Clin Rheumatol DOI 10.1007/s10067-014-2683-2

CASE BASED REVIEW

Lucio’s phenomenon: report of five cases Pablo Finucci Curi & Julieta Solis Villaroel & Nora Migliore & Adriana Albertengo & María Laura Aquino & Federico Ceccato & Sergio Paira

Received: 23 April 2014 / Revised: 13 May 2014 / Accepted: 15 May 2014 # Clinical Rheumatology 2014

Abstract The different clinical forms of leprosy are mainly related to the variety of immunological responses to the infection. Several forms of lepromatous leprosy are recognized, including macular, nodular, and diffuse. Lucio’s phenomenon is a rare but distinctive skin eruption seen in patients with diffuse lepromatous leprosy. The diffuse lesions of Lucio’s phenomenon have a predilection for the extremities, can include nodules, and heal with atrophic stellate scars; histologically, a necrotizing vasculitis accompanied by a nonspecific inflammatory reaction may be seen. Because of its rarity and similarity with some manifestations of the rheumatic disease and other causes of vasculitis, Lucio’s phenomenon may not be easily recognized, especially in non-endemic countries, which leads to confusing diagnosis and loss of time for treatment. We report five patients with vasculitis caused by Lucio’s phenomenon.

Introduction

A. Albertengo Department of Pathology, Hospital Iturraspe, Santa Fe, Argentina

Leprosy or Hansen’s disease is a chronic infection produced by the Mycobacterium leprae. Though its prevalence has decreased considerably and more than 15 million patients found a cure through an international eradication plan organized by the World Health Organization, this disease remains a health issue in endemic areas [1]. In early 2011, the number of reported cases in the region of the Americas was 33,953 with a prevalence of 0.38/10,000 inhabitants. Within that region, leprosy’s endemic area circumscribe mainly to Latin American countries, with Brazil reporting the most cases [2]. Leprosy reactions are rare immunologically-mediated states that disrupt the usual chronic course and clinical stability of patients with leprosy. They may be separated clinically and histopathologically in two or three different variants: reverse reaction (type I), erythema nodosum leprosum (type II), erythema polymorphous (type II), and Lucio’s phenomenon, mainly considered a type II reaction [3]. The similarities between leprosy and the common rheumatic syndromes extend beyond rheumatoid arthritis, glomerulonephritis, myositis, uveitis, iridocyclitis, vasculitis, cryoglobulinemia, and findings such as butterfly rash, swollen hands, Raynaud’s phenomenon, Gottron-like lesions, lymph node enlargement, and hepatosplenomegaly seen in leprosy could mislead clinicians to the diagnoses of polyarteritis nodosa, reactive arthritis, systemic lupus erythematosus, and dermatomyositis [4–6]. We report five patients with Lucio’s phenomenon, two of which had been described previously [5]. A representative case is presented in detail here, and the main clinical and laboratory characteristics of all patients are summarized in Table 1.

M. L. Aquino Department of Internal Medicine, Sanatorio Chaco SRL, Chaco, Argentina

Case A 71-year-old male was referred for rheumatological consultation. Ten months before, he had been admitted to a

Keywords Leprosy . Lucio’s phenomenon . Rheumatic manifestations . Vasculitis P. F. Curi : F. Ceccato : S. Paira (*) Rheumatology Section, Hospital JM Cullen, Av Freyre 2150- (3000), Santa Fe, Argentina e-mail: [email protected] J. S. Villaroel Department of Internal Medicine, Hospital Interzonal San Juan Bautista, Catamarca, Argentina N. Migliore Department of Pathology, Hospital JM Cullen, Santa Fe, Argentina

Yes

No (refused treatment for leprosy) Prolonged febrile syndrome, malaise, alopecia of the eyebrows. Liver and spleen enlargement.

Palpably nodular purple-reddish lesions (non-painful) in the arm, legs, and abdomen. Diffuse infiltrate in the face. The skin lesions gradually developed into vesicles, blisters, and necrosis. Anemia, leukopenia, ESR ↑. Urea, creatinine, liver enzyme tests, bilirubin, and complete urine were normal.

Polymorphonuclear infiltrate with plasmocytes, eosinophils, lymphocytes, and fibrinoid necrosis. Acid-fast bacilli were seen.

Positive Dapsone, rifampin, and steroids (1 mg/kg/day) Died of sepsis

History of leprosy

Leprosy treatment at admission Clinical features

Characteristics of skin lesions

Skin biopsy

Skin-scraping test Treatment

Outcome

Laboratory

52 Male

Age (years) Gender

Case 1

Normal values of complete blood count. Urea, creatinine, liver enzyme tests, bilirubin, and complete urine were normal. ESR ↑, ANA (−), DNAn (−), RF (−) Necrotizing vasculitis (polymorphonuclear infiltrate with foamy histiocytes, plasmocytes, eosinophils, and lymphocytes in the dermis and hypodermis, and fibrinoid necrosis in the vessel wall). Positive Dapsone, clofazimine, and steroids (1 mg/kg/day) Died

Plaques and nodules (non-painful, non-tender) in the arm, legs, thorax, and buttocks. Some of these lesions changed into pustules and ulcers covered with a crust.

Yes (8 years, denied the disease at consultation) No (denied the disease and refused treatment) Fever, myalgias, epistaxis, partial alopecia of the eyebrows. Diffuse infiltrate of the face.

57 Female

Case 2

Table 1 Clinical and laboratory characteristics of five patients with Lucio’s phenomenon

Pancytopenia, ESR ↑, ANA (−), DNAn (−) ANCA P y C (−), cryoglobulins (−). Normal renal and hepatic function.

Anemia, leukocytosis, ESR ↑. ANA (−), DNAn (−), ANCA P y C (−). Urea, creatinine, liver enzyme tests, bilirubin, and urine were normal. Necrotizing vasculitis

Died of sepsis

Positive Dapsone and steroids

Positive Dapsone, clofazimine, and steroids (1 mg/kg/day) Alive

Necrotizing vasculitis acid-fast bacilli were seen.

Fever, nasal septal perforation, alopecia of the eyebrows, riding saddle nose, lymphadenopathy, dysesthesia in the hands. Liver and spleen enlargement. Necrotic ulcer lesions, erythematous-violaceous plaques in both arms and legs.

Fever, nasal septal perforation, alopecia of the eyebrows, saddle nose riding. Skin and soft tissue infection.

Necrotic ulcers in both hands.

No

No

59 Female

Case 4

No

Yes

74 Male

Case 3

Positive Dapsone, clofazimine, and steroids (1 mg/kg/day) Alive

Vasculitis septal and lobulillarhypodermitis

RF (−), ANA (−), cryoglobulins (−), ANCA (−), VDRL (−), DNA (−). Anticardiolipin antibodies (aCL) 20 GPL U/mL and 200 MPL U/mL

Macular and atrophic scarring skin lesions on the ear lobule and both lower extremities with alteration of thermalgesic sensitivity on these lesions.

Rhinorrhea, fever, paresthesias in the lower extremities, loss of eyebrow tails, nasal septum ulcer. Adenopathies.

No

No

71 Male

Case 5

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different hospital for purpuric skin lesions with a rapid necrohemorrhagic evolution that involved, sequentially, the lower extremities, the hands, and the lobule and helix in both ears (Figs. 1 and 2). At that time, laboratory data showed blood and urine culture negative, hypoalbuminemia, and normal complement C3 and C4. Rheumatoid factor, antinuclear antibody, cryoglobulins, antineutrophil cytoplasmatic antibody, VDRL, and anti DNA antibodies were negative. Anticardiolipin antibodies (aCL) titers were 20 GPL U/mL and 200 MPL U/mL (normal ranges 20 GPL and 10 MPL). A skin biopsy showed septal and lobulillar vasculitis and hypodermitis. With a diagnosis of necrotizing vasculitis and antiphospholipid syndrome, he was treated with corticosteroids and aspirin. At the time of our consultation, while receiving 20 mg/day of prednisone and 200 mg/day of AAS, he alluded to episodes of rhinorrhea with bloody mucus (3–4 times a year) and fever in approximately the last 2 years, in addition to the aforementioned paresthesias in the lower extremities and skin lesions. On physical examination, the patient was feverless and showed macular and atrophic scarring skin lesions on both lower extremities with altered sensitivity—mainly thermalgesic—on those lesions (anesthesia/ dysesthesia areas), loss of the eyebrow tails, and nasal septum ulcer. The patient also presented scars in both ear lobules and adenopathies in the right axillar region. Laboratory data showed normal values of complete blood count, blood urea and creatinine, alkaline phosphatase, serum proteins, urine, and liver function test. The ESR and CRP were elevated. Slit-skin smear examination from the ears, elbows, and knees revealed acid-fast bacilli (AFB) 3+ (bacteriologic index

Fig. 1 Necrotic lesions of the lobule and helix in both ears

Fig. 2 Necrotic lesions of the lower extremities

3+). A new biopsy of the skin lesions (Figs. 3 and 4) showed small-vessel vasculitis and the Fite-Faraco stain in the nerve fillets revealed the presence of numerous acid-alcohol resistant bacilli. The diagnosis of Lucio’s phenomenon was made and the patient was given dapsone, clofazimine, and steroids.

Discussion Rheumatic manifestations formed the third prevalent complication after dermatologic and neurologic abnormalities. Among the protean clinical and histopathological features of leprosy, the polar form known as lepromatous leprosy, the systemic presentation of the disease, usually manifest itself with papules and nodules all over the body, this is the nodular form. However, there is another well-known form of lepromatous leprosy, which presents itself without papules or nodules, that is, as a diffuse form or diffuse lepromatous leprosy, in which there is a widespread and dense infiltration of the whole skin by bacilli, without papules or nodules and commonly in association with alopecia of the eyebrows and eyelashes. Diffuse lepromatous leprosy (Lucio’s and Alvarado phenomenon) was first described by Lucio and Alvarado in 1852. In 1948, Latapí y Chávez studied again this peculiar form of leprosy and recognized it as a histopathologic vasculitis restricted to patients with diffuse, nonnodular lepromatous leprosy [7]. It is frequent in Mexico and in Costa Rica and very rare in other countries. It is characterized by a diffuse infiltration of all the skin which never is transformed into nodule, a complete alopecia of the eyebrows and eyelashes and body hair, destructive rhinitis, anhydrotic and dysesthesic zones of the skin, and by a peculiar type of lepra reaction named Lucio’s phenomenon or necrotic erythema which is a vasculitis of the vessels especially of the dermo-hypodermic union and of the

Clin Rheumatol

Fig. 3 Fite-Faraco ×40. Large number of bacilli in the vessel wall

hypodermis. Lucio’s phenomenon is clinically characterized by crops of wine–red irregular spots with burning sensation sharply delineated and a capricious center, which turn purpuric and become necrotic leaving atrophic stellar scars. Histopathologically, there are acid-fast bacilli in aggregates in vascular endothelium, areas of fibrinoid necrosis, leukocytoclastic vasculitis, and epidermal ischemic necrosis [8]. These lesions have a tendency to appear on the extremities. Fever, leukocytosis, neutrophilia, lymphopenia, and splenomegaly, have been reported. All of our five patients with vasculitis caused by Lucio’s phenomenon had fever, elevation of erythrocyte sedimentation rate, and diffuse nodular reddish lesions that became necrotic. They showed necrotizing histologic vasculitis of the subepidermal vessels, accompanied by a nonspecific inflammatory response. Rea et al., Pursley et al., and Magaña et al. support that in Lucio’s phenomenon macrophages are the target cell of

Fig. 4 Hematoxylin and eosin ×40. Vasculitic phenomena with thickening of the vessel wall and erythrocyte extravasation

M. Leprae involving also blood vessels [7, 9, 10]. Lucio’s phenomenon is a necrotizing panvasculitis due to an excess of antigen, not only as entire bacilli or its fragments but as a globi, which can be easily seen inside macrophages that infiltrate the vessel walls, mostly of muscular or medium size arteries (which explains the cutaneous infarcts) but also those of arterioles, venules, and medium size veins. Smaller and more superficial vessels exhibit a leukocytoclastic vasculitis with immune complex deposition. Differential diagnosis, such as antineutrophil cytoplasm antibodies (ANCA)-positive vasculitis, antiphospholipid antibody syndrome, polyarteritis nodosa, cryoglobulinemia, pyoderma gangrenosum, and connective tissue disorders, can be difficult. This applies in particular to those diseases presenting clinical cutaneous lesions and vasculitis on biopsy. Lucio’s leprosy is rarely considered in the differential diagnosis of vasculitis. Other differential diagnoses to be considered are proteins C/S deficiency, infections, treatments with warfarin and heparin, purpura fulminas, disseminated intravascular coagulation, cryofibrinogenemia, thrombotic thrombocytopenia, myeloblastemia, hemolytic uremic syndrome, cutaneous tuberculosis, deep mycoses, and tertiary syphilis [11–14]. Cryoglobulins, serum levels of enzymes derived from macrophages (specifically lysozyme and angiotensin converting enzyme), were found in high titers in patients with leprosy, but particularly high levels were observed in patients with Lucio’s phenomenon. The presence of autoantibodies such as antinuclear antibodies (0–30 %, low titers, mostly in multibacillary leprosy), rheumatoid factor (5–45 % of lepromatous patient), anti-cyclic citrullinated peptide (2.5–16 %), and ANCA (5– 20 %) can generate more confusion in the diagnosis [15–18]. Anticardiolipin (aCL) and anti-ß2 glycoprotein I antibodies (anti-ß2 GPI) have been reported in leprosy patients, mainly in association with lepromatous leprosy, and usually without APS-related clinical manifestations. The reported prevalence of anticardiolipin antibodies (aCL) ranges 37–98 %, whereas anti-ß2-glycoprotein I (antiGPI b2) 3–19 %, and 6–45 % in antiprothrombin (aPT) antibodies [18, 19]. In our study, both ANA and DNA were negative in four out of five patients, c-ANCA and p-ANCA—performed in three patients—were negative; FR and cryoglobulins dosage—performed in two patients—were also negative. A search for aCL, in one patient only, revealed high titers. Severe, prolonged morbidity and poor response to therapy were reported by Moschela [13] and by Donner et al. [14]. Lucio’s phenomenon is usually fatal, generally as a result of secondary infection and sepsis [20]. Three of our patients died for that reason. Because of its rarity and similarity with some manifestations of connective tissue diseases, Lucio’s phenomenon may not be easily recognized, especially in non-endemic countries, which leads to confusing diagnosis and loss of time for treatment.

Clin Rheumatol Acknowledgments The authors are grateful to Raúl Galoppe, Ph.D. (Montclair State University) for his help in translating the manuscript. Disclosure The authors declare that they have none to disclose.

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11. Kaur C, Thami GP, Mohan H (2005) Lucio phenomenon and Lucio leprosy. Clin Exp Dermatol 30:525–527 12. Quismorio FP Jr, Rea T, Chandor S, Levan N, Friou GJ (1978) Lucio’s phenomenon: an immune complex deposition s y n d r o m e i n l e p r o m a t o u s l e p r o s y. C l i n I m m u n o l Immunopathol 9:184–193 13. Moschella SL (1967) The lepra reaction with necrotizing skin lesions: a report of six cases. Arch Dermatol 95:565–575 14. Donner R, Shively J (1967) The Lucio’s phenomenon in diffuse leprosy. Ann Intern Med 67:831–836 15. Chavez-Legaspi M, Gomez-Vazquez A, García-De La Torre I (1985) Study of rheumatic manifestations and serologic abnormalities in patients with lepromatous leprosy. J Rheumatol 12: 738–741 16. Pradhan V, Badakere SS, Shankar KU (2004) Increased incidence of cytoplasmic ANCA (cANCA) and other auto antibodies in leprosy patients from western India. Lepr Rev 75: 50–56 17. Zavala-Cerna MG, Fafutis-Morris M, Guillen-Vargas C et al (2012) Anti-cyclic citrullinated peptide antibodies and rheumatoid factor sera titers in leprosy patients from Mexico. Rheumatol Int 32:3531– 3536 18. de Larrañaga GF, Forastiero RR, Martinuzzo ME et al (2000) High prevalence of antiphospholipid antibodies in leprosy: evaluation of antigen reactivity. Lupus 9:594–600 19. Loizou S, Singh S, Wypkema E, Asherson RA (2003) Anticardiolipin, anti-beta(2)-glycoprotein I and antiprothrombin antibodies in black South African patients with infectious disease. Ann Rheum Dis 62:1106–1111 20. Gelber R (1995) (Hansen’s disease) In: Mandell G, Bennett J, Dolin R, editors. Principles and Practice of Infectous Diseases. 4th ed. Vol 2. New York: Churchill-Livingston; P 2243–50

Lucio's phenomenon: report of five cases.

The different clinical forms of leprosy are mainly related to the variety of immunological responses to the infection. Several forms of lepromatous le...
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