.. JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
`.c - -
`.
`March 1997
`
`ISSN 0141-0768
`
`Volume 90
`
`Number 3
`
`Editorials
`Hazards of growing up
`Growth hormone for adults
`Issue of the day
`Are you competent with congenital heart disease?
`Original articles
`Death in heart disease
`Intestinal stenting to prevent adhesional obstruction
`Cardiac investigations before renal transplantation
`Review articles
`Why has stroke mortality been falling?
`Rosacea
`Economics of laboratory testing
`Case reports
`Eye drops and lethargy
`Long-term hypercalcaemia in sarcoidosis
`Lump in the groin--orthopaedic
`Kasabach-Merritt and Down's
`Enterocutaneous fistula in an Ethiopian
`Misleading presentation
`Chilblains .or cancer
`History:
`The missing doctor
`Per~onal papers
`Airships, space shuttles, and biologicals
`The treasures of Blythe House
`Art in hospitals
`The Gabo Fountain at St Thomas'
`Book · of the month
`Evolutionary psychiatry
`Letters
`Complementary medicine in the curriculum • useful plants •
`Community hospitals • Hospital-at-home • Save the ESR • Sailors,
`scurvy and science • Helicobacter pylori infection
`
`',
`Univ. ~; Minn
`Bio-Medical ·
`Librarv .
`97
`
`Published by The Royal Society of Medicine 1 Wimpole Street Lond
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1034
`
`The ROYAL
`SOCIETY lif
`MEDICINE
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`
`The ROYAL
`SOCIETY cif
`MEDICINE
`
`_ JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
`c__--
`
`March 1997
`
`Volume 90
`
`Number 3
`
`ISSN 0141-0768
`
`Editorials
`Hazards of growing up
`Growth hormone for adults
`
`lssue of the day
`Are you competent with congenital heart disease?
`
`Original articles
`Death in heart disease
`Intestinal stenting to prevent adhesional obstruction
`Cardiac investigations before renal transplantation
`Review articles
`Why has stroke mortality been falling?
`Rosacea
`Economics of laboratory testing
`Case reports
`Eye drops and lethargy
`Long-term hypercalcaemia in sarcoidosis
`Lump in the groin-orthopaedic
`Kasabach-Merritt and Down' s
`Enterocutaneous fistula in an Ethiopian
`Misleading presentation
`Chilblains or cancer
`History
`The missing doctor
`Personal papers
`Airships, space shuttles, and biologieals
`The treasures of Blythe House
`Art in hospitals
`The Gabo Fountain at St Thomas'
`
`Book of the month
`Evolutionary psychiatry
`letters
`Complementary medicine in the curriculum e useful plants e
`Community hospitals e Hospital-at-horne e Save the ESR e Sailors,
`scurvy and science e Helicobacter pylori infection
`
`Published by The Royal Society of Medicine 1 Wimpole Street London W1 M 8AE
`
`Exh. 1034
`
`

`
`JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 90 Marcll 1997
`
`Rosacea: classificatio and treatment
`Thomas Jansen MD Gerd Plewig MD
`
`J R Soc Med 1997;90:144-150
`
`Rosacea is a chronic skin disorder affecting the facial
`convexities, characterized by frequent flushing, persistent
`erythema, and telangiectases. During episodes of inflamma-
`tion additional features are swelling, papules and pustules.
`The disease was originally called acne rosacea, a misleading
`term that unfortunately persists 1•
`Rosacea is a common disease, especially in fair-skinned
`people of Celtic and northem European heritage; it has
`been called the curse of the Celts. It is rare in American and
`African blacks2. W omen are more often affected than men,
`but they seldom suffer the gross tissue and sebaceous gland
`hyperplasia of rhinophyma. Onset is usually between ages
`30 and 50. In a recent epidemiological study the prevalence
`was 10%, most of the patients having only a red face3. In
`young patients especially, there may be a history of acne and
`the conditions may coexist.
`
`PATHOGENESIS
`The exact aetiology of rosacea is unknown and theories
`abound4. Gastrointestinal disturbances, notably dyspepsia
`with gastric hypochlorhydria, were long suspected of being
`a causal factor, but controlled
`investigations with a
`gastrocamera5 and biopsy studies6 revealed no association.
`Helicobacter pylori has come under suspicion, but results are
`conflicting7 . For example, Powell et al. 8 found H. pylori
`antibody in 19 of 20 patients, while Schneider et al. 9 found
`no statistical difference in positivity between patients ( 49%)
`and controls
`( 43%). Psychogenic
`factors have been
`frequently implicated but there is no good evidence that
`the condition is associated with personality type or is
`precipitated by emotional disturbance.
`The theory of hypersensitivity to Demodex jolliculorum or
`its products is based primarily on the distribution of rosacea
`and the mite, the follicular nature of rosacea, and the
`finding of the mite in areas of acute inflammation in some
`cases of rosacea 10. However, D. jolliculorum mites are
`normal inhabitants of human follicles and sebaceous glands
`and application of 3% sulphur ointment, while resulting in
`clinical improvement of rosacea, did not affect the Demodex
`population11 . At most, the mite induces papule or pustule
`
`Department of Dermatology, Ludwig-Maximilians-University, Frauenlobstrasse
`9-11, D-80337 Munich, Germany
`Correspondence to: Thomas Jansen MD
`
`144
`
`in pre-existing rosacea. Rosacea was once
`formation
`regarded as a seborrhoeic disease. Seborrhoea is, however,
`not always present12 . Unlike acne vulgaris, rosacea is not
`primarily a disease of sebaceous follicles.
`The pathogenesis of rosacea thus remains obscure. What
`is certain, however, is that rosacea patients are constitu-
`tionally predisposed to blushing and flushing. The basic
`abnormality seems to be a microcirculatory disturbance of
`the function of the facial angular veins 13 . Statistical
`associations between rosacea-related flushing and migraine
`suggest a shared disorder of vascular regulation 14 but there
`is no direct evidence that rosacea is primarily a vascular
`disorder. The response of the facial vessels to adrenaline,
`histamine and acetylcholine is normal, 15 and the vessels do
`not seem abnormally fragile 16 so the main abnormality is
`probably in the dermis surrounding blood vessels rather
`than in vessel walls. In addition, the distribution of rosacea
`is not identical with the flush area. A very important
`background feature
`is sun damage. Rosacea is always
`associated with solar elastosis and often with helioderma-
`tosis 17 . Fair-skinned patients with rosacea type I will often
`give a history of sun sensitivity.
`
`CLINICAL FINDINGS
`Rosacea is usually symmetrically distributed over the face and
`is particularly obvious over the nose, cheeks, chin, forehead,
`and glabella. Occasionally, lesions are seen at extrafacial sites
`including the retroauricul~ areas, the V -shaped area of the
`ehest, the neck, the back, and the scalp and extremities 18 . The
`hallmarks of rosacea are papules and papulopustules, vivid-red
`erythema, and telangiectases and a history of flushing.
`Comedones are notably absent. In severe cases papules are
`numerous enough to be confluent. Granulomatous changes
`can develop in later stages, sometimes receiving special
`designations such as lupoid rosacea. Rhinophyma and other
`phymas are the ultimate tissue reactions. For didactic but also
`for therapeutic reasons rosacea is classified into stages and
`grades. The progression is not inevitable, and few patients
`experience the full course of the disease.
`
`Episodic erythema
`Most rosacea patients react with transient erythema on the
`central areas of the face, less often the neck and the V -shaped
`area of the ehest. These individuals are constitutionally
`
`Exh. 1034
`
`

`
`JOURNAL OF THE ROYAL SOCIETY OF MEDlCINE Volume 90 March 199
`
`predisposed to blushing and flushing (rosacea diathesis). The
`reactions are more frequent and more easily induced than
`ordinary blushing. Numerous non-specific stimuli such as
`ultraviolet radiation, heat, cold, chemical irritation, strong
`emotions, alcoholic beverages, hot drinks, and spicy food
`can trigger these flares. It is a mistaken belief that tea and
`coffee are precipitants; the specific stimulus is heat19 .
`Among the mediators proposed to be involved in the
`erythematous response are substance P, histamine, seroto-
`nin, and prostaglandins but the trigger remains unknown.
`
`Stage I
`The erythema persists for hours and days, hence the old
`description erythema congestivum. Erythema lasting only a
`few minutes is not early rosacea. Telangiectases become
`progressively more prominent, forming sprays on the nose,
`nasolabial
`folds, cheeks, and glabella. Most patients
`complain of sensitive skin that stings and burns after
`application of cosmetics, fragrances, and certain sunscreens.
`Trauma from abrasives and peeling agents readily induces
`long-lasting erythema. Thus the facial skin is unusually
`vulnerable to chemical and physical stimuli.
`
`Stage II
`Inflammatory papules and pustules develop and persist for
`weeks. Some papules show a small pustule at the top. The
`lesions are always follicular in origin-mainly sebaceous
`follicles but also the smaller and more numerous hair
`follicles. The deeper inflammatory lesions may heal with
`scarring, but scars are small and tend to be shallow. Facial
`pores become larger and more prominent. If there has been
`heavy solar exposure for decades, the stigmata of photo-
`darnage become superimposed-namely elastosis, solar
`comedones, and heliodermatosis. The papulopustular
`attacks become more frequent. Rosacea may extend over
`the entire face and even spread to the scalp, especially if the
`patient is balding. Itchy follicular pustules of the scalp are
`typical. Bacteriological studies of these pustules reveal
`nothing of interest. Finally the sides of the neck and the
`retroauricular and presternal area may be affected. Even the
`palms may show persistent erythema.
`
`Stage 111
`A small proportion of patients progress to the worst
`expressions of the disease-namely, large inflammatory
`nodules, furunculoid infiltrations, and tissue hyperplasia.
`These derangements occur particularly on the cheeks and
`nose, less often on the chin, forehead, or ears. The facial
`contours become coarse, thickened, and irregular. Finally
`the patient shows inflamed and thickened oedematous skin
`with large pores, resembling the surface of an orange (peau
`
`d' orange). These coarse features are due to inflammatory
`infiltratic>n, connective tissue hypertrophy with masses of
`collagen deposition, diffuse sebaceous gland hyperplasia,
`and overgrowth of individual sebaceous glands forming
`dozens of yellowish umbilicated papules on cheeks,
`forehead, temples and nose. Thickened folds and ridges
`create a grotesque appearance resembling the leonine fades
`of leprosy. The ultimate deformities are the phymas, of
`which rhinophyma is the archetype.
`
`ROSACEA VARIANTS
`The diagnosis of rosacea in its dassie forms presents no
`difficulty. The variants, however, may be overlooked or
`misdiagnosed.
`
`Persistent oedema of rosacea
`The published work hardly mentions this distressing variant.
`It has been reported as Morbihan disease or rosaceous
`lymphoedema20,21 . A hard non-pitting swelling is found on
`the areas involved, mainly on the forehead, glabella, nose,
`or cheeks. A similar oedema sometimes arises in acne andin
`the Melkersson-Rosenthal syndrome; it develops against a
`background of chronic inflammation of any cause, including
`bacterial infection.
`
`Ophthalmie rosacea
`Eye involvement is surprisingly common. Indeed, the disease
`may begin in the eye and escape diagnosis for a long time. The
`ophthalmic signs include blepharitis, conjunctivitis, iritis,
`iridocyclitis, hypopyon-iritis, and even' k~ratitis22 . The term
`ophthalmic rosacea covers all these signs. The incidence is not
`known but more than half of patients participating in a
`cooperative isotretinoin trial for the treatment of rosacea
`were diagnosed by ophthalmologists as having inflammatory
`eye involvement23 , blepharitis and conjunctivitis being the
`most common. The ophthalmic complications are indepen-
`dent of the severity of the facial rosacea but there is a strong
`correlation between the degree of eye involvement and a
`tendency to flushing24• Rosacea keratitis has an unfavourable
`prognosis, and in extreme cases leads to corneal opacity and
`blindness. Perhaps the most frequent" eye sign is chronically
`inflamed margins of the eyelids, with scales and crusts, quite
`similar to seborrhoeic dermatitis, with which it is often
`confused. Pain and photophobia may be present. All patients
`with progressive rosacea should be seen by an ophthalmologist.
`
`Lupoid or granulomatous rosacea
`Some patients develop epithelioid (lupoid) granulomas in a
`diffuse pattern25 . Clinically, dozens ofbrown-red papules or
`little nodules on a diffuse erythema, frequently involving the
`lower eyelids, are seen. Histopathological examination
`
`145
`
`Exh. 1034
`
`

`
`JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volurne 90 March 1997
`
`shows perifollicular and perivascular granulomas. The
`concept of a rosacea-like tuberculide of Lewandowsky was
`based only on the tuberculoid structure found histologically
`in many papules; however,
`the condition is probably
`unrelated
`to
`tuberculosis.
`Its course
`is chronic and
`unremittent. Differential diagnosis includes lupoid perioral
`dermatitis,
`lupoid steroid rosacea, and micronodular
`sarcoidosis.
`
`Steroid rosacea
`When a rosacea patient is erroneously treated with topical
`the disorder may at first respond, but the
`steroids
`improvement will be followed by steroid atrophy with
`thinning of the skin and an increase in telangiectases26 . The
`complexion becomes dark-red with a copper-like tone.
`Soon the surface becomes studded with follicular, round,
`deep papulopustules and firm nodules. The appearance is
`shocking, with a flaming red, scaling, papule-covered face.
`The distribution can extend over the entire area of
`application of the topical steroid, often up to the hairline.
`Steroid rosacea is a pitiable, avoidable condition which in
`addition
`to disfigurerneut
`is accompanied by severe
`discomfort and pain. Withdrawal of the steroid is followed
`by exacerbation of the disease.
`
`Gram-negative rosacea
`This is a newcomer among Gram-negative infections27.
`Clinically it looks like stage II or III disease. Multiple tiny
`yellow pustules (type I) or deep-seated nodules (type II)
`increase suspicion. Neither oral antibiotics nor metronida-
`zole will control it. The diagnosis rests on demonstration of
`Gram-negative organisms by culturing the contents of
`several pustules. The disease is analogaus to Gram-negative
`folliculitis which sometimes develops on top of acne
`vulgaris28 . The organisms· are the , same: Klebsiella, Proteus,
`Escherichia coli, Pseudomonas, Acinetobacter, and others.
`
`Rosacea conglobata
`Rarely a patient with severe rosacea shows a reaction that
`mirnies acne conglobata, with haemorrhagic nodular
`abscesses and indurated plaques. The course is progressive
`and chronic. This variant mainly occurs in women. It may
`be provoked by oral
`ingestion of halogen-containing
`preparations. Diagnostic features are pre-existing rosacea
`and Iimitation to the face, with no other signs of acne
`conglobata on back, ehest, shoulders, or extremities.
`
`Rosacea fulminans
`This variant was first described by O'Leary and Kierland29
`under the designation pyoderma faciale. It has been a matter
`of controversy ever since. One can say with certainty that it
`is not a variant of acne; neither is it pyoderma. The name
`
`rosacea fulminans was coined by analogy with its acne
`counterpart, acne fulminans 30,31 . This is a conglobate,
`nodular disease springing up abruptly on the face of young
`females. Curiously, it does not occur in males. Rosacea
`fulminans is confined to the face. Once seen it is never
`forgotten. Monstrous coalescent nodules and confluent
`draining sinuses occupy most of the face. The main
`locations are the chin, cheeks, and forehead. Ripe abscesses
`top of the
`form with multiple pustules riding on
`is diffusely reddened.
`carbunculoid nodules. The face
`Seborrhoea is a constant feature but may be overlooked.
`When questioned closely, patients will often describe the ·
`development of oiliness before the onset. Previous acne or
`rosacea
`is usually denied; however, we perceived a
`connection to rosacea because, after the stormy blow-up,
`their appearance. Some
`signs of rosacea often make
`patients, too, have been flushers and blushers. Aetiology
`remains obscure. Often blamed is severe emotional stress,
`such as the death of a family member, divorce, or loss of a
`lover, but some patients are stress-free. The prognosis is
`excellent. Once the disease has been brought under control
`it does not recur. Differential diagnosis includes acne
`conglobata (young patients, mostly males, Ionger history,
`other signs of acne, comedones, scars, seborrhoea, no
`flushing or blushing), acne fulminans (usually seen in
`teenage boys), bromoderma, iododerma, and virilizing tumours.
`
`PHYMAS IN ROSACEA
`Phyma is the Greek word for swelling, mass, or bulb.
`Phymas occur in various -;zreas of thtt face and ears,
`rhinophyma (rhinos=nose) heilig the commonest. It occurs
`exclusively in men and fortunately it is a rare complication.
`Rhinophyma may be perceived by the public as due to
`excessive alcohol consumption, as in the comedian W C
`Fields. The bulbous nose develops over many years as a
`increase
`in connective
`tissue,
`result of progressive
`sebaceous gland hyperplasia, ectatic veins, and chronic
`deep inflammation. Rhinophyma may accompany stage III
`rosacea but in some patients the signs of rosacea in the rest
`of the face are surprisingly mild. Four variants of
`rhinophyma can be recognized. In the glandular form, the
`nose is enlarged mainly because of enormous lobular
`sebaceous gland hyperplasia. The surface is pitted, with
`deeply indented and mildly distorted follicular orifices. The
`tumorous expansions of the nose are often asymmetrical
`and of varying size. Humps and sulci occur. Sebum
`excretion is increased. Compression by the fingers yields a
`white pasty substance consisting of an amalgam of
`corneocytes, sebum, bacteria, and sometimes Demodex
`mites. In the fibrous form, diffuse hyperplasia of the
`connective tissue dominates the picture32 . The amount of
`sebaceous hyperplasia is variable. In the fibroangiomatous
`
`146
`
`Exh. 1034
`
`

`
`JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Vo!ume 90 March 199
`
`form, the nose is copper-red to dark red, greatly enlarged,
`oedematous, and covered by a network of large ectatic
`veins. Pustules are frequently present. The actinic form is
`characterized by nodular masses of elastic tissue distorting
`the nose. These are similar to the elastomas that occur in
`older individuals with over-exposure to sunlight. This
`variety is mainly observed in people of Celtic origin.
`Phymas occur in other locations such as chin, forehead,
`eyelids and ears33,34.
`
`HISTOPATHOLOGY
`Histopathology of rosacea varies with the stage and type of
`disease35 . The changes often resemble those of other
`chronic disorders. Skin darnage by surrlight is a common
`background feature, so severe elastosis is often present. In
`stage I rosacea there are ectatic venules and lymphatics,
`slight oedema, and sparse lymphatic perivascular infiltra-
`tion. Moderate hyperplasia of the elastic tissue is present
`with increased curled, thickened elastic fibres ( elastolysis).
`In stage II there is increasing lymphohistiocytic perivascular
`and perifollicular infiltration. Intrafollicular collections of
`neutrophils are often found, and are always present when
`pustules are observed. The infiltrate likewise surrounds
`sebaceous ducts and glands. The veins are thickened and
`grossly dilated. Elastosis is more advanced. In stage III there
`is diffuse expansion of the connective tissue, accompanied
`by hyperplasia of sebaceous follicles with long, distorted
`follicular canals, and
`large,
`irregular sebaceous acini.
`Epithelialized tunnels undermine the hyperplastic tissue
`and are filled with inflammatory debris. The elastotic
`changes are prominent, often evident as amorphaus masses
`of degenerated elastic tissue. D. jolliculorum mites are often
`found within the follicular infundibula and sebaceous ducts.
`They are merely commensals. This is different from true
`Demodex folliculitis ( demodicosis). Epithelioid granulomas of
`the non-caseating type with multiple foreign-body multi-
`nucleated cells are the histopathological equivalent of lupoid
`rosacea. Abscesses with pseudoepitheliomatous hyperplasia,
`lakes of granulocytes are
`widespread necrosis, and
`characteristic of rosacea fulminans.
`
`DIFFERENTIAL DIAGNOSIS
`Acne vulaaris is distinguishable from rosacea by its lack of
`vascular component. T elangiectases and erythema are
`usually absent. Comedones and cysts are not seen in
`rosacea. Acne lesions may resolve into small fibrotic
`nodules and scars (which are absent in rosacea). Perioral
`is a symmetrical eruption consisting of tiny
`dermatitis
`vesicles and micropapules on an erythematous background.
`These lesions may appear in crops, sometimes with scaling.
`Occasionally, perioral dermatitis is accompanied by a
`similar eruption in the glabellar, malar, and periorbital
`
`regions. Rebound after discontinuation of potent topical
`corticosteroids seems
`to play a role
`in many cases.
`Seborrhoeic dermatitis, which may coexist with rosacea, is
`polymorphous, as are the other eczemas. Thus scaling and
`even mild vesiculation may occur. In cantrast to rosacea,
`seborrhoeic dermatitis involves the paranasal area,
`the
`nasalabial grooves, the retroauricular region, and several
`areas beyond the face. Photodermatitis can be toxic or allergic
`the polymorphic feature of
`in nature. When allergic,
`eczema occurs and the eruption is usually present in
`toxic,
`the
`extrafacial photo-distribution areas. When
`eruption resembles a sunbum. Polymorphaus liaht eruption
`is a photosensitive eruption usually appearing in spring or
`early summ er, consisting of erythematous papules or
`eczematous plaques. Unlike in rosacea, itching is common
`after intensive sun exposure and before the eruption. The
`diagnosis is confirmed by phototesting. Chronic discoid lupus
`ezythematosus has pigmentary changes, atrophy, and scarring
`which rule out rosacea. When lupus erythematosus is
`systemic and there is a symmetrical erythema especially
`intense over both malar areas, the distinction may be
`difficult. This difficulty is compounded by a positive lupus
`band test in the facial skin of some patients with rosacea36.
`A thorough evaluation for other evidence of systemic lupus
`erythematosus is indicated in these cases. Haber's syndrome is
`a rare familial rosacea-like genodermatosis with persistent
`facial erythema, telangiectases, follicular and verrucous
`papules, and atrophic pitted scars37. The patientsoften have
`dry facial skin and xerosis of their body. Finally, in patients
`with the sudden onset of severe flushing, systemic fiushinB
`disorders, such as carcinoid syndrome,_ must be considered.
`The 24-h urinary excretion of 5-hydr~xy.jndoleacetic acid is
`normal in rosacea38.
`
`TREATMENT
`Rosacea
`is
`treatable but seldom curable. Treatment
`schedules are determined by the stage and severity of the
`disease.
`
`Topical
`All sources of local irritation, such as soaps, alcoholic
`cleansers, tinctures and astringents, abrasives and peeling
`agents must be avoided. Only very mild soaps or properly
`diluted detergents are advised. Protection agairrst surrlight is
`important: sunscreens with a protecting factor (SPF) of 15
`or higher are always recommended, preferably of the broad
`spectrum UV-A plus UV-B type. For some it may be hard
`to find a sunscreen which is tolerated without buming or
`irritation. Fernale patients can be encouraged to hide
`telangiectases with cosmetic bases having a green tint.
`The antibiotics used in acne are sometimes effective.
`Tetracyclines, clindamycin, and erythromycin, usually in
`
`147
`
`Exh. 1034
`
`

`
`JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 90 March 199
`
`concentrations from 0.5% or 2.0%, are commercially
`available. In one study, twice daily application of 1%
`clindamycin phosphate lotion in an aqueous base was
`equivalent in efficacy to 250 mg oral tetracycline twice a
`day, without important side-effects over a 12-week triaP9.
`The mechanism of antibiotics may be anti-inflammatory
`rather than antibacterial. Tetracyclines and erythromycin
`reduce leucocyte migration and phagocytosis40.
`Metronidazole is a synthetic nitroimidazole-derivative
`antibacterial and antiprotozoal agent, available in the USA
`and the UKas a 0.75% aqueous gel (MetroGel). In clinical
`studies metronidazole 0. 7 5% topical gel or 1. 0% cream
`improved inflammatory lesions in 68-96% of patients41 .
`The gel is applied twice daily and is most effective in
`papular and pustular rosacea. It does not alter erythema,
`telangiectases, or flushing. When the drug is withdrawn,
`symptoms commonly recur. Where a registered prepara-
`tion is not available we suggest the following prescription:
`metronidazole 2.0; Eucerin lotion ad 100.0. This 2%
`metronidazole lotion is applied once or twice daily as long
`as necessary. The principal adverse effects of topically
`applied metronidazole are local reactions such as burning
`and stinging.
`treatment of
`increasingly used for
`Imidazoles are
`rosacea42. In our experience, not substantiated by clinical
`trials, ketoconazole cream (Nizoral cream) is the best
`choice, applied once or twice daily. The mechanisJ;n may be
`anti-inflammatory or
`immunosuppressive
`rather
`than
`bactericidal. Imidazoles seem to have low 'toxicity and are
`well tolerated by patients with sensitive skin.
`Old-time remedies such as drying lotions should not be
`forgotten43 . A very thin application at night is recom-
`mended. One can use commercial precipitated sulphur
`lotions. We prescribe: hydragyrum sulphur rubr 0.5;
`sulphur praecipitati 2. 0; Lotio zinci ad 1 00.0.
`T opical retinoids provide another option. The acneiform
`component responds to tretinoin44. Isotretinoin is worth a
`trial. There is preliminary evidence that 0. 2% isotretinoin
`in a bland cream is helpful45 ; it is less irritating than
`tretinoin and suppresses inflammatory lesions in stage II and
`III.
`
`In a double-blind randomized half-face comparison
`between 20% azelaic acid cream preparation and
`its
`identical-appearing vehicle as placebo, azelaic acid was
`effective against papules, pustules, and erythema
`in
`rosacea46. The only adverse effect over 9 weeks was minor
`skin irritation. Probably the anti-inflammatory activity of
`azelaic acid accounts for a substantial proportion of the
`therapeutic effect.
`that Demodex
`As stated above, we do not think
`jolliculorum mites have a causal role in rosacea. However,
`massive infestations may aggravate the condition. A check
`for mites is best done with the skin-surface biopsy technique
`
`(place a drop of cyanoacrylate on a glass slide, cover with
`immersion oil, and examine with the 10 X or 20 X objec-
`tive in the light microscope)47. The mites are satisfactorily
`controlled with lindane (y-hexachlorocyclohexane), crota-
`miton, or benzyl benzoate once daily for two to five days.
`T opical corticosteroids should not be used, except in
`rosacea fulminans30·31 . In these patients short courses of
`high-potency topical corticosteroids are a reasonable option
`to reduce the inflammation.
`
`Systemic
`to oral antibiotics.
`Rosacea generally responds well
`is often effective, but tetracyclines are
`Erythromycin
`preferable48. Tetracycline-HCl, oxytetracycline, doxycy-
`cline, and minocycline are usually effective in controlling
`papulopustular rosacea and even reducing erythema. One
`should start with large doses-1 . 0-1.5 g tetracycline-H Cl
`or oxytetracycline per day. 50 mg of minocycline or
`doxycycline
`twice daily can be given. As soon as
`papulopustules are fully controlled (usually after two to
`three weeks) doses of 250-500 mg tetracycline-HCl or
`oxytetracycline, or 50 mg minocycline or doxycycline, per
`day are generally sufficient. Rosacea patients often titrate
`to disease activity and should be
`doses according
`encouraged
`to do so. Some get by with 250 mg
`tetracycline-HCl on altemate days. Oral tetracyclines are
`effective in ophthalmic rosacea49. Antibiotic use in rosacea
`is often not sufficiently monitored. The disease has its ups
`and downs. Too often patients are on a fixed oral dose for
`many years when topical dr?-gs might be sufficient.
`(13-cis-reti~oi~ acid)
`is
`exceptionally
`Isotretinoin
`effective though far more risky than tetracyclines23,50-52.
`It may be appropriate for all forms of severe or therapy-
`resistant rosacea, especially the variants unresponsive to
`antibiotics, e.g. lupoid rosacea, stage III rosacea, Gram-
`negative rosacea, rosacea conglobata, and rosacea fulmi-
`nans. It is particularly helpful in patients who have oily,
`wide-pored skin and multiple sebaceous gland hyperplasias.
`In addition, all forms of phyma are indications. The dose
`required for control of rosacea varies. Three treatment
`schedules will be outlined.here. The dose of isotretinoin is
`0. 5-l. 0 mg/kg per day as used in acne. Side-effects on the
`eyes make
`this dose
`intolerable for many patients.
`Ophthalmie rosacea may get worse and likewise dry eye
`and blepharitis. Patients may become unable to use contact
`lenses. The high dose is used only in rosacea fulminans, or
`preoperatively for a couple of months to shrink rhinophyma
`before surgical reduction. Low-dose isotretinoin is much
`better and safer. 0.1-0.2 mg/kg per day is usually effective
`in severe rosacea, though clearing may take Ionger.
`Minidose isotretinom is 2. 5 mg or 5. 0 mg daily (not
`adjusted to bodyweight). This dose is surprisingly helpful in
`
`148
`
`Exh. 1034
`
`

`
`JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 90 March 199
`
`many forms of the clisease, especially stage III rosacea,
`lupoid rosacea, and persistent oedema in rosacea. Side-
`effects on the eyes are negligible. Duration of therapy is
`Ionger than with the other doses, about 6 months. The
`cumulative dose, however, is low. The usual precautions
`apply. Isotretinoin is a teratogen and is contraindicated in
`women of childbearing age unless they meet all
`the
`requirements on the package Iabel. Aminotransferases,
`cholesterol, and triglycerides must be measured before
`thereafter. With
`therapy and monthly or bimonthly
`minidose isotretinoin no laboratory abnormalities have
`been observed.
`In an uncontrolled study of 13 J apanese male rosacea
`patients53 good results were reported with spironolactone.
`50 mg daily over four weeks seemed to improve itching and
`erythema, perhaps via inhibition of epidermal cytochrome P-
`450. Further stuclies are necessary
`to confirm
`this.
`Clonidine, in a limited trial, reduced facial flushing54, but
`doses which do not decrease blood pressure have little or no
`effect55 . Metronidazole is licensed for the treatment of
`infections
`caused by Trichomonas
`vaginalis, Entamoeba
`histolytica, and Giardia intestinalis. The usual dose is 500 mg
`twice daily for six days. Oral metronidazole is effective in all
`types of rosacea, including Stages II and III56. However' 20
`to 60 days may be needed to achieve control with a daily
`dose of 500 mg. It should be regarded as a second-line drug.
`Rosacea fulminans requires special care30,31 . Treatment
`starts with oral corticosteroids (e.g., prednisolone l.Omg/
`kg per day), for one week to cool down the fire~ Then
`isotretinoin is added, at around 0.2-0.5 mg/kg, rarely 1.0
`mg/kg, per day, with a slow tapering of the corticosteroid
`over the next two to three weeks. Isotretinoin is continued
`until all inflammatory lesions have clisappeared. This may
`require three to four months. Draining abscess.es should not
`be incised. Warm compresses can be applied, tagether with
`a potent corticosteroid cream (for the first 2 weeks only).
`
`Miscellaneous
`Facial massage has long been recommended. This is the so-
`called Sobye's massage57. Controlled studies are lacking.
`Twice daily gentle circular massage is given for several
`minutes to nose, cheeks, and forehead.
`There is no specific rosacea diet. Dietary limitations
`relate only to factors which provoke erythema, flushing and
`blushing such as alcoholic beverages, hot drinks, and spicy
`food. The patients themselves may find out which dietary
`items are troublesome.
`Obliteration of ectatic vessels, particularly on the nose,
`can be achieved by intravascualr insertion of a fine
`diathermy needle or by argon or