Volume 13Number 1July, 1985

Response of the cutaneous lesions of Reiter'ssyndrome to ketoconazoJe

To the Editor:Reiter's syndrome is classically defined as the triad

of arthritis, urethritis, and conjunctivitis or uveitis, al­though mucocutaneous lesions may also be a prominentpart of the syndrome. Postdysenteric and postvenerealforms are recognized, with organisms (such as Chla­mydia) presumably playing an important etiologic role.A significant association with HLA-B27 has been rec­ognized. Characteristic skin lesions may include kera­toderma blenorrhagicum, psoriasiform plaques, oralmucosal lesions, circinate balanitis, and nail dystrophy,thickening, and destruction.

We present a case of a young male patient withdisabling Reiter's syndrome treated with the oral,broad-spectrum antifungal agent ketoconazole, whichled to significant clearing of his cutaneous lesions as

Correspondence 161

well as moderate improvement in his joint symptoms.Although the mechanism of action of ketoconazole inthis patient is unknown, we will discuss our rationalefor using it and present some thoughts on the possibleinteractions of this agent in this disorder.

Case report. A 32-year-old man presented to the VeteransAdministration Hospital, Augusta, GA, in July 1982 with apapulovesicular scaling eruption on his feet. A potassiumhydroxide examination of the scales revealed no hyphae andthe patient was treated with triamcinolone 0.1 % cream fourtimes daily to affected areas. One month later there was pro­gressive involvement of the soles of the feet and toes, in­cluding the toenails, with pustule formation and hyperkera­totic scale. Several distal interphalangeal and proximal inter­phalangeal joints of the toes were swollen, red, warm, andtender. The patient complained of mile! dysuria, and urinalysisshowed twenty to thirty white blood cells per high-powerfield, although urine culture was negative. The patient wastreated with tetracycline, 500 mg by mouth four times daily,

Figs. i and 2. Swelling, erythema, and hyperkeratotic scaling plaques of the hands areshown, along with marked nail dystrophy and destruction.Figs. 3 and 4. Remarkable clearing of the patient's hand lesions after a 5-week course ofketoconazole, including normal nail regrowth, is demonstrated. (A surgical procedure tocorrect index finger deformity has been undertaken; corks are placed on protruding surgicalpins for protection.)

162 Correspondence

for 2 weeks and was continued on topical corticosteroids.However, the eruption spread to his hands and trunk, resultingin increased pain and disability (Figs. 1 and 2). With thediagnosis of disabling Reiter's syndrome, methotrexate ther­apy was selected, and the patient was hospitalized for a pre­treatment liver biopsy, which was interpreted as normal. Base­line laboratory and x-ray studies, including complete bloodcount, chemistry profile, urinalysis, and chest x-ray, were allnormal. The patient was started on methotrexate, 7.5 mg bymouth weekly, as a single dose. This dose was graduallyincreased over the next 2 months to a single dose of 20 mg/week. The patient's joint swelling, redness, and pain de­creased, and his skin lesions improved. However, metho­trexate was discontinued in February 1983 because of ele­vation in liver enzymes.

The patient was continued on topical corticosteroids, butgradually his condition worsened, with his major complaintrelating to the increasing deformity of his hands. Liver en­zymes had retumed to normal, and in May 1983 he was startedon ketoconazole, 200 mg by mouth daily. Within 10 daysthere was decreased swel1ing and erythema of his toes andfingers, and over the next several weeks his cutaneous lesionsshowed striking improvement, with greater than 90% clearingnoted by the end of a 5-week course of this medication (Figs.3 and 4). In addition, his arthralgias decreased considerably.Ketoconazole was discontinued in June 1983. At follow-up3 months later, only slight scaling and erythema remained,in addition to marked joint deformities of the hands, and hisfingernails had regrown normally.

Discussion. The diagnosis of Reiter's syndrome inthis patient was based on clinical findings of arthritis,urethritis, and characteristic cutaneous lesions. The pa­tient's nail involvement was particularly disturbing tohim, and our use of ketoconazole was in part directedat eradication of any secondary fungal invaders thatmay have been contributing to his nail disease. In ad­dition, we were reminded of the similarities betweenReiter's syndrome and psoriasis, and of the research ofthe University of Tennessee dermatology group, whichled them to propose the hypothesis that psoriasis mayresult from interactions between an altered alternativecomplement pathway and various organisms (e.g.,yeasts or streptococci), and that eradication of theseorganisms might lead to improvement of psoriasis. 1,2This same group, in fact, demonstrated improvementin psoriasis of the scalp and nails in patients treatedwith oral ketoconazole. 3 These results, in part,prompted our use of ketoconazole to treat Reiter's syn­drome, and, while the mechanism of action remainsspeculative, we believe that the antimicrobial mecha­nism proposed by these researchers at the Universityof Tennessee must be considered as one possible modeof action.

Journal of theAmerican Academy of

Dermatology

It has been suggested that ketoconazole may producea number of central and peripheral' 'immune-modulat­ing" effects, and we propose that this may representanother potential mechanism whereby ketoconazolecould have influenced the disease course in our patient.For example, ketoconazole blocks testosterone synthe­sis,4 and the sexual hormones have in tum been shownto influence the activity of T lymphocytes.s Ketocona~zole can inhibit adrenal steroid production,6 another"central" effect of uncertain significance in Reiter'ssyndrome.

Laboratory studies of ketoconazole's effects on im­mune effector cells have produced mixed results. Theagent restored the diminished lymphocyte blastogenicresponse in patients with invasive fungal disease,7 butit impaired histoplasma-stimulated lymphocyte blasto­genesis in cells from normal patients. 8 Ketoconazoledemonstrated no impairment of neutrophil function9 andeven normalized a serum-dependent neutrophil phago­cytic defect in a patient with chronic mucocutaneouscandidiasis. 10 However, in an in vitro study, ketocona­zole suppressed granulocyte progenitor cells in cul­ture." Again, the potential significance of any of theseimmune effects of ketoconazole in Reiter's syndromeremains unknown and must await studies that definethe specific immune "set" of Reiter's patients and theinfluence of ketoconazole on specific immune param­eters in these patients.

Final comments. We have presented a case dem­onstrating the striking effectiveness of a 5-week courseof ketoconazole in clearing the cutaneous and nail le­sions of Reiter's syndrome. Although the mechanismof action of this agentin this disorderremains unknown,we submit that the antimicrobial and immune-modu­lating effects of ketoconazole may play a significantrole.

One must weigh, in each Reiter's patient, the po­tential risks of side effects from ketoconazole, such ashepatotoxicity,12 against the potential for disabling anddeforming skin, nail, and joint disease. Based on ourfindings, a trial of ketoconazole prior to the use ofmethotrexate may be warranted in certain patients.

We believe that in selected patients with an unsat­isfactory response to more conservative treatment reg­imens, ketoconazole may represent an exciting and ef­fective new addition to our therapeutic armamentarium.

Jack L. Lesher, Jr., M.D., andDan K. Chalker, M.D.

Department of Dermatology,Medical College of Georgia, Augusta, GA 30912

Volume 13Number 1July, 1985

REFERENCES

1. Marley WM, Belew PW, Rosenberg EW, et al: Abnor­malities in the alternative pathway of complement inpsoriasis. Clin Exp Dermatol 7:387-396, 1982.

2. Rosenberg EW, Belew PW: Microbial factors in pso­riasis. Arch Dermatol1l8: 143, 1982. (Letter to Editor.)

3. Rosenberg EW, Belew PW: Improvement of psoriasis ofthe scalp with ketoconazole. Arch Dermatol 118:370­371, 1982. (Letter to Editor.)

4. Pont A, Williams PL, Azhar A, et al: Ketoconazoleblocks testosterone synthesis. Clin Res 30:32A, 1982.

5. Grossman CJ: Interactions between the gonadal steroidsand the immune system. Science 227:257-261, 1985.

6. Pont A, Williams PL, Loose DS, et al: Ketoconazoleinhibits adrenal steroid synthesis. Clin Res 30:99A,1982.

7. Marshall GD Jr, Wilson JB, Mader II, Reinarz JA: Im­muno-stimulatory effects of ketoconazole in patients withinvasive fungal disease. Clin Res 29:372A, 1981.

8. Alford RH, Cartwright BB: Comparison ofketoconazole

Correspondence 163

and amphotericin B in interference with thymidine uptakeand by blastogenesis of lymphocytes stimulated with His­toplasma capsulatum antigens. Antimicrob Agents Che­mother 24:575-578, 1983.

9. Marmer DJ, Field BT Jr, France GL, Steele RW: Ke­toconazole, amphotericin B, and amphotericin B methylester: Comparative in vitro and in vivo toxicological ef­fects on neutrophil function. Antimicrob Agents Che­mother 20:660-665, 1981.

10. Kennedy CTC, Valdimarsson H, Hay RJ: Chronic mu­cocutaneous candidiasis with a serum-dependent neutro­phil defect: Response to ketoconazole. J R Soc Med74: 158-162, 1981.

11. Meeker TC, Siegel MS, Shiota FM, et al: Toxicity ofamphotericin B, miconazole, and ketoconazole to humangranulocyte progenitor cells in vitro. Antimicrob AgentsChemother 23:169-171, 1983.

12. Duarte PA, Chow CC, Simmons F, Ruskin J: Fatal hep­atitis associated with ketoconazole therapy. Arch InternMed 144:1069-1070,1984.

ABSTRACTS

Cardiocutaneous fistula after left ventricularaneurysm repair. Case report and review of theliterature

Deuvaert FE, Wellens F, De Paepe J, et al: JCardiovasc Surg (Torino) 25:560-562, 1984

This article offers more on the subject of fistulization­this type may need early surgical repair to avoid extraordinarybleeding, so to speak, "from the skin."

P. C.A.

The onset of disease in twins and siblings withsystemic lupus erythematosus

Kaplan D: J Rheumatol 11:648-652, 1984

In a neat analysis, the authors find that SLE tends to involvepairs of siblings close together in time, suggesting some en­vironmental trigger may be at work.

P. C.A.

A new approach to contact allergenicity screening

Bos JD: Med Hypotheses 15: 103-108, 1984

From the Netherlands is this suggestion to determine animmunogen-Langerhans cell-binding index, with the notionthat a chemical that fails to bind is inert, and if bindingispassive (no effect on migration) the chemical is inert. Clearlypositive tests, the author implies, should be predictive forcontact allergy.

P. C. A.

Carriage of Corynebacterium diphtheriae inchildren of the eastern highlands province

Montgomery J: Papua New Guinea Med J 27:20-23,1984

Diphtheria of the skin was the diagnosis in 88% of chil­dren's skin ulcers reported from this eastern highlands. regionof New Guinea.

P. C. A.

Human subcutaneous dirofilariasis. 1. Two newcases in Venice. Identification of the causal agentas Dirofilaria repens Raillet and Henry, 1911

Pampiglione S. Franco F, Canestri Trotti G:Parassitologia 24: 155-165, 1982

Venice has some filaria-infested dogs, and transmission tohumans is, of course, going to occur. The boy had a largenodule on the scrotum. Serologic tests were positive but theexpected eosinophilia was under 10% of the differential count.

P. C.Il.

Intra-epithelial changes in childhood nevisimulating malignant melanoma

Cullity G: Pathology 16:307-311, 1984

Pathologists often do not agree. Here the problem was the"invasion" of melanoma cells. TeChnical details are dis­cussed.

P. C. A.