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Successful Treatment of Cutaneous Sarcoidosis Using Topical Photodynamic Therapy
Sigrid Karrer, MD;
Christoph Abels, MD;
Monika Beatrix Wimmershoff, MD;
Michael Landthaler, MD;
Rolf-Markus Szeimies, MD
From the Department of Dermatology, University of Regensburg, Regensburg,
Germany.
Arch Dermatol. 2002;138:581-584.
REPORT OF A CASE
A 67-year-old woman had a 17-year history of increasing numbers of asymptomatic
but disfiguring red-brown, flat papules on the extremities. She was otherwise
well and had no pulmonary or systemic symptoms. Seven years ago, the patient
was referred to our department, and the diagnosis of cutaneous sarcoidosis
(small nodular type) was repeatedly confirmed by skin biopsy results.
The physical examination revealed numerous painless, red-brown, slightly
elevated papules and plaques up to 1 cm in diameter, disseminated and partially
confluent at the extensor aspects of the legs and to a lesser extent on the
upper arms (Figure 1). On results
of diascopy, the lesions appeared gray yellowish. Other body areas were not
affected.
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Figure 1. Partly aggregated reddish brown
papules on the extensor surfaces of the leg before initiation of photodynamic
therapy using 5-aminolevulinic acid.
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Results of the histological evaluation of formalin-fixed, paraffin-embedded
biopsy specimens repeatedly obtained from the lesional skin revealed noncaseous
epithelioid-cell granulomas with several multinucleated foreign body giant
cells and a sparse perifocal lymphohistiocytic infiltrate in the dermis. Results
of examination of sections stained with periodic acid–Schiff and Ziehl-Neelsen
failed to detect fungi or acid-fast bacilli, respectively. Special cultures
repeatedly yielded negative findings for mycobacteria.
Results of internal examinations showed no lung involvement, and pulmonary
function test findings were normal. Findings on chest x-ray examination, electrocardiography,
abdominal ultrasonography, and neurologic and ophthalmologic examinations
revealed no abnormalities. No enlarged peripheral lymph nodes or parotid glands
were seen.
Laboratory investigations, including complete blood cell count, liver
and renal function tests, serum electrophoresis, and measurement of electrolyte
(including calcium), angiotensin-converting enzyme,  2-microglobulin,
and  -globulin concentrations, were within reference limits. The erythrocyte
sedimentation rate and antinuclear antibody concentration were slightly raised.
Results of the tine tuberculin reaction test were positive (x3), whereas
acute tuberculosis and former bacille Calmette-Guérin vaccination were
excluded.
THERAPEUTIC CHALLENGE
Since the diagnosis was made, several treatments had been tried without
success. Repeated cryotherapy, topical application of vitamin E, and intralesional
and topical corticosteroids did not result in clinical improvement. Oral therapy
with clofazimine at a starting dosage of 200 mg/d, followed by 100 mg 3 times
weekly for more than 3 months, and a subsequent 1-year course of allopurinol,
300 mg/d, were ineffective. A 1-year course of methylprednisolone-21-hydrogensuccinate
with a starting dosage of 40 mg/d, and slow reduction to 8 mg/d yielded improvement,
followed by rapid recurrence after discontinuation of the therapy. Therapy
consisting of an 8-methoxypsoralen bath combined with UVA light was performed
4 times weekly for 2 months (number of treatments, 20; cumulative light dose,
27.3 J/cm2). Because the lesions did not improve even slightly,
the patient did not want to continue this therapy.
SOLUTION
In our experience, topical photodynamic therapy (PDT) using 5-aminolevulinic
acid (ALA) has shown good results in the treatment of various recalcitrant
inflammatory skin disorders in which UV therapy had failed (eg, chronic plaque-type
psoriasis, localized scleroderma, or chronic palmoplantar eczema). Because
of the failure of the previous therapeutic approaches in our patient with
cutaneous sarcoidosis, a therapeutic trial with topical ALA-PDT was started
after obtaining written informed consent. We applied 3% ALA in a gel containing
40% dimethyl sulfoxide to the lesions on the patient's arms and legs and covered
these with an occlusive plaster impervious to light. Six hours later, the
lesions underwent irradiation by means of an incoherent source (PDT 1200;
Waldmann Medizintechnik, VS-Schwenningen, Germany) emitting light at a wavelength
of 580 to 740 nm (light intensity, 40 mW/cm2; energy density, 20
J/cm2). Photodynamic therapy was performed twice weekly for the
first 8 weeks, followed by treatments once a week.
A total of 22 treatments were performed within 3 months. The only adverse
effects were a slight burning sensation during irradiation, followed by erythema
and edema of the treated area, which lasted for about 2 days after PDT (Figure 2). Roughly 4 weeks after the onset
of therapy, the plaques flattened and faded. After 3 months, the skin lesions
resolved completely without the development of new lesions. Slight hyperpigmentation
of the treated area occurred after 2 weeks of treatment and persisted for
about 3 months after the end of PDT (Figure
3). Results of examination of a biopsy specimen obtained from a
former lesional site 4 months after therapy also showed histologically normal
skin. At the last visit, 18 months after PDT, the patient was still free of
skin disease and visceral involvement.
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Figure 2. Two days after the first photodynamic
therapy session, inflammatory reaction is sharply restricted to the affected
areas.
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Figure 3. Two months after a 3-month course
of photodynamic therapy using 5-aminolevulinic acid, complete remission of
the skin lesions is seen, with only a slight hyperpigmentation in the former
lesional area, which resolved within another 4 weeks.
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COMMENT
Sarcoidosis is a multiorgan systemic disease that is characterized by
the formation of noncaseous epithelioid-cell granulomas in all or several
organs. The lung is by far the most commonly involved organ in more than 90%
of all cases.1 In contrast, skin involvement
occurs in only about 25% of cases but may be the only manifestation of the
disease.2-3 The cause of sarcoidosis
remains unclear, although infectious causes such as mycobacteria or viruses
and genetic factors have been considered.4
Several therapeutic approaches have been reported for cutaneous sarcoidosis,
including topical and systemic corticosteroids, cryotherapy, and immunosuppressive
and antimalarial drugs. Some case reports have proposed alternative treatments,
such as oral isotretinoin,5 thalidomide,6 allopurinol,7 tranilast,8 psoralen–UV-A,9
or phonophoresis using hydrocortisone.10 However,
no consistently effective treatment for sarcoidosis exists.
The US Food and Drug Administration approved ALA, a precursor of endogenous
porphyrins in the biosynthetic pathway of heme, in December 1999 for PDT for
actinic keratoses. After topical application, ALA induces the biosynthesis
of photosensitizing concentrations of protoporphyrin IX within rapidly proliferating
cells.11 Subsequent exposure to photoactivating
light induces the generation of reactive oxygen species, particularly singlet
oxygen. Depending on the light dose applied, cytotoxic effects resulting in
tumor destruction and immunomodulatory effects resulting in improvement of
inflammatory skin diseases occur. Until now, topical ALA-PDT has been successfully
used for the management of superficial skin tumors such as basal cell carcinoma,
Bowen's disease, and actinic keratoses.12 Inflammatory
diseases of the skin, such as psoriasis and localized scleroderma,13-14 and human papillomavirus–induced
dermatoses, including condyloma acuminatum, epidermodysplasia verruciformis,
and verruca vulgaris,15-17
respond positively to ALA-PDT. However, to our knowledge PDT has not been
described for the treatment of granulomatous skin disorders affecting the
dermis.
The formation of granulomata in sarcoidosis occurs in the following
3 steps. First, an immune reaction and T-cell activation occurs. Second, preinflammatory
interactions between lymphocytes and macrophages occur, involving tumor necrosis
factor  , interleukin 1, and interferon-. Third, granuloma formation
follows a repair phase when chronic inflammation progresses, resulting in
the promotion of fibrosis. In general, a functional predominance of TH1 cells can be demonstrated in sarcoidosis, although the capacity for
producing TH2 cytokines seems to be maintained.18
Interleukin 1 is important for induction of granuloma formation, whereas
tumor necrosis factor may sustain the inflammatory process.19 This supposition is supported by a rapid regression
of fully developed immune granulomas on tumor necrosis factor depletion.20 The release of transforming growth factor
results in a decrease of interleukin 2 production, yielding the cessation
of inflammatory processes in sarcoidosis.18
Topically applied ALA is primarily taken up by epidermal keratinocytes.
On irradiation with red light, cytokines might be released, resulting in a
change of the cytokine environment and finally leading to a disruption of
the granuloma formation process. However, the exact mechanism by which ALA-PDT
exerts its anti-inflammatory effect in sarcoidosis remains to be elucidated.
In our patient, repeated application of topical ALA-PDT resulted in
a complete resolution of the skin lesions that had been persistent for more
than 17 years and had not responded to conventional and alternative treatments.
AUTHOR INFORMATION
Accepted for publication August 22, 2001.
Corresponding author and reprints: Rolf-Markus Szeimies, MD, Department
of Dermatology, University of Regensburg, D-93042 Regensburg, Germany (e-mail: Rolf-Markus.Szeimies{at}klinik.uni-regensburg.de).
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SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE
ANNA GLASER, MD; ELAINE SIEGFRIED, MD
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