AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

The tuberculids, first described by Darier in 1896, represent a form of cutaneous hypersensitivity reaction to tuberculosis (TB) antigens. Although many types of tuberculids have been described, most are now understood to not be uniquely caused by TB. However, papulonecrotic tuberculids (PNTs) and lichen scrofulosorum are still widely accepted as true tuberculids.

The entity PNT was first established by Pautrier in 1936 as a distinct TB-associated disorder, when he described the characteristic clinical and histopathologic features. PNT is a chronic, recurrent, and symmetric eruption of necrotizing skin papules arising in crops, involving primarily the arms and the legs. A hallmark of this condition is that lesions heal with varioliform scarring. The eruption is believed to represent a hypersensitivity reaction to TB antigens released from a distant focus of infection. Most patients react markedly to the Mantoux skin test (purified protein derivative, PPD) and may exhibit other evidence of current or past TB infection.

Pathophysiology

The pathophysiology of PNT is controversial. Most authors believe this disease entity is triggered by an initial Arthus reaction to mycobacterial antigens. This is then followed by a hypersensitivity reaction in which antigens undergo opsonization by antibodies, followed by immune complex deposition in small cutaneous blood vessels. The ensuing complement cascade triggers a leukocytoclastic vasculitis, leading to destruction of vessel walls with ensuing tissue necrosis. However, other authors dispute this mechanism, citing the lack of leukocytoclastic vasculitis in some cases. Instead, they propose that the primary lesion is the result of subacute lymphohistiocytic vasculitis that leads to thrombosis and subsequent tissue necrosis.

Whatever underlies the pathophysiology, a consensus has been reached that PNT represents a true hypersensitivity reaction rather than the result of a local cutaneous TB infection. This is based on the observation that PNT lesions have consistently failed to either stain positive for, or culture out, mycobacterial organisms. Although the organisms are absent, mycobacterial DNA have been detected in approximately half of the biopsy specimens subjected to polymerase chain reaction. These observations support the idea that lesions of PNT are the result of released mycobacterial antigens in the setting of a concurrent but distant infection.

Frequency

United States

A decreasing incidence of PNT began in the second half of the 1900s and the decline continues to this day. This phenomenon is attributed to aggressive TB control now found in wide practice. Currently, almost all cases come from areas outside of North America with high endemic rates of TB. However, a rare US case, involving a previously healthy 9-year-old girl from Chicago, Ill, was reported in 1990. Historically, reports indicate that young women and children are especially susceptible to this disorder. PNT-like lesions have also been associated with other mycobacterial infections, including Mycobacterium bovis and Mycobacterium kansasii, and from BCG vaccination. With the increased incidence of TB infection in patients with HIV, the frequency of PNT may increase, although this has not yet occurred, due possibly to effective public health measures to identify, isolate, and treat active cases of TB.

International

PNT is an uncommon disorder even in populations with a high prevalence of TB, occurring in less than 5% of active TB cases. In the literature, 91 cases were reported during a 17-year period in South Africa in 1974. In addition, 12 cases from a period of longer than 30 years in England were reported in 1986. In the latter study, most patients were immigrants and had presumably acquired the infection outside of England.

Mortality/Morbidity

The condition typically follows a prolonged and relapsing course lasting years, although spontaneous resolution has been reported. Significant varioliform scarring is a sequela, and progression to lupus vulgaris has been observed. An association with Takayasu arteritis of the aortic arch has also been documented.

Sex

Females seem to be at a slightly increased risk for developing this disorder.

Age

Children and young adults are more susceptible to this condition than other people. In the 1974 study from South Africa, two thirds of the patients were younger than 30 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

• The characteristic lesions are small, erythematous, inflammatory papules that undergo central ulceration and heal spontaneously within weeks, leaving a varioliform scar.
• Lesions arise in symmetric crops, typically with an acral predilection. Characteristically, lesions develop over the extensor surfaces, particularly the knees, the elbows, and the dorsum of the hands and the feet, although widespread involvement may be present.
• New lesions form as older lesions resolve, giving the eruption a polymorphous appearance.
• Oral lesions have not been reported to date.
• PNTs have been reported to coexist with lesions of erythema induratum, as well as lichen scrofulosorum. In several reports, cutaneous lesions resolved with appropriate anti-TB therapy.

Physical

• Primary lesion: The characteristic initial lesions are 2- to 8-mm, erythematous papules that become pustules and undergo central ulceration forming hemorrhagic-crusted papules.
• Distribution: Lesions arise in symmetric crops, typically with an acral predilection. Characteristically, lesions develop over the extensor surfaces, particularly the knees, the elbows, and the dorsum of the hands and the feet, although widespread involvement may occur. Involvement of the glans penis has also been reported.
• Color: Hyperpigmented to erythematous papules with central crusting are seen early, and the lesions generally heal with scarring.
• Lymph nodes: In one study, as many as one third of the cases were associated with cervical lymphadenopathy, and some patients developed scrofuloderma.

Causes

The eruption is a form of an exaggerated host immunologic response to a mycobacterial infection involving the cutaneous vessels. Active TB is reported in as many as 40% of patients.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Pityriasis lichenoides et varioliformis acuta (PLEVA)
Septicemia
Perforating granuloma annulare
Miliary TB (patients are ill and lesions are culture-positive for TB)
Suppurative folliculitis
Pustular syphilide
Drug eruption

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• Patients should be evaluated for evidence of active TB or other forms of mycobacterial infection. Tuberculous involvement of the female genital tract may account for the increased incidence in females, and a culture of menstrual fluid and endometrial biopsy may be of value in excluding occult disease.
• CBC count, chemistry panel, and urinalysis should be performed.
• The erythrocyte sedimentation rate is often very high and can be used to monitor treatment. It decreases 4-6 weeks after treatment is started.

Imaging Studies

• Chest radiography is needed to rule out active or past pulmonary TB.
• Abdominal radiographs may show lymph node calcifications typical of TB.

Other Tests

• Mantoux (PPD) intradermal skin tests are usually strongly positive. Some authors require this result for diagnosis. However, false-negative negative results can occur in the setting of immunosuppression. Hence, clinical correlation in such cases is prudent.

Histologic Findings

The histologic features vary with the timing of the biopsy. In an early lesion, evidence of a vasculitis, which is typically leukocytoclastic with fibrinoid necrosis of the vessel wall and karyorrhectic debris, should be present. However, some authors have found that the primary lesion consists of lymphohistiocytic, rather than leukocytoclastic, vasculitis.

Characteristic of the disorder is the presence of perivascular spongy edema. Later, because of the obliterative vascular changes, a wedge-shaped area of focal dermal necrosis develops, surrounded by a granulomatous inflammatory infiltrate with giant cells and epithelioid histiocytes. Well-formed tuberculoid granulomas with Langerhans giant cells are not usually present in the lesions. Special stains for mycobacteria are typically negative.

The histologic differential diagnosis depends on the timing of the biopsy as well as the histologic appearance. In particular, inflammatory palisading granulomas (ie, granuloma annulare and infectious granulomas) may look similar as compared to those found occasionally in PNT. However, the ability to exclude mucin and infectious organisms in effect rules out granuloma annulare and infectious granulomas, respectively.

TREATMENT

Section 6 of 10  

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• Introduction
• Clinical
• Differentials
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• Treatment
• Medication
• Follow-up
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• References

Medical Care

Treatment is directed at eradicating the underlying mycobacterial infection. TB treatment guidelines may vary from region to region and from different authorities (ie, the World Health Organization [WHO] and the Centers for Disease Control and Prevention [CDC]). Currently, for patients with active TB, a 4-drug therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) is recommended to avoid the development of resistance. PNTs respond promptly to appropriate anti-TB therapy. New lesions cease forming within days to weeks after therapy is initiated, and existing lesions heal rapidly, usually within several months. A minimum of 6 months of anti-TB therapy is recommended. Recurrences rarely occur after appropriate therapy.

MEDICATION

Section 7 of 10  

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• References

The goal of pharmacotherapy is to eradicate the underlying mycobacterial infection that causes PNT.

Drug Category: Antitubercular agents

These agents are effective in the treatment of mycobacterial infections. Therapy with a 4-drug combination of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) is recommended to avoid the development of resistance.

Drug Name	Rifampin (Rifadin, Rimactane)
Description	For use in combination with at least 1 other anti-TB drug. Inhibits DNA-dependent bacterial RNA polymerase but not mammalian RNA polymerase. Cross-resistance may occur. Treat for 6-9 mo or until 6 mo have elapsed from conversion to sputum culture negativity.
Adult Dose	600 mg PO/IV qd
Pediatric Dose	10-20 mg/kg PO/IV; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes (especially P450 CYP3A4-mediated metabolism), which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, digoxin, and other medications metabolized by this system; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Drug Name	Pyrazinamide
Description	Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on concentration of drug attained at site of infection; mechanism of action is unknown. Administer for initial 2 months of a 6-mo or longer treatment regimen for drug-susceptible patients. Treat drug-resistant patients with individualized regimens.
Adult Dose	15-30 mg/kg PO qd; not to exceed 2 g/d Indirectly observed therapy: 50-70 mg/kg PO 2 times/wk, not to exceed 4 g/d; or 50-70 mg/kg 3 times/wk, not to exceed 3 g/d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severe hepatic damage; acute gout
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only in combination with other effective anti-TB agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty arthritis; perform baseline LFTs (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus; coadministration of ethionamide may potentiate hepatotoxicity

Drug Name	Ethambutol (Myambutol)
Description	Diffuses into actively growing mycobacterial cells, such as tubercle bacilli. Impairs cell metabolism by inhibiting synthesis of one or more metabolites, which, in turn, causes cell death. No cross-resistance demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been previously administered. Administer qd until permanent bacteriologic conversion and maximal clinical improvement is seen. Absorption is not significantly altered by food.
Adult Dose	No previous anti-TB therapy: 15 mg/kg (7 mg/lb) PO qd Previous anti-TB therapy: 25 mg/kg (11 mg/lb) PO qd
Pediatric Dose	<13 years: Not recommended >13 years: Administer as in adults
Contraindications	Documented hypersensitivity; optic neuritis (unless clinically indicated)
Interactions	Aluminum salts may delay and reduce absorption (give several hours before or after ethambutol dose)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Reduce dose in impaired renal function; may have reversible visual adverse effects if promptly discontinued

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Complications

• Complications include significant varioliform scarring and those of TB infections, including progression to lupus vulgaris.

Prognosis

• Patients typically follow a waxing and waning course lasting many years, although spontaneous resolution has been reported.
• PNTs respond promptly to appropriate anti-TB therapy. New lesions cease forming within days to weeks after therapy is initiated, and existing lesions heal rapidly, usually within several months. Recurrences are rare after appropriate therapy.
• Unfortunately, despite even the most aggressive efforts, mortality is high in those infected with multidrug resistant TB.

MULTIMEDIA

Section 9 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Bilaterally symmetric papulonecrotic lesions on the lower extremities.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

• Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol. 2002;3(5):319-28. [Medline].
• Chalermdamrichai P, Puavilai S, Jerasutus S, et al. Sarcoidosis presenting as papulonecrotic tuberculid-like lesions: report of a case. J Med Assoc Thai. Jul 2004;87(7):839-44. [Medline].
• Darier MJ. Des "tuberculides" cutanees. Ann Dermatol Syph. 1896;7:1431-36.
• Fernandes C, Maltez F, Lourenço S, et al. Papulonecrotic tuberculid in a human immunodeficiency virus type-1 patient with multidrug-resistant tuberculosis. J Eur Acad Dermatol Venereol. May 2004;18(3):369-70. [Medline].
• Freiman A, Ting P, Miller M, Greenaway C. Papulonecrotic tuberculid: a rare form of cutaneous tuberculosis. Cutis. Jun 2005;75(6):341-6. [Medline].
• Iden DL, Rogers RS 3rd, Schroeter AL. Papulonecrotic tuberculid secondary to Mycobacterium bovis. Arch Dermatol. Apr 1978;114(4):564-6. [Medline].
• Jordaan HF, Van Niekerk DJ, Louw M. Papulonecrotic tuberculid. A clinical, histopathological, and immunohistochemical study of 15 patients. Am J Dermatopathol. Oct 1994;16(5):474-85. [Medline].
• Milligan A, Chen K, Graham-Brown RA. Two tuberculides in one patient--a case report of papulonecrotic tuberculide and erythema induratum occurring together. Clin Exp Dermatol. Jan 1990;15(1):21-3. [Medline].
• Morrison JG, Fourie ED. The papulonecrotic tuberculide. From Arthus reaction to lupus vulgaris. Br J Dermatol. Sep 1974;91(3):263-70. [Medline].
• Pautrier L-M. Tuberculose nodulare dermique á petits nodules. In: Darier J, ed. Nouvelle Pratique. Paris: Masson Editeur. 1936.
• Senol M, Ozcan A, Aydin A, et al. Disseminated lupus vulgaris and papulonecrotic tuberculid: case report. Pediatr Dermatol. Mar-Apr 2000;17(2):133-5. [Medline].
• Sloan JB, Medenica M. Papulonecrotic tuberculid in a 9-year-old American girl: case report andreview of the literature. Pediatr Dermatol. Sep 1990;7(3):191-5. [Medline].
• Thappa DM, Karthikeyan K, Jayanthi S. Tuberculid in a child: transformation from papulonecrotic to lichen scrofulosorum. Pediatr Dermatol. Jan-Feb 2003;20(1):91-3. [Medline].
• Victor T, Jordaan HF, Van Niekerk DJ, et al. Papulonecrotic tuberculid. Identification of Mycobacterium tuberculosisDNA by polymerase chain reaction. Am J Dermatopathol. Dec 1992;14(6):491-5. [Medline].
• Wilson-Jones E, Winkelmann RK. Papulonecrotic tuberculid: a neglected disease in Western countries. J Am Acad Dermatol. May 1986;14(5 Pt 1):815-26. [Medline].

Article Last Updated: Jan 26, 2007