Australasian Journal of Dermatology

(2003)

44

,

67–70

Correspondence: Davin S Lim, Department of Dermatology, MaterHospital, Raymond Tce, South Brisbane, QLD 4101, Australia. Email:davinlim@hotmail.com

Davin S Lim, MB BS. Joe Triscott, FRCPA.Submitted 27 February 2002; accepted 15 August 2002.

CASE REPORT

O’Brien’s actinic granuloma in association with prolonged doxycycline phototoxicity

Davin S Lim

1

and Joe Triscott

2

1

382 Health Flight, Royal Austalian Air Force Base, Amberley and

2

Queensland Medical Laboratory, Brisbane, Queensland, Australia

INTRODUCTION

In 1975, O’Brien

1

described annular lesions on sun-exposedarea in individuals with elastotic skin. He coined the termactinic granuloma to describe these lesions and furtherdescribed an acute variant of the condition, often precipitatedafter episodes of severe sunburn. Since his original descrip-tion over 25 years ago, there have been no other reports ofthese variants in the English literature. Furthermore, drug-induced actinic granuloma has not been reported. Wepresent two cases of acute actinic granuloma occurring on abackground of prolonged phototoxicity to doxycycline andspeculate on the aetiology of this phenomenon.

CASE REPORT

Both patients in this case report were part of a multinationaltask force sent to East Timor in September 1999. East Timorcomprise of a group of equatorial islands within theMalaysian archipelago and is malaria endemic. All per-sonnel who were deployed to East Timor were prescribed100 mg of doxycycline daily for malaria chemoprophylaxis.

The first patient was a 32-year-old aircraft technician whopresented with multiple mildly pruritic lesions on the neck,which had been present for 8 weeks. He had been in EastTimor for a total of 3 months and had noted the lesions in thesecond month of deployment. Initially, treatment of thelesions with miconazole cream for 3 weeks, followed by2 weeks with terbinafine cream, was unresponsive. He hadbeen in the military for 12 years and, because of his trade,had a long history of sun exposure. During his deploymentoverseas he had been prescribed doxycycline at a daily doseof 100 mg for malaria prophylaxis. He developed moderatephotosensitivity soon after commencing his doxycyclineregimen; however, he experienced an episode of severesunburn some 3 weeks into deployment, which required bedrest for 48 hours. Despite ongoing phototoxicity and twomore episodes of moderately severe sunburn he continued totake his medication for fear of contracting malaria. Onexamination he had 13 lesions in total, extending across boththe sides and posterior aspect of his neck (Fig. 1) Theselesions were mildly erythematous and consisted of papulesin both an annular and arcuate formation with a clinicallynormal centre. The diameter of the lesions varied in sizefrom 6 mm to 23 mm. No overlying scale was visible;however, a background of severe solar elastosis was evidentclinically. There were no other lesions elsewhere on thebody.

The second patient was a 31-year-old soldier who served atotal of 6 months in East Timor. During his fifth month intodeployment he noticed two semicircular papular lesions onthe nape of his neck bilaterally, which measured 8 mm and12 mm, respectively (Fig. 2). The lesions were refractory totreatment with miconazole cream applied daily for 3 weeks.Background solar elastosis was also noted. There were nolesions elsewhere. This patient also used doxycyclineprophylaxis at the recommended dosage, and exaggeratedsunburn reaction to this medication was experiencedthroughout his course of antibiotics. This was reflected by

SUMMARY

O’Brien’s actinic granuloma is clinically characterizedby annular papules and plaques on sun-exposed areasof skin. These lesions often occur insidiously on abackground of severe solar elastosis; however, anacute variant following sunburn has been reported inthe literature. We present two cases of acute actinicgranuloma precipitated by episodes of sunburnoccurring on a background of prolonged doxycyclinephototoxicity. Biopsies from both patients showed ahistiocytic infiltrate with multinucleate giant cellsengulfing elastotic material, with a reduction of elastintowards the centre of the papule. Marked resolution ofthe lesions was noted after 8 weeks of treatment withbetamethasone dipropionate 0.05% ointment inoptimized vehicle together with adequate photo-protection in the form of broad-spectrum sunscreens.

Key words: drug photosensitivity, elastase, malariaprophylaxis, O’Brien’s granuloma, ultraviolet A.

68 DS Lim and J Triscott

two presentations to the medical centre in East Timor forsevere sunburn. Neither patient gave any history suggestiveof polymorphic light eruption or photosensitivity, nor werethey on any other medication that could be implicated as acause of the rash.

Both patients had normal blood sugar levels and serologyto hepatitis B, hepatitis C, human immunodefiency virus andDengue virus was negative. Neither contracted malariaduring their deployment.

Histological findings from both cases showed strikingsimilarities. Biopsies taken from the edge of the papule inboth patients showed background solar elastosis, character-ized by an increased elastin content of the dermis. Aninterstitial histiocytic infiltrate, together with multinucleategiant cells engulfing elastotic material, was seen at the edgeof the lesion in both cases (Fig. 3). Acid Orcein stain forelastin confirmed the presence of solar elastotic material inthe papillary and middle reticular dermis adjacent to theinterstitial granulomatous infiltrate; however, the stain alsorevealed a marked reduction of elastosis toward the centre ofthe lesion (Fig. 4). Necrobiosis was not evident in either case

and colloidal iron staining showed no evidence of excessinterstitial mucin.

Our two patients were subsequently treated withbetamethasone dipropionate 0.05% in optimized vehicleointment and advised on the regular application of a broad-spectrum sunscreen. Noticeable resolution of the lesionswere achieved by the fourth week, with marked clearancenoted at 8 weeks, after which treatment was ceased. At finalfollow up 14 months after treatment, both cases showedcomplete resolution of their lesions with no recurrences.

DISCUSSION

Since O’Brien’s original description of actinic granulomas in1975,

1

this clinicopathological entity has been surrounded inmuch controversy. The term annular elastolytic giant cellgranuloma

2

has been suggested to encompass the similarhistological features found in O’Brien’s actinic granuloma,

1

atypical necrobiosis lipoidica

3

and granulomatosis disci-formis of Miescher.

4

Some authors

5

argued that lesions ofactinic granulomas are simply granuloma annulare occur-ring in sun-exposed areas, while others

6–8

concluded thatactinic granulomas and granuloma annulare are separateentities. Although both conditions are clinically indis-tinguishable, histopathological and immunocytochemicalfeatures

6

support the fact that actinic granuloma is a unique

Figure 1

Annular papules on the neck of Patient 1 occurring on abackground of solar elastosis.

Figure 2

A semicircular plaque on the nape of the neck in Patient 2.

Figure 3

Biopsy taken from the edge of one of the papular lesionsfrom Patient 1. Granuloma consisting of giant cells and histiocytesengulfing elastotic material (H&E).

O’Brien’s actinic granuloma 69

disease process. The findings of multinucleate giant cells andhistiocytes arranged interstially between collagen fibres arefeatures common to both actinic granuloma and granulomaannulare; however, the marked absence of normal elastinand solar elastotic material within the centre of the annulus,combined with fragmentation of elastotic material withingiant cells, is more suggestive of actinic granuloma.

1,6,7

AcidOrcein stains for elastic fibres confirmed the markedabsence of elastin towards the centre of the lesion in both ourpatients. Excess mucin, often found in copious amounts ingranuloma annulare,

7

was not present in our specimens.Necrobiosis, a prominent finding in granuloma annulare,was notably absent. Although the features in our casesstrongly support the diagnosis of actininc granuloma and notgranuloma annulare, the use of immunohistochemistry maybe a novel approach in differentiating these two entities ifhistopathology is equivocal. Studies have shown that with anindirect immunoperoxidase stain, the giant cells of actinicgranuloma are intensely positive for lysozyme, while themononuclear histiocytic infiltrate shows minimal reactivity.In contrast, histiocytes of granuloma annulare revealmarked reactivity for lysozyme.

6

By taking biopsies of the annulus and centre of the lesionsin both our cases, we believe that these lesions representactinic granuloma and not granuloma annulare occurring insun-exposed areas.

In O’Brien’s original report in 1975,

1

he described an acutevariant of actinic granuloma, often precipitated after frequentepisodes of sunburn. To date there are no other reports of thisvariant in the English literature. The patients describedwithin this case report differ from others in the literature inthat the age of the patients in our case report (31 and 32 yearsof

age,

respectively)

is

somewhat

younger

compared

withthose in the literature. A large study of 12 patients withactinic granuloma showed an average age of 53 years (range41–76 years).

7

Doxycycline phototoxicity in association with

actinic granuloma has not been reported in the literature. Wefeel that the patients described within this case representacute

variants

of

O’Brien’s

actinic

granuloma

precipitatedby episodes of sunburn occurring on a background ofdoxycycline photosensitivity.

As a member of the tetracycline group of antibiotics,doxycycline is frequently prescribed by dermatologists forthe treatment of inflammatory skin conditions such as acneand rosacea, and is also used for chemoprophylaxis in manymalaria-endemic countries.

9

Doxycycline is a well-tolerateddrug; however, light-sensitive phototoxic reactions andphoto-oncycholysis are rare side-effects of therapy.

10–12

Phototoxic eruptions are thought to be a result of light in theultraviolet (UV)A wavelength

13

and appear to be dosedependent, with reports in the literature ranging from 3%

10

to 10%

14

on those taking 100 mg of doxycycline daily; therecommended dosage for malaria prophylaxis. In patientstaking 200 mg of doxycycline, up to 42% of individuals haveexhibited phototoxic eruptions.

10

To date, the most compre-hensive studies on the phototoxic potential of doxycyclinehave been in the UK.

10

The incidence of reactions may behigher in equatorial countries with higher UV exposure. Ofthe troops in one unit that served in East Timor, 16% (22/135)exhibited phototoxic reactions to doxycycline taken at100 mg daily (unpubl. obs., DS Lim, 1999). Clinically, thephototoxic reactions resembled exaggerated sunburn, withdiffuse, oedematous, erythematous plaques, more pro-nounced on sun-exposed areas such as the face, neck anddorsa of the hands. Both patients described in this casereported a history of pronounced sunburn reaction while ondoxycycline, with a subsequent lack of problems oncedoxycycline was ceased.

In O’Brien’s original paper, he postulated that granulomaformation

may

be

secondary

to

an

immune

responseagainst

actinally

damaged

fibres.

1

It

was

subsequentlyfound that lesions of actinic granulomas were infiltrated byT-helper cells, and therefore postulated that granulomaformation may be secondary to an immune-mediated cellreaction to antigenic determinants on actinally damagedelastic fibres.

6

Abnormal

responses

to

UV

light,

including

conditionssuch as polymorphic light eruption and drug photosensitiz-ation

are

known

to

cause

an

inflammatory

infiltrate

ofT-lymphocytes.

15,16

We postulate that prolonged phototoxicity as a result ofdoxycycline may potentiate actinic damage to elastin fibresand additionally provide a stimulus in the form of a chroniccell-mediated infiltrate, which may, in certain individualswith actinically damaged elastic fibres, result in granulomaformation. Actinic granuloma has not been reported in thesetting of phototoxicity as a result of other drugs. In additionto phototoxic effects, doxycycline may have thus contributedto granuloma formation. In recent studies, doxycycline andother tetracycline derivatives are shown to be inhibitors ofelastase belonging to the matrix metalloproteinase family(MMP).

17,18

Inhibition of MMP in the dermis may lead to anincrease in the elastin content of the skin, which is a featureof solar elastosis. Furthermore, inhibition of elastase bydoxycycline prevents degradation of actinically damaged,

Figure 4

Transition zone biopsy taken from Patient 1 to includeboth the edge of the papule and its centre. Note the marked reductionof elastotic material towards the centre of the lesion (left of thephotograph) (Orcein stain).

70 DS Lim and J Triscott

and hence antigenically modified, elastic fibres, which mayultimately lead to granuloma formation.

The continuous use of doxycycline for malaria prophylaxisin equatorial climates, and the subsequent phototoxicreactions in predisposed individuals, may give us furtherinsight into long-term effects of chronic phototoxicity to thismedication in the future.

REFERENCES

1. O’Brien JP. Actinic granuloma – An annular connective tissuedisease affecting sun- and heat-damaged (elastotic) skin.

Arch.Dermatol.

1975;

111

: 460–6.2. Hanke CW, Bailin PL, Roenigk HH. Annular elastolytic giant cell

granuloma.

J. Am. Acad. Dermatol.

1979;

1

: 413–21.3. Wilson-Jones

E.

Necrobiosis

lipoidica

presenting

on

theface

and

scalp.

Trans.

St

John’s

Dermatol.

Soc.

1971;

57

:202–20.

4. Mehregan AH, Altman J. Miesher’s granuloma of the face: Avariant of the necrobiosis lipolidica–granuloma annularespectrum.

Arch. Dermatol.

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: 62–4.5. Ragaz A, Ackerman AB. Is actinic granuloma a specific con-

dition?

Am. J. Dermatopathol.

1979;

1

: 43–50.6. McGrae

JD.

Actinic

granuloma:

A

clinical,

histopathologicand

immunocytochemical

study.

Arch.

Dermatol. 1986; 122:43–7.

7. Steffen C. Actinic granuloma (O’Brien). J. Cutan. Pathol. 1988;15: 66–74.

8. Moulin G, Moyne G, Franc MP, Barrut D. Le granulomeactinique de O’Brien. Ann. Dermatol. Venereol. 1982; 109:135–49 (In French with English abstract).

9. Kitchener SJ, Auliff AM, Rieckmann KM. Malaria in theAustralian Defence Force during and after participation in theInternational Force in East Timor (INTERFET). Med. J. Aust.2000; 173: 583–5.

10. Layton AM, Cunliffe WJ. Phototoxic eruptions due to doxy-cycline – A dose-related phenomenon. Clin. Exp. Dermatol.1993; 18: 425–7.

11. Frost P, Weinatein GD, Gomez EC. Phototoxic potential ofminocycline and doxycycline. Arch. Dermatol. 1972; 105:681–3.

12. Cavens TR. Onycholysis of the thumbs probably due to photo-toxic reaction from doxycycline. Cutis 1981; 27: 53–4.

13. Johnson BE, Ferguson J. Drug and chemical photosensitivity.Semin. Dermatol. 1990; 9: 39–46.

14. Rosen K, Swanbeck G. Phototoxic reactions from some commondrugs provoked by a high-intensity UVA lamp. Acta Derm.Venereol. 1982; 62: 246–8.

15. Norris PG, Morris J, McGibbon DM, Chu AC, Hawk JL.Polymorphic light eruption: An immunopathological study ofevolving lesions. Br. J. Dermatol. 1989; 120: 173–83.

16. Lim HW. Abnormal responses to ultraviolet radiation photo-sensitivity induced by exogenous agents. In: Freedberg IM,Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI,Fitzpatrick TB (eds). Fitzpatrick’s Dermatology in GeneralMedicine, Vol. 1, 5th edn. New York: McGraw Hill, 1999;1589–98.

17. Curci J, Petrinec D, Liao S, Golub LM, Thompson RW.Pharmacologic suppression of experimental abdominal aorticaneurysms: A comparison of doxycycline and four chemicallymodified tetracyclines. J. Vasc. Surg. 1998; 28: 1082–93.

18. Thompson RW, Baxter BT. MMP inhibition in abdominal aorticaneurysms. Rationale for a prospective randomized clinicaltrial. Ann. NY Acad. Sci. 1999; 878: 159–78.