Eruptions

other side effects.

pressive effects [68].

tetracycline [70].

treatment [72].

Long‐standing OR will end up with irregular eyelid margins and misdirected eyelashes (trichiasis). Untreated corneal involvement will lead to vision loss.

The long‐term use of topical steroids may cause increased intraocular pressure, cataract formation, corneal thinning, and exacerbation of underlying herpes. Chronic use of systemic antibiotics makes necessary to control the hepatic functions.

Although it is recommended to use low dose with a long duration, clinician should be cautious about the potential side effects of oral tetracycline as gastrointestinal discomfort, vaginal yeast infections, photosensitivity, and decreased effectiveness of oral contraceptives. It is not appropriate for the children <8 years old, because of its accumulation in bone, color changes in teeth, and interfering enamel development [76].

Oral isotretinoin, which has both anti‐inflammatory and immunomodulatory properties, has been used as a treatment for severe rosacea, particularly phymatous presentation by dermatologists [77]. In these cases, routine ophthalmologic follow‐up should be recommended since the retinoids may cause blepharoconjunctivitis, worsening telangiectasias and may lead to severe keratitis [78].

### **8. Conclusion**

Rosacea, mainly being a dermatological disease, may show ocular manifestations that sometimes may have severe consequences. The diagnosis mainly depends on the clinical findings and suspicion of the clinician. The evaluation and management should be performed by a collaborative approach by both dermatologist and ophthalmologist. The management should have a stepwise structure. The complications of both the disease and the treatment should be considered during the disease course.

### **Author details**

### Aysun Sanal Dogan

Address all correspondence to<EMAIL_ADDRESS>
Ophthalmology Department, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey

### **References**

**Author details**

206 Acne and Acneiform Eruptions

Aysun Sanal Dogan

Ankara, Turkey

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Ophthalmology Department, Diskapi Yildirim Beyazit Training and Research Hospital,

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dkn007.

### *Edited by Selda Pelin Kartal and Muzeyyen Gonul*

The aim of this book is to give readers a broad review of acne vulgaris and acneiform dermatoses, which may affect people from birth to death, and their treatment options. This book has a total of 14 chapters. The "Introductory Review" chapter focuses on the terms "acne" and "acneiform," one of which is a multifactorial disease of pilosebaceous unit and the other refers to dermatoses, which resemble acne vulgaris clinically but have different etiopathogenesis. Other 13 chapters are created by experts in different fields like dermatology, dermatosurgery, pathology, and ophthalmology. This book is easy to read and it includes illustrations, tables, patient photographs, and histopathological slides to support the written text and to enhance the reader's understanding. We are grateful to all the contributors and leading experts for their valuable chapters, which provide an in-depth view of all aspects of the content, backed with the most current literature in the field.

Acne and Acneiform Eruptions

Acne and Acneiform

Eruptions

*Edited by Selda Pelin Kartal and Muzeyyen Gonul*

Photo by Obencem / iStock