Disclaimer: This post is referenced in APA style, and so I need to learn the standard referencing system in dermatology. I try!
Type One Rosacea, Angiogenesis, Treatment and Retinoids
Crawford, Pelle, and James (2004) note that rosacea has been historically divided into stages which corresponds with a statement or implication that the disease will progress through the stages. In 2002 members of an expert committee assembled by the National Rosacea Society who met to standardise rosacea diagnostic criteria, did not discuss the stages (Crawford, Pelle, and James, 2004). They recognised only separate variants of rosacea.
Crawford, Pelle, and James (2004) argue that the most important factor in diagnosing rosacea is persistent erythema in the central portion of the face which lasts for at least 3 months. Generally the periocular skin is spared. Indeed, they state it should be the sole factor in diagnosing rosacea. Other features such as telangiectasia are viewed as supporting the diagnosis, but unnecessary for the diagnosis to be made (Crawford, Pelle, and James, 2004). Secondary features such as burning or stinging are indicative of the patient’s subtype of rosacea (Crawford, Pelle, and James, 2004).
Rosacea flushing usually lasts longer than 10 minutes, and this tendency allows the differentiation between mere blushing and flushing. Generally the central portion of the face flushes the most but the ears, neck, peripheral face, and upper chest may be involved too (Crawford, Pelle, and James, 2004). The periocular skin is spared. Flushing may triggered by stimuli such as alcohol or emotions (Crawford, Pelle, and James, 2004). Other times there may be no known stimuli. Burning and stinging may accompany flushing but sweating, light-headedness or palpitations do not (Crawford, Pelle, and James, 2004). Generally there is no history of acne (Crawford, Pelle, and James, 2004).
It is common for patients who request a diagnosis and treatment for rosacea to only have severe sun damage (Crawford, Pelle, and James, 2004). As is the case with rosacea sun damage can produce erythema which generally spares the periocular skin, and notable telangiectases. However these features are found on most sun exposed surfaces such as the neck and the upper part of the chest, mostly in women (Crawford, Pelle, and James, 2004). This is because sun damage is a mildly inflammatory process. Dyspigmentation is present in the majority of patients (Crawford, Pelle, and James, 2004).
Individuals with erythematotelangiectatic rosacea, are unfortunate, in that their symptoms are difficult to treat (Korting, & Schöllmann, 2009). Often they respond poorly to topical or oral medications. However there is evidence to suggest that isotretinoin may improve inflammation caused erythema for some time (Korting, & Schöllmann, 2009). Light therapy, vascular laser and medications that help prevent flushing have proven beneficial in controlling the condition (Korting, & Schöllmann, 2009).
In regards to the general use of antibiotics in treating rosacea, it is generally agreed by researchers that it the non-antibiotic properties of the tetracyclines that are responsible for their usefulness in treating skin diseases, including rosacea (Korting, & Schöllmann, 2009). These non-antibiotic properties include the inhibition of angiogenesis, the inhibition of pro-inflammatory cytokines, the inhibition of neutrophil chemotaxis, and the inhibition of matrix metalloproteineses. It follows that because antibiotics have various non-antibiotic effects, which can be used to treat a myriad of conditions including autoimmune disorders such as rheumatoid arthritis, sarcoidosis, and aortic aneurysms (Korting, & Schöllmann, 2009). The ability of tetracyclines to reduce the inflammatory response is particularly relevant to the treatment of rosacea (Greewald et al, as cited in Korting, & Schöllmann, 2009).
Second generation tetracyclines offer advantages in the treatment of rosacea in comparison to their classic variants (Korting, & Schöllmann, 2009). These include minocycline and doxycycline (Korting, & Schöllmann, 2009). They have improved bioavailability, can be taken with food to reduce gastrointestinal side effects, and have a longer elimination half-life. They are helpful in treating rosacea at a sub-antimicrobial dose, which also exerts anti-inflammatory effects (Korting, & Schöllmann, 2009). This allows for the evasion of the disadvantages associated with long term antibiotic use including candial vulvovaginitis, gastrointestinal distress, and the development of bacterial resistance (Korting, & Schöllmann, 2009). It follows that when microbial pathogenesis is not indicated that such treatments as low dose doxycycline should constitute a preferred treatment in dealing with rosacea (Korting, & Schöllmann, 2009).
It could be argued that the anti-angiogenic and anti- inflammatory function of antibiotics might be useful in alleviating erythematotelangiectatic rosacea to some degree.
Isotretinoin is useful in treating several rosacea subtypes, however the studies concerning its use are generally poor (Korting, & Schöllmann, 2009). Only small poor studies are available. In one study isotretinoin was effective in treating both erythematotelangiectatic and papulopustular rosacea erythematotelangiectatic and papulopustular rosacea. Interestingly, reduced facial cutaneous blood flow was noted in isotretinoin treated individuals but not in the oxytetracycline treated comparison group (Irvine et al, as cited in Korting, & Schöllmann, 2009). Another study showed that four months of low dose isotretinoin therapy (10mg daily) was useful in treating 22 patients with therapy-resistant rosacea. Isotretinoin led to a reduction in inflammatory lesions, erythema and telangiectasia, however its effects manifested slower in comparison to the oral antibiotics used to treat the comparison group (Korting, & Schöllmann, 2009).
Because I have acne and mild rosacea like symptoms I have decided to find data on the use of topical retinoids which are often used to treating mild to moderate acne. A few studies have shown that retinoids like tretinoin can be useful in treating rosacea, however the clinical response if often delayed (Korting, & Schöllmann, 2009). It can take 2 months or more until clinical response is evident. Generally topical retinoids are avoided because of the notion that retinoids can encourage angiogenesis (Korting, & Schöllmann, 2009). However an increase in cutaneous vascularity and the development of telangiectasia have not been observed (Korting, & Schöllmann, 2009). Indeed, a lessening of erythema coupled with a partial to complete disappearance of telangiectasia has been noted for patients treated with 0.025% tretinoin cream (Korting, & Schöllmann, 2009). Despite this the evidence is based on a trial situation which is relatively poor (Korting, & Schöllmann, 2009).
Relatedly Kligman (1993) treated nineteen adult women with persistent papulopustular rosacea. A low strength 0.025% tretinoin (Retin-A, Johnson & Johnson) cream was employed for a period of 6-12 months (Kligman, 1993). The dosage was well tolerated, and near half of the patients experienced complete clearing for 6 months after finishing treatment. Erythema lessened and there was at least a partial reduction in telangiectasia (Kligman, 1993). It is believed that the anti-inflammatory and photo damage ameliorating properties of tretinoin were at least partly responsible for the improvement (Kligman, 1993). That said tretinoin is indeed comedolytic which is not relevant to rosacea.
Adapalene is derived from naphthoic acid and has potent retinoid properties, it has demonstrated anti-inflammatory and antiproliferative activityin vitro and vivo studies (Altinyazer, Koca, Teken & EÍtürk , 2004). Acne patients tend to find it is less irritating than tretinoin gel.
Altinyazer et al (2004) treated 55 patients with papulopustular rosacea with either adapalene (0.1%) or metronidazole (0.75%) in an investigator blind comparison. Patients were randomly assigned to either condition after the initial sample was subject to a systematic process of exclusion. For examples patients using medications that might affect the adapalene or metronidazole were excluded (Altinyazer et al, 2004). Only patients diagnosed with papulopustular rosacea according to the Standards of the National Society Expert Committee and who had at least 10 papules or pustules were accepted into the study. Sun protection SPF 20 was used by all patients (Altinyazer et al, 2004). The nature and number of papules and pustules, erythema and telangiectasia were scored at baseline, and then after 2, 4, 8, and 12 weeks (Altinyazer et al, 2004). Additionally patient side effects were reported at each visit.
Altinyazer et al (2004) found that adapalene (0.1%) was useful in treating papules and pustules but had little effect on erythema and telangiectastic. Adapalene is less irritating than other retinoids, it was generally well tolerated in the study with some patients experiencing mild transitory irritation (Altinyazer et al, 2004). It found to be effective in treating the papules and pustules in patients with rosacea but not in reducing the erythema and telangiectasia (Altinyazer et al, 2004). However the study only lasted for 3 months, a vehicle control was not used, and the study was not double blinded.
As noted by Kligman (1993) Pharmacologic and preclinical studies have demonstrated that adapalene may reduce photo-aging which might explain its usefulness in treating rosacea (Altinyazer et al, 2004).
Interestingly Dr Pelle uses topical retinoids to treat rosacea on the basis that it can help repair the dermal anatomy by decreasingly abnormal elastin, increase collagen, increase glycosamonoglycans and decrease telangiectasias (Heymann, 2004). That said, Dr Pelle recommends preparing the skin with a moisturiser first. Relatedly Lachgar et al demonstrated that the quantity of cell-associated and secreted VEGF decreased strongly with retinoid concentration (Heymann, 2004). It was concluded that the decrease in VEGF expression by keratinocytes caused by retinoids might prevent skin angiogenesis in diseases like rosacea (Heymann, 2004). Furthermore retinoid is recognised by the Angiogenesis Foundation as a known angiogenesis inhibitor (2014).
The evidence, even though there it is limited and not of quality, seems to suggest that topical retinoids would be acceptable to treating acne rosacea. However there appear to be differences in the effectiveness of the sorts of topical retinoids available. At face value, it would seem that Retin A is more effective than adapalene, however adapalene is much less irritating than Retin A. I do not think there is not enough evidence to suggest conclusively state that Retin A should be employed over adapalene. I note that the Retin A in Kligman’s (1993) study was created by Johnson & Johnson, and I wonder why the name of the company was mentioned in the abstract.
What’s really interesting is the possibility that topical retinoids can be antiangiogenic as noted by Korting and Schöllmann (2009) and Heymann (2004). Their photo-damage reducing properties also appear useful (Altinyazer et al, 2004; Kligman, 1993; Heymann, 2004). Naturally the antiangiogenic properties also apply to oral antibiotics (Korting & Schöllmann, 2009). That said I do not believe topical retinoids are the best topical treatment for the most forms of rosacea. In my case it could be especially risky as it not yet known whether my rosacea like symptoms were mediated by Accutane. If you were to use topical retinoids in treating rosacea I would use a cream version as it acts as a buffer, use a weaker retinoid to start, use the retinoid sparingly, and perhaps mix it into your moisturiser. As a final note, I think it is possible that topical retinoids have a unique role in slowing down the early signs of rosacea due to their antiangiogenic properties.
Altinyazer, H., Koca, R., Tekin, N., & EÍtürk, E. (2004). Adapalene vs. Metronidazole Gel for the Treatment of Rosacea. International Journal of Dermatology. 44 (3), 252-255.
Crawford, G., Pelle, M., & James, W. (2004). Rosacea: I. Etiology, pathogenesis, and subtype classification. Journal of the American Academy of Dermatology. 51 (3), 327–341.
Heymann, R. (2004). Rosacea Subtype Directed Therapy. Journal of the American Academy for Dermatology. 51 (1), 90-92.
Kligman, A. (1993). Topical tretinoin for rosacea: a preliminary report. Journal of Dermatological Treatment. 4 (2), 71-73.
Korting, H., & Schöllmann C. (2009). Current Topical and Systematic Approaches to Treatment of Rosacea. Journal of the European Academy of Dermatology and Venereology. 23 (8), 876-882.
The Angiogenesis Foundation, (2014). Growth Factors & Inhibitors. Retrieved from http://www.angio.org/learn/angiogenesis/