DRUG THERAPY TOPICS A Review of the Anti-inflammatory Properties of Clindamycin in the Treatment of Acne Vulgaris James Q. Del Rosso, DO; Nicholas F. Schmidt, PhD This article reviews anti-inflammatory properties associated with topical clindamycin when used to of clindamycin, which is often used topically for treat acne vulgaris. Given these observations, it is not the management of acne vulgaris, usually in com- surprising that the combination of clindamycin and a bination with other agents. The efficacy of clinda- topical retinoid in the same topical acne treatment mycin in acne treatment has been shown to be regimen or single vehicle formulation (ie, clindamy- sustained for more than 3 decades. It is likely that cin phosphate 1.2%–tretinoin 0.025% gel) is known anti-inflammatory effects play an importantCUTIS role in to be more therapeutically effective than either drug the therapeutic activity of topical clindamycin. used alone.1-3 Cutis. 2010;85:15-24. Do NotWhat Copy information is available on the pathogenesis his article reviews anti-inflammatory properties of acne that may correlate with the clinical of clindamycin, which is commonly used topi- relevance of anti-inflammatory properties of T cally for the management of acne vulgaris. Top- therapeutic agents used to treat acne vulgaris? ical clindamycin is most often utilized in combination The pathogenesis of acne is not completely under- with other topical agents, such as benzoyl perox- stood. However, it generally is agreed that develop- ide, and/or a retinoid. Anti-inflammatory properties ment of acne lesions occurs in relation to several reported in association with clindamycin, expressed factors, including hormones, primarily androgenic at the cellular and molecular level, may correlate stimulation of the sebaceous follicle (piloseba- with positive therapeutic outcomes observed during ceous unit); excess sebum production; abnormal acne treatment. This article serves as a compilation follicular keratinization; follicular proliferation of of data from multiple sources that allow the reader Propionibacterium acnes; stimulation of innate immune to develop an overall appreciation for the potential response by P acnes; induction and perpetuation of an therapeutic relevance of anti-inflammatory properties inflammatory cascade by several proinflammatory enzymes, cytokines, and chemokines; and a second- ary inflammatory response to follicular disruption Dr. Del Rosso is from Valley Hospital Medical Center, when present.1,4-8 Las Vegas, Nevada. Dr. Schmidt is an independent consultant, Proinflammatory agents involved in the acne- Roxbury, Connecticut. Dr. Del Rosso is a consultant, researcher, and speaker for genic inflammatory cascade include enzymes such Allergan, Inc; Coria Laboratories, Ltd; Galderma Laboratories, as lipase that are known to release cytotoxic free LP; Graceway Pharmaceuticals, LLC; Intendis, Inc; Medicis fatty acids from sebum, as well as protease, hyal- Pharmaceutical Corporation; Obagi Medical Products, Inc; Onset uronidase, and neuramidase. These enzymes can Therapeutics; OrthoNeutrogena; Quinnova Pharmaceuticals, Inc; damage the follicular wall leading to leakage of Ranbaxy Laboratories Ltd; SkinMedica, Inc; Stiefel Laboratories, Inc; Triax Pharmaceuticals, LLC; Unilever; and Warner Chilcott. contents into the surrounding dermis, which fur- 9-15 Dr. Schmidt is a consultant for Medicis Pharmaceutical Corporation. ther propagates inflammation. Other proin- Correspondence not available. flammatory agents that have been associated with VOLUME 85, JANUARY 2010 15 Copyright Cutis 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Drug Therapy Topics P acnes include heat shock proteins, porphyrin, and extensive family of biologically active cytokines that squalene peroxides.6,13,16,17 P acnes can upregulate, 3 important subgroups play The pilosebaceous unit can be considered an an important role as proinflammatory mediators immunocompetent organ.18 As such, it is sensitive during the early stages of acne lesion development: to changes and stimuli that signal the beginning (1) chemokines, which function as chemotactic of a localized inflammatory process. Although the cytokines; (2) cytokines, which serve as messenger earliest sequence of events leading to an inflamed molecules; and (3) interleukins, which can serve to acne lesion remains somewhat controversial, attract specific inflammatory cells.31,32 Table 1 sum- generally it is accepted that the first objective marizes the spectrum of proinflammatory agents and evidence of a subclinical acne lesion is the micro- subsequent inflammatory challenges associated with comedone.8 At this early stage, it is now believed P acnes. that an inflammatory cascade may simultaneously In acne lesion development, a variety of immu- occur in many cases.19,20 In some affected follicles nologically active cell types respond and contribute but not others, progression to the development to the localized inflammatory cascade, including of visible comedones and/or inflammatory acne T cells, CD41 cells, and CD141 cells.18,44,47-50 Acti- lesions occurs.8 vated monocytes transform into macrophages and Importantly, P acnes releases potent low-molecular- begin to surround and engulf foreign materials weight (LMW) chemotactic factors and lipase present in the perifollicular region. Intracellularly, enzyme during the early stages of preinflammatory phagocytosing neutrophils and macrophages release and inflammatory acne lesion development.21-26 various degradative lysosomal enzymes and toxic These proinflammatory factors enter the dermis chemicals such as reactive oxygen species (ROS) surrounding the follicle, thus attracting inflam- that attempt to remove P acnes and its extracellular matory cells such as neutrophils, monocytes/ products.51-54 With continued stimulation, the inflam- macrophages, and lymphocytes to the affected matory cascade amplifies, the cycle perpetuates, and perifollicular region.4,14,21,27-30 there is further damage and rupture of follicular Cytokines are LMW peptides andCUTIS glycoproteins wall integrity.6,55-58 that represent components of the host response pro- Some other proinflammatory factors have been viding chemical communications and transmissions implicated as potential pathogenic mechanisms between cellular constituents of the immune sys- in acne vulgaris such as granulocyte-macrophage tem. Importantly, these chemical mediators serve to colony-stimulating factor (GM-CSF), leukotri- Do Not Copy7,14,18,47,59,60 direct cellular “traffic” so that an organized immu- ene B4, and HLA-DR. Granulocyte- nologic defense can be mounted.31 Within the macrophage colony-stimulating factor promotes Table 1. Proinflammatory Agents Associated With Acne Lesion Development/ Propionibacterium acnes Proinflammatory Cytokine Early Response Factors P acnes Tissue P acnes P acnes Cytokine (Chemokines/Interleukins/ Damage Factors Chemotactic Factors Stimulant Factors Interferons/Others) Fatty acids6,15,33,34 Lipase enzyme23,37 Heat shock IL-1a17,18,38-43 proteins13,16-18 Porphyrin13,35,36 Other neutrophil and IL-1b41,44 immunocyte chemotactic 6 17,38,39,42,43 Squalene peroxides factors4,14,21,24,27-30 IL-6 Protease, hyaluronidase, C5a18 IL-841,44,45 neuramidase9,11,12,14,37 TNF-a17,18,41,42 Keratin1,6 IFN-g18,46 Abbreviations: TNF-a, tumor necrosis factor a; IFN-g, interferon-g. ® 16 CUTIS Copyright Cutis 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Drug Therapy Topics growth of leukocytes involved in the inflamma- clindamycin reduces the presence of many chemotac- tory response, and leukotriene B4 has been shown tic and cytotoxic proinflammatory agents produced to recruit and activate neutrophils, monocytes, by the organism. As such, the antibiotic effect of and eosinophils to sites of infection. This latter clindamycin serves to downregulate the inflammatory cytokine is synthesized from arachidonic acid response because the source of these inflammatory through the combined action of the 2 enzymes mediators, namely P acnes, has been quantitatively 5-lipoxygenase and leukotriene A4 hydro- suppressed. It has been established that clindamycin lase.7,14,18,59,60 HLA-DR is a specialized protein reduces the proliferation of P acnes.72 As a result, the upregulated by Langerhans cells during an infec- immunogenic potential of P acnes is diminished. tious challenge, which helps to present antigens and activate the local immune response.47 Complement- activated C5-derived neutrophil chemotactic How does clindamycin-associated decrease in factors attract more leukocytes and propagate lipase production potentially correlate with further inflammation. Other important factors anti-inflammatory activity in acne treatment? and mediators associated with P acnes inflam- Follicular proliferation of P acnes results in increased mation are IL-12, toll-like receptors, activator production of extracellular lipase, the enzyme respon- protein-1 transcription factor, vascular cell adhe- sible for the conversion of sebum triglycerides to free sion molecules, degranulation in macrophages, fatty acids.23,37 Interestingly, subinhibitory levels of growth factors, and expression of transglutaminase clindamycin against P acnes have been shown to sup- and lipoxygenase.38,44,46,47,50,61-69 press the in vitro production of lipase enzyme from 2 different strains of Propionibacterium species.73