Lymphadenopathy and systemic lupus erythematosus

Abstracts

A linfadenopatia no lúpus eritematoso sistêmico (LES) é um achado benigno encontrado comumente em jovens, com atividade cutânea e sintomas constitucionais, apresentando boa resposta à corticoterapia. O achado mais frequente à biópsia é a hiperplasia folicular reacional. Relatamos o caso de um paciente que, desde os 13 anos de idade, apresentava surtos recorrentes de linfadenopatia, acompanhados de hepatoesplenomegalia, febre e emagrecimento. Na evolução, apareceram artrite, hipertensão arterial, proteinúria, miocardiopatia e neuropatia periférica. Foi amplamente investigado sem esclarecimento diagnóstico e submetido a tratamento empírico de tuberculose. Somente após cinco anos de evolução firmou-se o diagnóstico de LES e recebeu tratamento específico. O diagnóstico precoce nestes casos é difícil, pois a investigação laboratorial pode ainda não demonstrar presença de autoanticorpos ou hipocomplementemia.

lúpus eritematoso sistêmico; febre de origem indeterminada; síndrome consumptiva; autoanticorpos; linfadenopatia

CASE REPORT

Lymphadenopathy and systemic lupus erythematosus

Nilton Salles Rosa Neto^I; Karina Rossi Bonfiglioli^I; Fernanda Manente Milanez^I; Patrícia Andrade de Macêdo^I; Maurício Levy-Neto^II

^IRheumatology Residents of Hospital das Clínicas of the Medical School of Universidade de São Paulo (HC-FMUSP)

^IIPhysician of the Rheumatology Department of HC-FMUSP

Correspondence to

ABSTRACT

Lymphadenopathy is a benign finding in systemic lupus erythematosus (SLE), commonly seen in young patients with cutaneous involvement and constitutional symptoms, with good response to corticosteroids. Reactive follicular hyperplasia is the most frequent finding in biopsies. We report the case of a patient with recurrent episodes of lymphadenopathy associated with hepatosplenomegaly, fever, and weight loss since the age of 13 years. The patient also developed arthritis, hypertension, proteinuria, cardiomyopathy, and peripheral neuropathy. His condition was investigated extensively without diagnostic clarification; he was treated, empirically, for tuberculosis. The patient received a diagnosis of SLE only five years after the original presentation and received the specific treatment. Early diagnosis in those cases is difficult because laboratorial exams may not show the presence of auto-antibodies and low complement levels.

Keywords: systemic lupus erythematosus, fever of unknown origin, wasting syndrome, auto-antibodies, lymphadenopathy.

INTRODUCTION

Lymphadenopathy is characterized by changes in the number, characteristics, or size of the lymph nodes. It results from reticuloendothelial proliferation secondary to inflammation, infection, or malignancies. In systemic lupus erythematosus (SLE) it represents a benign finding, with a mononucleosislike behavior, and it can be seen in any phase of the disease.^1-3

Biopsy commonly shows reactive follicular hyperplasia (RFH), with or without atypical cells, and it is considered a non-specific finding. Coagulative necrosis with hematoxylin bodies, typical findings in SLE, is rarely seen.^4,5

We report the case of a patient with recurrent episodes of lymphadenopathy treated initially as infectious in origin, who was later diagnosed with SLE.

CASE REPORT

This is an 18 years old male patient from São Paulo, SP. In 2003, the patient developed recurrent episodes of lymphadenomegaly, hepatomegaly, fever in the evening, diaphoresis, and weight loss, lasting several months and with spontaneous regression.

In 2004, the patient developed anasarca, which subsided, and hypertension, which persisted. In the following year the patient developed arthritis in the knees. At that time, rheumatoid factor and anti-nuclear factor (ANF) were negative and complement levels were normal.

Repeated biopsy of the lymph nodes showed RFH, and investigation for tuberculosis was negative. He had a PPD of 5 mm and normal chest X-ray, but the team responsible for his cared instituted treatment for tuberculosis (rifampin, isoniazid, and pyrazinamide). With recurrence of the symptoms, ethambutol was added to the regimen for therapeutic failure. After a new recurrence in 2008 associated with polyarthritis and proximal muscular weakness, the patient was referred to the reference hospital due to refractory tuberculosis, where pleural and pericardial effusion, hepatosplenomegaly, and generalized lymphadenomegaly, along with a 20-kg weight loss, were identified.

After ruling out infectious causes, a new lymph node biopsy showed RFH (Figure 1). This time the ANF was positive and the patient was referred to a rheumatologist.

Laboratory test revealed anemia of chronic disease, normal muscle enzymes, proteinuria of 1.99 g/24 hours without hematuria/leukocyturia, and elevated inflammatory acute phase reactants. The ultrasound scan showed parenchymatous nephropathy, and the echocardiogram showed diffuse hypokinesis and ejection fraction 55% (in a previous exam it was higher than 70%). Electroneuromyography showed chronic peripheral neuropathy without evidence of myopathy. Neoplastic causes were ruled out.

The patient had positive ANF with a speckled pattern (titer higher than 1/320), and positive anti-Ro, anti-P, and IgG and IgM anticardiolipin antibodies. Kidney biopsy showed membranous glomerulonephritis.

The patient received the diagnosis of SLE and treatment with prednisone, 60 mg/d, chloroquine diphosphate, 250 mg/d, and azathioprine, 100 mg/d, was instituted. The patient is currently asymptomatic and on decreasing doses of prednisone.

DISCUSSION

The clinical presentation and evolution of SLE shows a wide variety. The immunopathogenesis of SLE is associated with genetically determined loss of self-tolerance and cellular activation dependent of non-genetic factors, such as environmental, hormonal, and infectious. Activation of T lymphocytes by γ-interferon stimulates the sequence of progressive and persistent expansion of apoptosis-resistant polyclonal B lymphocytes, which produce auto-antibodies characteristics of the disease.⁶

Lupus lymphadenopathy (LL) has an estimated prevalence between 5 and 7%, at the onset of the disease, and 12 to 15%, at stage of the disease.^7,8 Lupus lymphadenopathy involves, mainly, the cervical and axillary regions, and the lymph nodes are soft, mobile, painful, and non-adherent to deep planes.² In case of significant lymphadenopathy, lymph node biopsy is indicated to rule out infectious or lymphoproliferative disorders.^1-3 Table 1 includes the most important differential diagnosis in those cases.

Lupus lymphadenopathy can be classified as localized (involvement of up to two lymph node chains) or generalized (three or more). Findings of malar erythema, photosensitivity, alopecia, oral ulcers, fever, weight loss, nocturnal sudoresis, and hepatosplenomegaly are expected. Kojima et al.⁵ demonstrated a higher incidence of LL in women, association with systemic symptoms and altered laboratorial exams, and RFH on histology. However, they identified atypical histological characteristics and classified them as:

• RFH with giant follicles: irregular follicles, increased in size, with hyperplastic germinal center, and cytolysis.

• Aspects similar to Castleman's disease (CD): plasmacytosis and interfollicular vascular proliferation; it might be mistaken for the mixed form of CD.

• Atypical paracortical hyperplasia with lymphoid follicles: immunohistochemistry (IH) allows differentiating it from angioimmunoblastic T cell lymphoma. It is associated with fever, polyclonal hypergammaglobulinemia, and circulating immune complexes.

• Atypical immunoblastic and lymphoplasmacytic proliferation: lymphoplasmacytic and policlonal B-immunoblastic infiltration; without lymphoid follicles or vascular proliferation.

A classification of the patterns of lymph node lesions in SLE, similar to the classes of lupus nephritis, has been suggested; however, those types do not seem to be specific enough to establish the diagnosis of SLE.⁴

The increased risk of lymphomas, especially non-Hodgkin's lymphoma, in lupus patients led to further studies of those atypical changes. The symptoms of both disorders can be similar, which can delay the diagnosis and treatment of the neoplasia. Complete differentiation depends on IH.^9-12

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, a self-limiting disease of young people, involving mainly cervical lymph nodes, should also be ruled out. Its histological characteristics allow recognizing it as a specific disease. Its development before, after, or concomitantly to the diagnosis of SLE has been reported. Since LL courses with coagulative necrosis, it raises doubts on the cases reported in the literature as the association of SLE and KFD. The differential diagnosis between those two entities requires IH of all suspicious lymph nodes because LL has a very small number of cytotoxic T cells while KFD has a high number of those cells.¹³

In summary, lymphadenopathy is a common manifestation in SLE. As illustrated by the case presented here, it can antecede the diagnosis of SLE by many years, when the presence of ANF, other auto-antibodies, or low complement levels cannot be detected. It is possible that the factors that induce lymph node proliferation are also responsible for the development of auto-antibodies.

REFERENCES

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Publication Dates

• Publication in this collection
  10 Mar 2010
• Date of issue
  Feb 2010

History

• Accepted
  06 Oct 2009
• Received
  19 Jan 2009