Acne Vulgaris - Current Opinion and New Phototherapeutic Options

Transcription

1 Acne Vulgaris - Current Opinion and New Phototherapeutic Options WILLIAM J. CUNLIFFE, MD FRCP Skin Research Center, Leeds University, Leeds General Infirmary, Leeds, UK INTRODUCTION. Acne is a very common problem affecting in various degrees most of the adolescent population. In about twenty percent it is of clinical significance. It usually begins around puberty, reaching a peak incidence and severity between 17 and 20 years and in 93% of the cases resolves at about the age of 25 years. In those seven percent in whom it persists the disease may last up to the age of 45 years. It is a disease of a specialised skin appendage the pilosebaceous follicle which is present predominantly on the face, back and chest. This review briefly discusses the etiology, clinical picture and therapy of acne. Etiology The four cardinal etiological factors of acne are: An increased sebum production Hypercornification of the pilosebaceous duct Colonization of the duct with Propioni-bacterium acnes (P.acnes) Inflammation Seborrhoea The sebaceous gland is an endocrine target gland; androgens have a major sebo-stimulatory role, estrogens have a relatively small sebo-suppressive action. Patients with acne produce more sebum than controls and this is often severity related and presents as seborrhoea. However, most patients are not endocrine misfits and only in exceptional cases is it necessary to investigate the patient for disorders such as polycystic ovarian syndrome. Hypercornification of the Duct This is represented clinically as whiteheads and blackheads, both of which probably start as histologically evident only, as microcomedones. This excessive accumulation of ductal corneo-cytes in the lumen of such lesions is due to hyperproliferation of ductal keratinocytes, but whether it is also due to failure of separation of the ductal keratinocytes is not known. The ductal keratinocytes are controlled by androgens, the composition of the sebum and cytokines produced within the duct. P.acnes Colonization Acne is not infectious but P.acnes, through their colonization of the duct, are likely to be central in the production of inflammation. P.acnes are non-motile. How they colonize the duct and produce biological substances such as inflammatory medicators and poryphrins is uncertain but such events may relate to the micro-environment of the duct. Inflammation Inflammation is a response of the circulating white cells to inflammatory mediators released from within the duct. In papules, T-helper cells are of paramount importance and duct rupture is by no means essential for early papule formation. In pustules the polymorphonucleocyte is the most important cell type. Late stage inflammation does involve duct rupture and in the most significant stage of inflammation a giant cell reaction is common. Resolution Little is known about the way individual lesions and the disease as a whole resolve. Copyright 2002 the Lumenis group of companies. All rights reserved.

2 2 CUNLIFFE: ACNE VULGARIS Acne PhotoClearing TM Application Note No. 2: Feb Clinical Presentation Patients with acne present with: Seborrhoea Non-inflamed lesions whiteheads and black-heads Superficial inflamed lesions papules and pustules Deep inflamed lesions nodules and deep pustules Scars due to loss of tissue atrophic scars Scars due to increase of tissue hypertrophic/ keloid scars Treatment Treatment principles should include: Patient discussion Compliance Topical therapy Oral therapy Physical therapy Patient Discussion This is essential and should include statements relating to the following facts: Food does not cause acne. Stress might make acne worse. Premenstrual flare occurs in 70% of females. Sunshine may help resolve acne. Make-up may be used it need not be medicated. Acne is a chronic disease. Oral therapy is likely to be prescribed inter-mittently for months. Topical therapy could be required for even longer. Other therapies exist including recently developed physical methods of treatment. The patient should be reassured that much can be done to help patients with acne. Compliance Time spent on the need to comply with therapy is essential. Topical Therapy The table below lists types of topical therapy used in various types of acne: ANTICOMEDONAL ANTI-INFLAMMATORY All trans retinoic acid Benzoyl peroxide Topical isotretinoin Antibiotics Adapalene Ezeleic acid Oral Therapy The table below lists drugs commonly used and their dosages: 1. Antibiotics: Tetracycline- 500mg BD Minocycline - 100(-200)mg/day Doxycycline - 100mg/day Erythromycin - 500mg BD 2. Dianette in sexually active females and where period control is required. 3. Oral isotretinoin for very severe disease and otherwise therapy resistant acne. Physical Therapy This includes physical removal of blackheads, aspiration of- and steroid injections into more recently developed cysts, and cryotherapy to older nodular cysts. More recently there have been developed new technologies relating to the use of phototherapy. This is highlighted later. Expected Response / Poor Responding Patients Most patients should do quite well showing approximately a 20% improvement each month attaining an 80% improvement at 8 months. However, in the past few years it has been observed that the response rate with all but oral isotretinoin therapy is less successful than it was. There could be several explanations for this. These include:

3 Acne PhotoClearing TM Application Note No. 2: Feb CUNLIFFE: ACNE VULGARIS 3 Inadequate compliance. Resistance of P.acnes to commonly used antibiotics. This phenomenon is an increasing event. Certain types of acne, such as in patients with sandpaper comedones and macrocomedones. Increasingly so patients demands and expectations for more effective and safer therapies. There are several possible side effects of therapy these include: A significant irritant dermatitis produced by topical therapy. Gastro-intestinal problems and vaginal candi-diasis with antibiotics. Pigmentation, benign intracranial hypertension and lupus erythematosus from Minocycline. Weight gain from Dianette. Oral isotretinoin has many muco-cutaneous and systemic side effects. The most serious side-effects are teratogenicity and adverse psychiatric events. Among other events which can lead to an inappropriate response is a failure by the physicians to adequately assess the acne in terms of its physical and psychosocial status. If the physician does not use adequate assessment techniques, which are really simple to use and are referenced, then errors in patient management may occur. The Future Much basic and clinical research is required to develop specific antiandrogen therapy, oral retinoids with a better benefit/risk ratio and specific anti P.acnes antimicrobial therapy. Phototherapy Of Acne Recently, and still ongoing are new developments in the phototherapy of acne. The concept is quite simple. P.acnes is the most prevalent microorganism on the skin and in the follicles of sebaceous rich areas. P.acnes produces endogenously porphyrins, in small amounts, the major component of which is coproporphyrin III. The production of these porphyrins is increased when the bacteria are exposed to wavelengths at violet/blue light spectrum, with a maximum at 415nm. The consequence of the photoactivation of bacterial porphyrines is singlet oxygen which is cytotoxic, resulting in an impaired function of P.acnes and death of the organism. For the interested reader, this destructive phenomenon is described in more detail. The exposure of P.acnes porphyrins to light around 415nm leads to photon absorption and photodynamic excitation of the porphyrins. In order to return to a stable molecular ground state, the porphyrins transfer the aquired excess energy to molecular triplet oxygen. Consequently, a labile cytotoxic singlet oxygen is released. This process results in peroxidation of cellular structures such as lipids, abundant in the cell wall of P.acnes. The eventual outcome is impaired function of P.acnes and bacterial death. The photodynamic treatment modality is dependent on the presence of three factors: a photosensitizer, light at an optimal wavelength, and oxygen. P.acnes is commonly referred to as anaerobic bacteria, however, it is microaerophilic in that it uses oxygen for energy-yielding respiration, but at lower concentrations than found in the air. Such microenvironmental conditions exist in the acne diseased A B C Figure 1: Before (A) and immediately after 8 bi-weekly treatments with ClearLight TM (B) and 1 month follow-up (C). Note the further improvement 1 month following cessation of treatment. Photos courtesy of Dr. Yoram Harth, Haifa, Israel

4 4 CUNLIFFE: ACNE VULGARIS Acne PhotoClearing TM Application Note No. 2: Feb pilosebaceous unit. Phototherapy using violet/blue visible light is therefore a reasonable option for the treatment of acne vulgaris. This type of phototherapy modulates a natural occurring mechanism, without introducing artificial additives. Moreover, this phototherapy selectively targets the porphyrins of P.acnes, which do not accumulate in the human host cells. The reaction is a fast enough procedure to be localized in the bacteria and not to affect the surrounding host cells. ClearLight is a new device based on phototherapy, using light at a wavelength spectrum of nm. Open studies and more recently a double blind half face study has shown the benefit of ClearLight therapy in reducing both noninflamed lesions and inflamed lesions over a 4-6 week period. The effect is most dramatic on inflamed lesions which fits well with the mechanism of porphyrin metabolism in controlling the growth and function of P.acnes. It has also been shown that such therapy has a direct effect on the modulation of inflammation. The therapy offers other advantages: The therapy is limited currently to 8 visits per course of therapy. It is likely to be associated with good compliance. It is virtually free of side effects. It should affect equally P.acnes which are sensitive to and resistant to antibiotics. It should not induce resistance to antibiotics in P.acnes. The therapy is associated with maintained improvement for up to 12 weeks post therapy and possibly longer. Repeat courses can be given. It is not likely to have a long term pre-malignant or malignant inducing effect, but long term surveillance is required. It can be combined with other therapies to prolong the remission period. Acne phototherapy can also be employed using a combination of low intensity red and blue light at 420nm and 670nm (84 sessions). This low power red and blue phototherapy has been shown in one study to be as effective as benzoyl peroxide. Photodynamic therapy with red or polychromatic visible light and the topical application of aminolevulinic acid has also been shown to be helpful in 2 studies. The aminolevulinic acid is taken up not only by P.acnes but also by the pilosebaceous unit and is metabolized to protoporphyrin IX. Treatment regimes are single or multiple. It was associated in some patients with considerable temporary pain and longer lasting perifollicular hyperpigmentation. Please note that phototherapy of acne is still in its relative infancy but it is likely to be a promising option. Of the available phototherapies, the greatest clinical experience is with ClearLight. However, many well controlled studies are required to assess what is the optimum time of therapy, frequency of therapy and which patients benefit the most as well as studies to understand the mechanisms of action. A B Figure 2: Before (A) and immediately after 8 bi-weekly treatments with ClearLight TM (B). Photos courtesy of Dr. Monica Elman, Holon, Israel

5 Acne PhotoClearing TM Application Note No. 2: Feb CUNLIFFE: ACNE VULGARIS 5 References 1. Alberts B. Bray D. Lewis J. Raff M. Roberts K. Watson JD. Molecular biology of the cell. Chapter 9: Energy conversion. 1983; Garland Publishing, Inc. New York. 2. Arakane K. Rya A. Hayashi C. Masunaga T. Shinmoto K. Mashiko S. Nagano T. Hirobe M. Singlet oxygen generation from coproporphyrin in Proprionibacterium acnes on irridiation. Biochem. Biophys. Res. Commun. 1996; 223: Cunliffe WJ. Gollnick HP. Acne diagnosis and management. 2001; Martin Dunitz, London. pp Cunliffe WJ. Goulden V. Phototherapy and acne vulgaris. Br. J. Dermatol. 2000; 142: Hongcharu W. Taylor CR. Chang Y. Aghassi D. Suthamjariya K. Anderson RR. Topical ALAphotodynamic therapy for the treatment of acne vulgaris. J. Invest. Dermatol. 2000; 115: Itoh Y. Ninimiya Y. Tajima S. Ishibashi A. Photodynamic therapy of acne vulgaris with topical delta-aminolaevulinic acid and incoherent light in Japanese patients. Br. J. Dermatol. 2001; 144: Lee WL. Shalita AR. Poh-Fitzpatrick MB. Comparative studies of porphyrin production in Propionibacterium acnes and Propionibacterium granulosum. J. Bacteriol. 1978; 133: Leyden JJ. Therapy for acne vulgaris. New England J. Med. 1997; 336: Obrien SC. Lewis JL. Cunliffe WJ. The Leeds revised acne grading system. J. Dermatol. Treatment 1998; 9: Papageorgiou P. Katsambas A. Chu A. Phototherapy with blue (415nm) and read (660nm) light in the treatment of acne vulgaris. Br. J Dermatol. 2000; 142: Peng Q. Warloe T. Berg K. et al. 5-aminolevulinic acid-badsed photodynamic therapy. Cancer 1997; 79: Strauss JS. Thiboutot DM. diseases of the sebaceous glands. Chapter 73 in Fitzpatrick RE, Dermatology in general medicine 6th ed. 1999; McGraw Hill, New York. 7. Kjelstad B. Johonsason A. An action spectrum for blue and near ultraviolet inactivation of P.acnes with emphasis on a possible porphyrin photosensitization. Photochem. Photobiol. 1986; 43: CLINICAL APPLICATION NOTES VOLUME 9 NUMBER 2

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