Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Visceral leishmaniasis mimicking systemic lupus erythematosus: Case series and a systematic literature review Iuri Usêda Santana, MDa, Blenda Dias, MDb, Eduardo Araújo Santana Nunes, MDb, Francisco Airton Castro da Rocha, MD, PhDc, Francisco Saraiva Silva Jr, MDc, Mittermayer Barreto Santiago, MD, PhDb,n a b c
Serviço de Clínica Médica do Hospital Geral Roberto Santos, Salvador, Brazil Serviços Especializados em Reumatologia (SER) da Bahia, Rua Conde Filho, 117, Graça, Salvador, Bahia CEP 40150-150, Brazil Serviço de Reumatologia do Hospital Universitário Walter Cantídio, Ceará, Brazil
a r t i c l e in fo
Keywords: Systemic lupus erythematosus Visceral leishmaniasis Autoantibodies Case series
a b s t r a c t Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease that may present manifestations that resemble other diseases. Visceral leishmaniasis (VL) is a parasitic infection whose hallmarks may mimic SLE symptoms. Here, we report a case series and evaluate the published, scientific evidence of the relationship between SLE and VL infection. Methods: To assess original studies reporting cases of VL-infected patients presenting manifestations that are capable of leading to inappropriate suspicions of SLE or mimicking an SLE flare, we performed an extensive search in several scientific databases (MEDLINE, LILACS, SciELO, and Scopus). Two authors independently screened all citations and abstracts identified by the search strategy to identify eligible studies. Secondary references were additionally obtained from the selected articles. Results: The literature search identified 53 eligible studies, but only 17 articles met our criteria. Among these, 10 lupus patients with VL mimicking an SLE flare and 18 cases of VL leading to unappropriated suspicions of SLE were described. The most common manifestations in patients infected with VL were intermittent fever, pancytopenia, visceromegaly, and increased serum level of acute phase reactants. The most frequent autoantibodies were antinuclear antibodies, rheumatoid factor, and direct Coombs’ test. Conclusion: In endemic areas for VL, the diagnosis of SLE or its exacerbation may be a clinical dilemma. Hepatosplenomegaly or isolated splenomegaly was identified in the majority of the reported cases where VL occurred, leading to unappropriated suspicions of SLE or mimicking an SLE flare. Furthermore, the lack of response to steroids, the normal levels of complement proteins C3 and C4, and the increased level of transaminases suggest a possible infectious origin. & 2015 Elsevier Inc. All rights reserved.
Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease classically characterized by chronic, multisystemic inflammation of unknown etiology. Many patients alternate between periods of exacerbation (flare) and reduced disease activity [1]. It is characterized by polyclonal activation of B lymphocytes with production of multiple autoantibodies. Physiologically, polyclonal B cell activation occurs in chronic infectious diseases, such as VL. Additionally, patients with SLE (particularly those treated with immunosuppressive drugs) are at an increased risk for infections that can complicate, exacerbate, or mimic their symptoms [2].
n
Corresponding author. E-mail address: [email protected] (M.B. Santiago).
http://dx.doi.org/10.1016/j.semarthrit.2014.12.004 0049-0172/& 2015 Elsevier Inc. All rights reserved.
Visceral leishmaniasis (VL) is an acute or chronic systemic protozoan infection transmitted to humans by sandflies of the Phlebotomus species. Dogs are the main host reservoir. VL is a major public health problem in tropical and subtropical countries. Specifically, it is endemic in 64 countries, and 90% of the world’s cases are reported in India, Bangladesh, Nepal, Sudan, and Brazil [3]. In Brazil, VL was originally restricted to rural areas, mainly in the Northeast region of the country, but since the 1980s, the geographical distribution of this disease has expanded with increasing urbanization, reaching virtually all regions, with an average annual incidence rate of two cases per 100,000 inhabitants [4,5]. The disease has a wide clinical spectrum: from asymptomatic infection to an acute or chronic life-threatening condition with fever, hepatosplenomegaly, and pancytopenia. Therefore, the objective of this study is to describe three cases of VL mimicking the symptoms of SLE and systematically
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review the literature on the relationship between these two conditions.
Case series Case 1 A 25-year-old woman was admitted to our hospital with a 2-year history of additive and symmetric polyarthritis (mostly in hand and knee joints) with partial improvement with the use of nonsteroidal anti-inflammatory drugs. She reported worsening of joint manifestations associated with daily fever since the time she became pregnant. Hepatosplenomegaly, jaundice, nonerosive arthritis, and positive antinuclear antibody (ANA) 1:80 speckled pattern were reported by another hospital to which she was admitted; at that time, the diagnosis of SLE with hepatic involvement was suggested. Pulse therapy with methylprednisolone (1 g) for 3 days was administered with considerable clinical improvement, and the patient was discharged with prednisone (80 mg/ day). Four days after her discharge, she relapsed with fever, polyarthritis, and abdominal pain. She was referred to our hospital and delivered a stillborn fetus at 26 weeks of pregnancy. On examination, she was febrile (39.01C) with pale mucous membranes, hepatosplenomegaly, and limitation of motion due to diffuse articular pain. The rest of her physical examination was unremarkable. Laboratory tests revealed mild anemia and negative hepatitis B surface antigen, anti-hepatitis C virus antibody, antiHIV antibody, IgM anti-cytomegalovirus antibody, ANA, antidouble stranded DNA (anti-dsDNA) antibody, anti-Ro antibody, anti-La antibody, anti-Sm antibody, anti-liver kidney microsomes antibody type 1, anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA), and IgM and IgG anti-cardiolipin antibodies. Cefepime was initiated despite the negative results of blood and urine culture, and prednisone was reduced to 20 mg/ day. However, as there was no clinical improvement, her bone marrow was examined; there were amastigote forms inside the phagocytic cells. Amphotericin B deoxycholate was administered for 32 days with considerable clinical and laboratory improvement; she was discharged after treatment and remained asymptomatic on follow-up examination therefore. SLE diagnosis was not confirmed. Case 2 A 27-year-old woman was admitted to our hospital reporting a history of intermittent fever for approximately 12 months without proper investigation. At 30 days before admission, she reported persistent fever associated with profuse dry coughing, low back pain, abdominal pain, asthenia, and arthralgia. She had been under treatment for SLE (prednisone 10 mg/day), which had been diagnosed approximately 6 years prior; at that time, she had presented with cutaneous involvement (malar rash and photosensitive rash in the chest), renal involvement (nephritic proteinuria, hematuria, and cellular casts), hematological involvement (anemia, leukopenia, and lymphopenia), articular involvement (arthritis and Jaccoud’s arthropathy), hypocomplementemia, positive ANA (1:320), positive anti-Ro, and positive anti-dsDNA. Her previous history also included infectious endocarditis in the mitral valve (diagnosed 5 years prior) with proper treatment and osteomyelitis in the right lower limb (diagnosed 4 years prior) treated with antibiotics and surgery. On examination, she presented with fever (38.51C), blood pressure of 100 70 mmHg, tachycardia, pale mucous membranes, cushingoid appearance, butterfly-shaped malar rash, and painless mouth ulcers without palpable lymph nodes. There was a systolic murmur in the mitral and the tricuspid areas; abdominal
examination revealed diffuse abdominal distension and splenomegaly. The rest of the physical examination was unremarkable. On admission, her laboratory results were as follows: hemoglobin, 11.0 g/dL; white blood cell count, 3570/mm3; platelet count, 80,000/mm3; ionized calcium, 1.09 mmol/L; creatinine, 0.4 mg/ dL; aspartate transaminase, 348 mg/dL; alanine transaminase, 99 mg/dL; alkaline phosphatase, 468 mg/dL; and γ-glutamyltransferase, 777 mg/dL. Bone marrow aspiration was normal. By transthoracic echocardiogram, there was moderate mitral regurgitation, mild tricuspid regurgitation, and preserved systolic and diastolic function. Crystalline penicillin, oxacillin, and amikacin were initiated despite the negative results of blood and urine culture and the absence of valve vegetation. The patient developed respiratory discomfort and worsening cough; by chest radiography and tomography, there was left lung consolidation and bilateral exudative pleural effusion, which was drained. Later, she presented worsening thrombocytopenia with moderate epistaxis and hematemesis, which was treated with a platelet transfusion and proton-pump inhibitor. As the patient’s clinical condition was not improving, despite the use of broader-spectrum antimicrobial agents (at that time, meropenem, teicoplanin, fluconazole, and polymyxin B), pulse therapy with methylprednisolone (1 g) was administered for 3 days with partial improvement. However, as there was no full clinical improvement, a new bone marrow study with biopsy was performed; however, the patient’s clinical condition rapidly deteriorated with refractory disseminated intravascular coagulation and septic shock. Unfortunately, despite intensive care treatment, she died. Postmortem examination of the bone marrow biopsy demonstrated amastigote forms of Leishmania donovani. Case 3 An 18-year-old woman was admitted to our hospital with a 5-month history of fever, almost daily and mainly in the mornings without chills or drenching sweats. She had been under treatment for SLE, which had been diagnosed approximately 1 year prior; at that time, she had presented with cutaneous involvement (malar rash and photosensitive rash in the chest and the arms), renal involvement (nephrotic syndrome), positive ANA (1:1280), low-grade fever, and axillar and cervical lymphadenopathy. With this initial diagnosis, she started prednisone and mycophenolate mofetil (2 g/day). Because she became pregnant, mycophenolate was interrupted and prednisone was maintained, and she was referred to an obstetrician. The patient evolved with miscarriage 30 days later, and uterine curettage was performed. Thereafter, she developed a febrile condition (without other signs or symptoms) and was treated with ciprofloxacin plus metronidazole for 14 days without improvement. She had no other relevant past medical history and no alcohol intake, smoking, or drug abuse. On examination, she presented with fever (39.51C), blood pressure of 120 80 mmHg (using captopril 50 mg/day), tachycardia, pale mucous membranes, cushingoid appearance, mild butterfly-shaped malar rash, and mild bilateral leg edema. The rest of the physical examination was unremarkable. On admission, her laboratory results were as follows: hemoglobin, 8.2 g/dL; white blood cell count, 2320/ mm3; platelet count, 80,600/mm3; creatinine, 0.8 mg/dL; erythrocyte sedimentation rate (ESR), 34 mm/h; C-reactive protein (CRP), 3.2 mg/dL; C3, 52 mg/dL; C4, 4 mg/dL; positive antidsDNA, 1:320; and 24-h proteinuria, 2440 mg. By abdominal ultrasonography, there was splenomegaly (15.2 cm) and gall bladder stones without cholecystitis signs. She had negative serologic tests for HIV and viral hepatitis and a positive recombinant K39 antigen (rK39) strip test. A bone marrow examination was performed, which revealed amastigotes inside phagocytic
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cells. Liposomal amphotericin B (5 mg/kg) was administered with prompt improvement in the febrile condition; the patient was discharged after the treatment and remained asymptomatic after a 1-year follow-up examination.
Systematic review of the literature Methods We performed a systematic search in several scientific databases (MEDLINE, LILACS, SciELO, and Scopus) using the following keywords: visceral leishmaniasis, kala-azar, calazar, black fever, dumdum fever, systemic lupus erythematosus, SLE, lupus, and LES. We used MeSH, the U.S. National Library of Medicine’s controlled vocabulary, which is used for indexing articles for MEDLINE. There was no restriction regarding the time of publication or language. Two authors independently screened all citations and abstracts to identify eligible studies. In addition, secondary references were obtained from the selected articles. We included original studies assessing cases of VL-infected patients presenting clinical and laboratory manifestations that are capable of leading to inappropriate suspicions of SLE or mimicking an SLE flare.
Results From the primary search, we identified a total of 201 citations by title and/or abstract. Of them, 41 were considered eligible for our study; they were evaluated in their entirety. Furthermore, 12 secondary references were obtained. From these 53 articles, only 17 met our previously established criteria. The types of studies selected were 14 case reports and three case series. Overall, 10 studies described cases of VL mimicking an SLE flare, and seven articles described cases of VL leading to misdiagnosis of SLE.
VL infection in SLE patients mimicking an SLE flare In the literature, we reviewed a total of 10 cases with VL mimicking an SLE flare (three male and seven female patients; mean age of 36.5 years, and median age of 32.5 years) (Table 1). All reported cases were on prior medical accompaniment due to the diagnosis of SLE (Table 2). All the patients presented with intermittent fever. Only three patients had no splenomegaly or hepatosplenomegaly during the course of the disease. Renal disorders were present in four of 10 patients (impaired renal function in three cases and nephrotic proteinuria associated with impaired renal function in one case). Nine out of 10 cases had pancytopenia. An increased serum level of acute phase reactants was observed in all reported cases (including high levels of CRP in most cases). The serum levels of complement proteins C3 and/or C4 were normal in five of seven reported cases. An increased serum level of gamma globulins was present in seven of eight tested patients. The diagnosis of VL was confirmed by the identification of Leishmania amastigotes in a bone marrow smear and/or biopsy in nine cases and in a splenic aspiration in one case. A positive serologic test for Leishmania antibodies was present in all the six tested cases. Four studies did not mention this test. Treatment was performed using liposomal amphotericin B or pentavalent antimony in all cases. Two deaths were reported despite the introduction of specific treatment.
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VL infection leading to inappropriate suspicions of SLE In the literature, we reviewed a total of 18 cases with VL mimicking SLE (six male and 12 female patients; mean age of 48.2 years, and median age of 50 years) (Table 3). Intermittent fever was present in most of the described cases. Only two cases showed no splenomegaly or hepatosplenomegaly. Renal abnormalities were reported in only two patients (nephritic proteinuria in one case and another with impaired renal function associated with nephritic proteinuria). Arthralgia was the most common joint manifestation, and only one patient presented with arthritis. Of 18 cases, 15 presented with cytopenia. Overall, 13 cases had an increased serum level of acute phase reactants (including high levels of CRP in most cases). The results of these tests were not mentioned for five patients. A decreased serum level of C3 and/or C4 was reported in only three out of 15 patients. The results of these tests were not mentioned for three patients. Of 17 patients, 14 presented an increased serum level of gamma globulin. The presence of autoantibodies was reported in the following frequency: ANA in 17 cases (94%); rheumatoid factor (RF) in 10 cases (55%); direct Coombs’ test in nine cases (50%); ASMA in six cases (33%); anti-dsDNA in three cases (16%); lupus anticoagulant in two cases (11%); and anti-cyclic citrullinated peptide antibody, anti-Sm, IgM anti-cardiolipin antibody, atypical anti-neutrophil cytoplasmic antibody (a-ANCA), cytoplasmic ANCA (c-ANCA), AMA, and anti-thyroid antibodies in one case each (5%). The diagnosis was confirmed by a positive bone marrow smear and/or biopsy in 17 cases and positive serologic tests for Leishmania antibodies in nine patients. This test was not mentioned for nine patients. Treatment was performed using liposomal amphotericin B or pentavalent antimony in all 18 patients; no deaths were reported.
Discussion Infections and complications of renal disease represent important cause of death in SLE patients; they require prompt diagnosis and treatment. However, in a patient with SLE, it is sometimes difficult to distinguish an infection from an SLE flare based on clinical and laboratory findings. Early recognition of Leishmania infections in patients with SLE is extremely important as misdiagnosis and inadequate treatment (such as increasing the immunosuppression) may lead to a disastrous consequence; VL may be transformed into a rapidly progressive disease. This systematic review identified 17 studies reporting cases on the relationship between VL and SLE. Our findings suggest that clinical and laboratory features of VL may clearly mimic SLE. Clinical and laboratory features such as intermittent fever, pancytopenia, hypergammaglobulinemia, and the presence of several autoantibodies are common in both the conditions [18,23–25]; therefore, the distinction is sometimes difficult. VL manifestations are a consequence of the host immunologic response against the parasite. Splenomegaly (eventually accompanied by hepatomegaly and lymphadenopathy) is secondary to hyperplasia of the infected reticuloendothelial system. Pancytopenia can be explained by hypersplenism, hemophagocytosis, chronic inflammation, and dietary factors [26]. The production of autoantibodies and hypergammaglobulinemia is related to a polyclonal B cell activation and to molecular mimicry between Leishmania antigens and ribonucleoproteins [18,23]. Notably, from our review, hepatosplenomegaly or isolated splenomegaly was identified in the majority of the reported cases in which VL mimicking SLE occurred. As this finding is observed only in the minority of SLE patients, it may be a red flag for the
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Table 1 Characteristics of SLE patients with concomitant VL mimicking an SLE flare Age/gender
Fever
HS
Renal
Joint
P
CRP/ESR
C3/C4
γ
AntiLeishmania antibodies
Diagnosis
Treatment
Outcome
Moore and Brown [6]
United Kingdom
55/Female
Yes
No
Yes
No
No
97/NR
NR
NR
NR
LAB 200 mg/day for 60 days followed by miltefosine
Cured
Celant et al. [7]
Italy
53/Male
Yes
S
No
No
Yes
9.4/NR
Normal
30.4
Positive
Ossandon et al. [8]
Italy
33/Male
Yes
HS
Yes
No
Yes
12/84
31/8
31
Positive
Biopsy (anatomic site not accurately informed) Splenic aspiration Serology BM smear Culture Serology BM smear
Ravelli et al. [9]
Italy
16/Female
Yes
No
Yes
No
Yes
85/99
148/27
0.8
Positive
Serology BM smear
32/Female
Yes
HS
No
No
Yes
11.9/NR
122/11.2
44.2
NR
Sternal smear
38/Female
Yes
S
No
Arthralgia
Yes
118/NR
NR/4–7
24
Positive
34/Female
Yes
HS
No
No
Yes
Weakly positive/140
Normal
27
Positive
Serology BM smear Serology BM smear
Perez Spain Silvestre et al. [10] Granel et al. France [11] Wallis and China Clark [12] Braun et al. [13]
Germany
58/Female
Yes
No
No
No
Yes
18/40
80/12
NR
Positive
Serology BM biopsy
FernándezGuerrero et al. [14] López-Soto and Lopez [15]
Spain
25/Female
Yes
HS
Yes
No
Yes
NR/NR
NR
6.46
NR
BM smear Autopsy
Spain
23/Male
Yes
S
No
No
Yes
NR/90
NR
40
NR
BM smear
LAB 3 mg/kg/day for 10 Cured days LAB 3 mg/kg/day for 5 days þ single additional dose on day 10 LAB 3 mg/kg/day for 5 days þ single additional dose on day 10 LAB 200 mg/kg/day for 5 days Antimony (interrupted) LAB þ Allopurinol Sodium stibogluconate 600 mg/day for 25 days Meglumine antimonite 60 mg/kg/day in three daily doses Stibogluconate þ meglumine antimonite Meglumine antimonite 20 mg/kg/day for 20 days
Cured
Cured
Cured
Cured Cured
Died (pneumococcal septic shock) Died (disseminated VL) Cured
Abbreviations: CRP: C-reactive protein (mg/L); ESR: erythrocyte sedimentation rate (mm/h); P: pancytopenia; γ: gamma globulins (g/L); HS: hepatosplenomegaly; H: hepatomegaly; S: splenomegaly; BM: bone marrow; LAB: liposomal amphotericin B; NR: not reported.
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Origin
Study
Table 2 Clinical and laboratory criteria for previous diagnosis of SLE Age at SLE diagnosis
Skin
Joint
Hemolytic anemia
Leukopenia
Thrombocytopenia
Renal
Serositis
Neurologic
APS
Immunologic
Hypocomplementemia
Others
Moore and Brown [6] Celant et al. [7]
35
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
43
Malar rash Vasculitis
Arthralgia
No
Yes
No
No
No
No
Anti-RNP Anti-Ro
Yes
Fever Lymphadenopathy
Ossandon et al. [8]
25
Malar rash
Arthralgia
No
Yes
No
Lupus nephritis class IV Lupus nephritis class IV
Yes
No
No
Yes
Fever
Lupus nephritis class IV NR
No
No
No
ANA Anti-dsDNA Anti-Ro Anti-La ANA Anti-dsDNA
Yes
Alopecia
NR
NR
Yes
NR
NR
Lupus nephritis class IV
No
No
Yes
NR at the time of SLE diagnosis ANA
NR
Anti-dsDNA Anti-platelet ANA
Skin biopsy compatible with SLE Mixed cryoglobulinemia NR
Mild splenomegaly
Ravelli et al. [9]
13
Malar rash
Arthritis
No
No
No
Perez Silvestre et al. [10]
26
NR
NR
NR
NR
NR
Granel et al. [11]
37
Livedo reticularis
Arthralgia
No
No
No
Wallis and Clark [12] Braun et al. [13]
32
Rash on face and trunk Malar rash
No
No
Yes
Yes
Nephritis
Yes
No
No
48
No
Arthralgia
No
No
No
No
No
No
No
ANA Anti-dsDNA
NR
FernándezGuerrero et al. [14] López-Soto and Lopez [15]
NR
No
Yes (not specified)
No
No
No
Yes (not No specified)
Yes
No
NR
NR
23
Photosensitivity
No
No
No
No
No
No
No
ANA Anti-dsDNA
Yes
Yes
Yes
Fever Pulmonary fibrosis Myalgia Cardiac involvement (not specified)
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Study
NR
Abbreviations: APS: antiphospholipid syndrome; ANA: antinuclear antibody; anti-dsDNA: anti-double stranded DNA antibody; SLE: systemic lupus erythematosus; NR: not reported.
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Table 3 Characteristics of VL-infected patients leading to inappropriate suspicions of SLE Origin
Age/gender
Fever
HS
Renal
Joint
P
CRP/ESR
C3/C4
γ
Immunologic
AntiLeishmania antibodies
Diagnosis
Treatment
Outcome
Tunccan et al. [16]
Turkey
26/Female
Yes
HS
No
Arthritis
Yes
19.9/65
Normal
Elevated
ANA ASMA
Yes
BM smear BM biopsy Liver biopsy Serology Liver biopsy Histology of spleen Culture PCR BM smear (5) Serology (1)
LAB 4 mg/kg/day for 5 days þ single dose on day 10 þ weekly dose for 4 weeks
Cured
LAB 4 mg/kg/day for 5 days þ single dose on day 10 þ weekly dose for 4 weeks
Cured
LAB (6)
Cured (6)
AMA
Arlet et al. [17]
France
55/Female
Yes
HS
Yes
Arthralgia
Yes
54/NR
Normal
Normal
RF ANA
Yes
Anti-dsDNA
Anti-CCP Sakkas et al. [18]
Greece
28/Female
NR
S (6)
NR
NR
Yes (6)
Elevated CRP (6)
Normal or NR
Elevated (6)
17/Female 56/Male 54/Male 71/Male 79/Female Voulgari et al. [19]
Greece
50/Male
Yes
S
No
Arthralgia
Yes
56/50
NR
Elevated
Castellino et al. [20]
Italy
36/Female
Yes
S
No
Arthralgia
Yes
2.9/93
NR
NR
Voulgarelis et al. [21]
Greece
37/Female
Yes (2)
S (2)
Yes (1)
Arthralgia (2)
Yes (3)
80/50
74/23
Elevated (3)
75/70 NR/93
Normal 136/9
NR
Low (2)
62/Female 50/Male Liberopoulos et al. [22]
Greece
43/Female 72/Female 24/Male 80/Female 29/Female
Yes (5)
S (4)
No
Arthralgia (1)
Yes (2)
Elevated (3)
ANA (5) dCoombs (5) ASMA (4) RF (4) Anti-dsDNA (1) Anti-CL IgM (1) Anti-ANCA (1) ANA Anti-Sm LA VDRL dCoombs RF ANA Anti-dsDNA LA dCoombs ANA (3)
dCoombs (1) RF (1) VDRL (1) ANA (5) RF (3) CG (2) dCoombs (1) iCoombs (1) c-ANCA (1) ASMA (1) Anti-thyroid (1)
NR
Yes
BM biopsy Serology
Sodium antimony gluconate for 4 weeks
Cured
NR
BM smear
LAB
Cured
NR
BM smear
LAB 4 mg/kg/day for 5 days þ single dose on day 10 (2); Antimony for 4 weeks (1)
Cured (3)
Yes (5)
BM smear (5)
NR
Cured (5)
Abbreviations: CRP: C-reactive protein (mg/L); ESR: erythrocyte sedimentation rate (mm/h); P: pancytopenia; γ: gamma globulins (g/L); HS: hepatosplenomegaly; H: hepatomegaly; S: splenomegaly; BM: bone marrow; PCR: polymerase chain reaction; LAB: liposomal amphotericin B; ANA: antinuclear antibody; anti-dsDNA: anti-double stranded DNA antibody; a-CL: anti-cardiolipin antibody; dCoombs: direct Coombs’ test; iCoombs: indirect Coombs’ test; a-ANCA: atypical anti-neutrophil cytoplasmic antibodies; c-ANCA: cytoplasmic anti-neutrophil cytoplasmic antibodies; ASMA: anti-smooth muscle antibody; anti-Sm: anti-Sm antibody; LA: lupus anticoagulant test; VDRL: venereal disease research laboratory test; RF: rheumatoid factor; AMA: anti-mitochondrial antibodies; CG: Cryoglobulins; anti-CCP: anti-cyclic citrullinated peptide antibody; NR: not reported. The numbers in brackets indicate the numbers of reported cases in each series.
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Study
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diagnosis of concomitant or isolated VL in endemic areas for this infection. Oppositely, arthritis was described only in one patient infected with VL; therefore, when present, it may suggest an inflammatory cause. Also, the lack of response to steroids, the normal levels of C3 and C4, and abnormal liver function tests suggest a possible infectious origin. Renal abnormalities were described only in two patients infected with VL. There are evidences suggesting that renal involvement may be seen in patients infected with VL, presenting a wide spectrum of renal disorders [27–29]. The autoantibodies that are more prevalent in patients infected with VL, without the diagnostic criteria for SLE, were ANA (94%), RF (55%), and positive direct Coombs’ test (50%). These results also reinforce the need for caution when analyzing immunological tests out of an appropriate clinical context, even for tests generally considered highly specific, such as the anti-dsDNA (16%). A Brazilian study evaluating 45 patients with VL showed the following prevalence of autoantibodies: 24.4%, RF; 17.8%, IgG anti-cardiolipin; 6.7%, IgM anti-cardiolipin; 4.5%, anti-dsDNA; 4.4%, ANA; and 1.1%, anti-La [24]. The same study found positive serum levels of anti-Leishmania antibodies in 100% of the patients. A Greek study evaluating 16 patients infected with VL observed the following prevalence of autoantibodies: 88%, ANA; 63%, RF; 25%, ASMA; 25%, perinuclear ANCA; 25%, anti-extractable nuclear antigens antibody; 13%, IgG anti-cardiolipin; 13%, direct Coombs’ test; 13%, anti-Ro; 6%, indirect Coombs’ test; 6%, anti-thyroid peroxidase antibody; 6%, anti-myeloperoxidase; and 6%, anti-Sm. They also reported the presence of cryoglobulins in 50% of patients and a decreased serum level of C3 (13%) and C4 (50%). No laboratory autoimmune manifestations were detectable in all the patients who were reevaluated 3 months after specific treatments [25]. In a previous study evaluating 30 patients with a VL infection, we observed a significant prevalence of the following autoantibodies by ELISA: 53%, anti-beta 2 glycoprotein I; 6%, IgG anti-cardiolipin; and 3%, IgM anti-cardiolipin [30]. The prevalence of autoantibodies showed large variations among the studies, which should be investigated in further research addressing genetic and population characteristics and differences between the leishmaniasis strains. From our review, it was noted that the diagnosis of VL can be often difficult, requiring multiple diagnostic approaches that can delay the introduction of specific treatment. It was also found that patients with SLE may have negative serology for Leishmania antigens, but a positive test, even in a low titer, should be valued. The diagnosis of VL is based on a combination of demographic, clinical, and laboratory findings and confirmatory parasitological tests. Parasitological tests remain the gold standard for the diagnosis of VL because of their high specificity [31] despite their relatively low sensitivity. Molecular methods, such as PCR targeting the DNA of kinetoplast or ribosomal RNA genes, can considerably increase the sensitivity of the technique for microbiologic diagnosis [32]. Microscopy and culture techniques should also be performed because they could increase specificity and allow drug resistance evaluation. However, in endemic areas, the identification of protozoa in microbiologic analysis does not necessarily indicate active disease, as Leishmania may persist in tissues in asymptomatic patients or in most immunosuppressed patients following successful treatments. Presently, many serologic methods for the detection of antibodies against Leishmania are available and are useful for epidemiologic studies and for VL diagnosis in immunocompetent individuals from non-endemic areas [33]. In contrast, serologic investigations can be negative in patients with asymptomatic VL infection [34] at the early stages of the disease or in immunosuppressed patients [35,36] and fail to indicate active disease or progression of asymptomatic patients in endemic areas [37,38]. Notably, in immunosuppressed patients, even low titers of
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these antibodies may have diagnostic value when combined with appropriated clinical manifestations. The results of this study also highlight a high fatality rate in cases of VL infection in SLE patients (23% of deaths, despite specific treatment), in accordance with what is observed in the literature for other types of immunosuppression. The treatment of leishmaniasis classically involves the use of pentavalent antimony or amphotericin B. In HIV-infected patients, the treatment can present therapeutic failure rates as high as 50%; the mortality in East Africa is as high as 15–33% [39,40]. These co-infected patients present a high rate of disease relapse (approaching 90%) in those who are not receiving highly active antiretroviral therapy (HAART) [41]. Also, HAART is apparently only partially protective [42]. Similarly, other immunocompromising conditions may present high rates of therapeutic failure [14]. For this group of patients, new therapeutic regimens should be evaluated, these include miltefosine, paramomycin, and the combination of drugs, as well as the use of preventive treatment and secondary prophylaxis [43].
Conclusion In endemic areas for VL, the diagnosis or exacerbation of SLE may be problematic. However, there are some characteristics that could help to distinguish each other: 1. Massive splenomegaly is not a common sign in SLE. 2. Arthritis is not a common clinical feature of VL. 3. High values of CRP are not common in SLE patients unless in the presence of infections. 4. Complement serum levels may be decreased during an SLE flare, but they usually are normal in VL. 5. SLE patients with VL may present negative anti-Leishmania antibodies, but a positive test (at even low titers) should be valued.
Acknowledgments M.S. is currently receiving a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). References [1] Guzman J, Cardiel MH, Arce-Salinas A, Sanchez-Guerrero J, Alarcon-Segovia D. Measurement of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices. J Rheumatol 1992;19:1551–8. [2] Hellmann DB, Petri M, Whiting-O’Keefe Q. Fatal infections in systemic lupus erythematosus: the role of opportunistic organisms. Medicine (Baltimore) 1987;66:341–8. [3] Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, et al. Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2002;2: 494–501. [4] Barreto ML, Teixeira MG, Bastos FI, Ximenes RA, Barata RB, Rodrigues LC. Successes and failures in the control of infectious diseases in Brazil: social and environmental context, policies, interventions, and research needs. Lancet 2011;377:1877–89. [5] Martins-Melo FR, Lima Mda S, Ramos ANAN Jr., Alencar CH, Heukelbach J. Mortality and case fatality due to visceral leishmaniasis in Brazil: a nationwide analysis of epidemiology, trends and spatial patterns. PLoS One 2014;9: e93770. [6] Moore J, Brown K. Sun, sangria and sandflies: leishmaniasis in an immunosuppressed patient returning from Spain. Travel Med Infect Dis 2013;11:119–22. [7] Celant A, Chichino G, Dal Bello B, Massarotti M, Minoli L, Marasini B. Visceral leishmaniasis, systemic lupus erythematosus and acute hepatitis. Rheumatol Int 2008;29:111–2. [8] Ossandon A, Bompane D, Alessandri C, Marocchi E, Conti F, Valesini G. Leishmania in SLE mimicking an exacerbation. Clin Exp Rheumatol 2006;24:186–90.
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[27] Salgado Filho N, Ferreira TM, Costa JM. Involvement of the renal function in patients with visceral leishmaniasis (kala-azar). Rev Soc Bras Med Trop 2003;36:217–21. [28] Lima Verde FA, Lima Verde IA, Silva Junior GB, Daher EF, Lima Verde EM. Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil. J Nephrol 2007;20:430–6. [29] Silva Junior GB, Barros EJ, Daher Ede F. Kidney involvement in leishmaniasis—a review. Braz J Infect Dis 2014;18:434–40. [30] Santiago M, Martinelli R, Ko A, Reis EA, Fontes RD, Nascimento EG, et al. Antibeta2 glycoprotein I and anticardiolipin antibodies in leptospirosis, syphilis and Kala-azar. Clin Exp Rheumatol 2001;19:425–30. [31] Herwaldt BL. Leishmaniasis. Lancet 1999;354:1191–9. [32] Antinori S, Calattini S, Longhi E, Bestetti G, Piolini R, Magni C, et al. Clinical use of polymerase chain reaction performed on peripheral blood and bone marrow samples for the diagnosis and monitoring of visceral leishmaniasis in HIV-infected and HIV-uninfected patients: a single-center, 8-year experience in Italy and review of the literature. Clin Infect Dis 2007;44:1602–10. [33] Srivastava P, Dayama A, Mehrotra S, Sundar S. Diagnosis of visceral leishmaniasis. Trans R Soc Trop Med Hyg 2011;105:1–6. [34] Silva LA, Romero HD, Nogueira Nascentes GA, Costa RT, Rodrigues V, Prata A. Antileishmania immunological tests for asymptomatic subjects living in a visceral leishmaniasis-endemic area in Brazil. Am J Trop Med Hyg 2011;84: 261–6. [35] Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and nonHIV-infected patients. A comparative study. Medicine (Baltimore) 2001; 80:54–73. [36] Cota GF, de Sousa MR, Demarqui FN, Rabello A. The diagnostic accuracy of serologic and molecular methods for detecting visceral leishmaniasis in HIV infected patients: meta-analysis. PLoS Negl Trop Dis 2012;6:e1665. [37] Buchetont B, El-Safi SH, Hammad A, Kheir MM, Eudes N, Mirgani A, et al. Antileishmanial antibodies in an outbreak of visceral leishmaniasis in eastern Sudan: high antibody responses occur in resistant subjects and are not predictive of disease. Trans R Soc Trop Med Hyg 2003;97:463–8. [38] Lockwood DN, Sundar S. Serological tests for visceral leishmaniasis. Br Med J 2006;333:711–2. [39] Alvar J, Aparicio P, Aseffa A, Den Boer M, Canavate C, Dedet JP, et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 2008;21:334–59 [table of contents]. [40] Hurissa Z, Gebre-Silassie S, Hailu W, Tefera T, Lalloo DG, Cuevas LE, et al. Clinical characteristics and treatment outcome of patients with visceral leishmaniasis and HIV co-infection in northwest Ethiopia. Trop Med Int Health 2010;15:848–55. [41] Antinori S, Schifanella L, Corbellino M. Leishmaniasis: new insights from an old and neglected disease. Eur J Clin Microbiol Infect Dis 2012;31:109–18. [42] ter Horst R, Collin SM, Ritmeijer K, Bogale A, Davidson RN. Concordant HIV infection and visceral leishmaniasis in Ethiopia: the influence of antiretroviral treatment and other factors on outcome. Clin Infect Dis 2008;46:1702–9. [43] van Griensven J, Diro E, Lopez-Velez R, Ritmeijer K, Boelaert M, Zijlstra EE, et al. A screen-and-treat strategy targeting visceral leishmaniasis in HIVinfected individuals in endemic East African Countries: the way forward? PLoS Negl Trop Dis 2014;8:e3011.
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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Visceral leishmaniasis mimicking systemic lupus erythematosus: Case series and a systematic literature review Iuri Usêda Santana, MDa, Blenda Dias, MDb, Eduardo Araújo Santana Nunes, MDb, Francisco Airton Castro da Rocha, MD, PhDc, Francisco Saraiva Silva Jr, MDc, Mittermayer Barreto Santiago, MD, PhDb,n a b c
Serviço de Clínica Médica do Hospital Geral Roberto Santos, Salvador, Brazil Serviços Especializados em Reumatologia (SER) da Bahia, Rua Conde Filho, 117, Graça, Salvador, Bahia CEP 40150-150, Brazil Serviço de Reumatologia do Hospital Universitário Walter Cantídio, Ceará, Brazil
a r t i c l e in fo
Keywords: Systemic lupus erythematosus Visceral leishmaniasis Autoantibodies Case series
a b s t r a c t Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease that may present manifestations that resemble other diseases. Visceral leishmaniasis (VL) is a parasitic infection whose hallmarks may mimic SLE symptoms. Here, we report a case series and evaluate the published, scientific evidence of the relationship between SLE and VL infection. Methods: To assess original studies reporting cases of VL-infected patients presenting manifestations that are capable of leading to inappropriate suspicions of SLE or mimicking an SLE flare, we performed an extensive search in several scientific databases (MEDLINE, LILACS, SciELO, and Scopus). Two authors independently screened all citations and abstracts identified by the search strategy to identify eligible studies. Secondary references were additionally obtained from the selected articles. Results: The literature search identified 53 eligible studies, but only 17 articles met our criteria. Among these, 10 lupus patients with VL mimicking an SLE flare and 18 cases of VL leading to unappropriated suspicions of SLE were described. The most common manifestations in patients infected with VL were intermittent fever, pancytopenia, visceromegaly, and increased serum level of acute phase reactants. The most frequent autoantibodies were antinuclear antibodies, rheumatoid factor, and direct Coombs’ test. Conclusion: In endemic areas for VL, the diagnosis of SLE or its exacerbation may be a clinical dilemma. Hepatosplenomegaly or isolated splenomegaly was identified in the majority of the reported cases where VL occurred, leading to unappropriated suspicions of SLE or mimicking an SLE flare. Furthermore, the lack of response to steroids, the normal levels of complement proteins C3 and C4, and the increased level of transaminases suggest a possible infectious origin. & 2015 Elsevier Inc. All rights reserved.
Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease classically characterized by chronic, multisystemic inflammation of unknown etiology. Many patients alternate between periods of exacerbation (flare) and reduced disease activity [1]. It is characterized by polyclonal activation of B lymphocytes with production of multiple autoantibodies. Physiologically, polyclonal B cell activation occurs in chronic infectious diseases, such as VL. Additionally, patients with SLE (particularly those treated with immunosuppressive drugs) are at an increased risk for infections that can complicate, exacerbate, or mimic their symptoms [2].
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Corresponding author. E-mail address: [email protected] (M.B. Santiago).
http://dx.doi.org/10.1016/j.semarthrit.2014.12.004 0049-0172/& 2015 Elsevier Inc. All rights reserved.
Visceral leishmaniasis (VL) is an acute or chronic systemic protozoan infection transmitted to humans by sandflies of the Phlebotomus species. Dogs are the main host reservoir. VL is a major public health problem in tropical and subtropical countries. Specifically, it is endemic in 64 countries, and 90% of the world’s cases are reported in India, Bangladesh, Nepal, Sudan, and Brazil [3]. In Brazil, VL was originally restricted to rural areas, mainly in the Northeast region of the country, but since the 1980s, the geographical distribution of this disease has expanded with increasing urbanization, reaching virtually all regions, with an average annual incidence rate of two cases per 100,000 inhabitants [4,5]. The disease has a wide clinical spectrum: from asymptomatic infection to an acute or chronic life-threatening condition with fever, hepatosplenomegaly, and pancytopenia. Therefore, the objective of this study is to describe three cases of VL mimicking the symptoms of SLE and systematically
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review the literature on the relationship between these two conditions.
Case series Case 1 A 25-year-old woman was admitted to our hospital with a 2-year history of additive and symmetric polyarthritis (mostly in hand and knee joints) with partial improvement with the use of nonsteroidal anti-inflammatory drugs. She reported worsening of joint manifestations associated with daily fever since the time she became pregnant. Hepatosplenomegaly, jaundice, nonerosive arthritis, and positive antinuclear antibody (ANA) 1:80 speckled pattern were reported by another hospital to which she was admitted; at that time, the diagnosis of SLE with hepatic involvement was suggested. Pulse therapy with methylprednisolone (1 g) for 3 days was administered with considerable clinical improvement, and the patient was discharged with prednisone (80 mg/ day). Four days after her discharge, she relapsed with fever, polyarthritis, and abdominal pain. She was referred to our hospital and delivered a stillborn fetus at 26 weeks of pregnancy. On examination, she was febrile (39.01C) with pale mucous membranes, hepatosplenomegaly, and limitation of motion due to diffuse articular pain. The rest of her physical examination was unremarkable. Laboratory tests revealed mild anemia and negative hepatitis B surface antigen, anti-hepatitis C virus antibody, antiHIV antibody, IgM anti-cytomegalovirus antibody, ANA, antidouble stranded DNA (anti-dsDNA) antibody, anti-Ro antibody, anti-La antibody, anti-Sm antibody, anti-liver kidney microsomes antibody type 1, anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA), and IgM and IgG anti-cardiolipin antibodies. Cefepime was initiated despite the negative results of blood and urine culture, and prednisone was reduced to 20 mg/ day. However, as there was no clinical improvement, her bone marrow was examined; there were amastigote forms inside the phagocytic cells. Amphotericin B deoxycholate was administered for 32 days with considerable clinical and laboratory improvement; she was discharged after treatment and remained asymptomatic on follow-up examination therefore. SLE diagnosis was not confirmed. Case 2 A 27-year-old woman was admitted to our hospital reporting a history of intermittent fever for approximately 12 months without proper investigation. At 30 days before admission, she reported persistent fever associated with profuse dry coughing, low back pain, abdominal pain, asthenia, and arthralgia. She had been under treatment for SLE (prednisone 10 mg/day), which had been diagnosed approximately 6 years prior; at that time, she had presented with cutaneous involvement (malar rash and photosensitive rash in the chest), renal involvement (nephritic proteinuria, hematuria, and cellular casts), hematological involvement (anemia, leukopenia, and lymphopenia), articular involvement (arthritis and Jaccoud’s arthropathy), hypocomplementemia, positive ANA (1:320), positive anti-Ro, and positive anti-dsDNA. Her previous history also included infectious endocarditis in the mitral valve (diagnosed 5 years prior) with proper treatment and osteomyelitis in the right lower limb (diagnosed 4 years prior) treated with antibiotics and surgery. On examination, she presented with fever (38.51C), blood pressure of 100 70 mmHg, tachycardia, pale mucous membranes, cushingoid appearance, butterfly-shaped malar rash, and painless mouth ulcers without palpable lymph nodes. There was a systolic murmur in the mitral and the tricuspid areas; abdominal
examination revealed diffuse abdominal distension and splenomegaly. The rest of the physical examination was unremarkable. On admission, her laboratory results were as follows: hemoglobin, 11.0 g/dL; white blood cell count, 3570/mm3; platelet count, 80,000/mm3; ionized calcium, 1.09 mmol/L; creatinine, 0.4 mg/ dL; aspartate transaminase, 348 mg/dL; alanine transaminase, 99 mg/dL; alkaline phosphatase, 468 mg/dL; and γ-glutamyltransferase, 777 mg/dL. Bone marrow aspiration was normal. By transthoracic echocardiogram, there was moderate mitral regurgitation, mild tricuspid regurgitation, and preserved systolic and diastolic function. Crystalline penicillin, oxacillin, and amikacin were initiated despite the negative results of blood and urine culture and the absence of valve vegetation. The patient developed respiratory discomfort and worsening cough; by chest radiography and tomography, there was left lung consolidation and bilateral exudative pleural effusion, which was drained. Later, she presented worsening thrombocytopenia with moderate epistaxis and hematemesis, which was treated with a platelet transfusion and proton-pump inhibitor. As the patient’s clinical condition was not improving, despite the use of broader-spectrum antimicrobial agents (at that time, meropenem, teicoplanin, fluconazole, and polymyxin B), pulse therapy with methylprednisolone (1 g) was administered for 3 days with partial improvement. However, as there was no full clinical improvement, a new bone marrow study with biopsy was performed; however, the patient’s clinical condition rapidly deteriorated with refractory disseminated intravascular coagulation and septic shock. Unfortunately, despite intensive care treatment, she died. Postmortem examination of the bone marrow biopsy demonstrated amastigote forms of Leishmania donovani. Case 3 An 18-year-old woman was admitted to our hospital with a 5-month history of fever, almost daily and mainly in the mornings without chills or drenching sweats. She had been under treatment for SLE, which had been diagnosed approximately 1 year prior; at that time, she had presented with cutaneous involvement (malar rash and photosensitive rash in the chest and the arms), renal involvement (nephrotic syndrome), positive ANA (1:1280), low-grade fever, and axillar and cervical lymphadenopathy. With this initial diagnosis, she started prednisone and mycophenolate mofetil (2 g/day). Because she became pregnant, mycophenolate was interrupted and prednisone was maintained, and she was referred to an obstetrician. The patient evolved with miscarriage 30 days later, and uterine curettage was performed. Thereafter, she developed a febrile condition (without other signs or symptoms) and was treated with ciprofloxacin plus metronidazole for 14 days without improvement. She had no other relevant past medical history and no alcohol intake, smoking, or drug abuse. On examination, she presented with fever (39.51C), blood pressure of 120 80 mmHg (using captopril 50 mg/day), tachycardia, pale mucous membranes, cushingoid appearance, mild butterfly-shaped malar rash, and mild bilateral leg edema. The rest of the physical examination was unremarkable. On admission, her laboratory results were as follows: hemoglobin, 8.2 g/dL; white blood cell count, 2320/ mm3; platelet count, 80,600/mm3; creatinine, 0.8 mg/dL; erythrocyte sedimentation rate (ESR), 34 mm/h; C-reactive protein (CRP), 3.2 mg/dL; C3, 52 mg/dL; C4, 4 mg/dL; positive antidsDNA, 1:320; and 24-h proteinuria, 2440 mg. By abdominal ultrasonography, there was splenomegaly (15.2 cm) and gall bladder stones without cholecystitis signs. She had negative serologic tests for HIV and viral hepatitis and a positive recombinant K39 antigen (rK39) strip test. A bone marrow examination was performed, which revealed amastigotes inside phagocytic
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cells. Liposomal amphotericin B (5 mg/kg) was administered with prompt improvement in the febrile condition; the patient was discharged after the treatment and remained asymptomatic after a 1-year follow-up examination.
Systematic review of the literature Methods We performed a systematic search in several scientific databases (MEDLINE, LILACS, SciELO, and Scopus) using the following keywords: visceral leishmaniasis, kala-azar, calazar, black fever, dumdum fever, systemic lupus erythematosus, SLE, lupus, and LES. We used MeSH, the U.S. National Library of Medicine’s controlled vocabulary, which is used for indexing articles for MEDLINE. There was no restriction regarding the time of publication or language. Two authors independently screened all citations and abstracts to identify eligible studies. In addition, secondary references were obtained from the selected articles. We included original studies assessing cases of VL-infected patients presenting clinical and laboratory manifestations that are capable of leading to inappropriate suspicions of SLE or mimicking an SLE flare.
Results From the primary search, we identified a total of 201 citations by title and/or abstract. Of them, 41 were considered eligible for our study; they were evaluated in their entirety. Furthermore, 12 secondary references were obtained. From these 53 articles, only 17 met our previously established criteria. The types of studies selected were 14 case reports and three case series. Overall, 10 studies described cases of VL mimicking an SLE flare, and seven articles described cases of VL leading to misdiagnosis of SLE.
VL infection in SLE patients mimicking an SLE flare In the literature, we reviewed a total of 10 cases with VL mimicking an SLE flare (three male and seven female patients; mean age of 36.5 years, and median age of 32.5 years) (Table 1). All reported cases were on prior medical accompaniment due to the diagnosis of SLE (Table 2). All the patients presented with intermittent fever. Only three patients had no splenomegaly or hepatosplenomegaly during the course of the disease. Renal disorders were present in four of 10 patients (impaired renal function in three cases and nephrotic proteinuria associated with impaired renal function in one case). Nine out of 10 cases had pancytopenia. An increased serum level of acute phase reactants was observed in all reported cases (including high levels of CRP in most cases). The serum levels of complement proteins C3 and/or C4 were normal in five of seven reported cases. An increased serum level of gamma globulins was present in seven of eight tested patients. The diagnosis of VL was confirmed by the identification of Leishmania amastigotes in a bone marrow smear and/or biopsy in nine cases and in a splenic aspiration in one case. A positive serologic test for Leishmania antibodies was present in all the six tested cases. Four studies did not mention this test. Treatment was performed using liposomal amphotericin B or pentavalent antimony in all cases. Two deaths were reported despite the introduction of specific treatment.
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VL infection leading to inappropriate suspicions of SLE In the literature, we reviewed a total of 18 cases with VL mimicking SLE (six male and 12 female patients; mean age of 48.2 years, and median age of 50 years) (Table 3). Intermittent fever was present in most of the described cases. Only two cases showed no splenomegaly or hepatosplenomegaly. Renal abnormalities were reported in only two patients (nephritic proteinuria in one case and another with impaired renal function associated with nephritic proteinuria). Arthralgia was the most common joint manifestation, and only one patient presented with arthritis. Of 18 cases, 15 presented with cytopenia. Overall, 13 cases had an increased serum level of acute phase reactants (including high levels of CRP in most cases). The results of these tests were not mentioned for five patients. A decreased serum level of C3 and/or C4 was reported in only three out of 15 patients. The results of these tests were not mentioned for three patients. Of 17 patients, 14 presented an increased serum level of gamma globulin. The presence of autoantibodies was reported in the following frequency: ANA in 17 cases (94%); rheumatoid factor (RF) in 10 cases (55%); direct Coombs’ test in nine cases (50%); ASMA in six cases (33%); anti-dsDNA in three cases (16%); lupus anticoagulant in two cases (11%); and anti-cyclic citrullinated peptide antibody, anti-Sm, IgM anti-cardiolipin antibody, atypical anti-neutrophil cytoplasmic antibody (a-ANCA), cytoplasmic ANCA (c-ANCA), AMA, and anti-thyroid antibodies in one case each (5%). The diagnosis was confirmed by a positive bone marrow smear and/or biopsy in 17 cases and positive serologic tests for Leishmania antibodies in nine patients. This test was not mentioned for nine patients. Treatment was performed using liposomal amphotericin B or pentavalent antimony in all 18 patients; no deaths were reported.
Discussion Infections and complications of renal disease represent important cause of death in SLE patients; they require prompt diagnosis and treatment. However, in a patient with SLE, it is sometimes difficult to distinguish an infection from an SLE flare based on clinical and laboratory findings. Early recognition of Leishmania infections in patients with SLE is extremely important as misdiagnosis and inadequate treatment (such as increasing the immunosuppression) may lead to a disastrous consequence; VL may be transformed into a rapidly progressive disease. This systematic review identified 17 studies reporting cases on the relationship between VL and SLE. Our findings suggest that clinical and laboratory features of VL may clearly mimic SLE. Clinical and laboratory features such as intermittent fever, pancytopenia, hypergammaglobulinemia, and the presence of several autoantibodies are common in both the conditions [18,23–25]; therefore, the distinction is sometimes difficult. VL manifestations are a consequence of the host immunologic response against the parasite. Splenomegaly (eventually accompanied by hepatomegaly and lymphadenopathy) is secondary to hyperplasia of the infected reticuloendothelial system. Pancytopenia can be explained by hypersplenism, hemophagocytosis, chronic inflammation, and dietary factors [26]. The production of autoantibodies and hypergammaglobulinemia is related to a polyclonal B cell activation and to molecular mimicry between Leishmania antigens and ribonucleoproteins [18,23]. Notably, from our review, hepatosplenomegaly or isolated splenomegaly was identified in the majority of the reported cases in which VL mimicking SLE occurred. As this finding is observed only in the minority of SLE patients, it may be a red flag for the
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Table 1 Characteristics of SLE patients with concomitant VL mimicking an SLE flare Age/gender
Fever
HS
Renal
Joint
P
CRP/ESR
C3/C4
γ
AntiLeishmania antibodies
Diagnosis
Treatment
Outcome
Moore and Brown [6]
United Kingdom
55/Female
Yes
No
Yes
No
No
97/NR
NR
NR
NR
LAB 200 mg/day for 60 days followed by miltefosine
Cured
Celant et al. [7]
Italy
53/Male
Yes
S
No
No
Yes
9.4/NR
Normal
30.4
Positive
Ossandon et al. [8]
Italy
33/Male
Yes
HS
Yes
No
Yes
12/84
31/8
31
Positive
Biopsy (anatomic site not accurately informed) Splenic aspiration Serology BM smear Culture Serology BM smear
Ravelli et al. [9]
Italy
16/Female
Yes
No
Yes
No
Yes
85/99
148/27
0.8
Positive
Serology BM smear
32/Female
Yes
HS
No
No
Yes
11.9/NR
122/11.2
44.2
NR
Sternal smear
38/Female
Yes
S
No
Arthralgia
Yes
118/NR
NR/4–7
24
Positive
34/Female
Yes
HS
No
No
Yes
Weakly positive/140
Normal
27
Positive
Serology BM smear Serology BM smear
Perez Spain Silvestre et al. [10] Granel et al. France [11] Wallis and China Clark [12] Braun et al. [13]
Germany
58/Female
Yes
No
No
No
Yes
18/40
80/12
NR
Positive
Serology BM biopsy
FernándezGuerrero et al. [14] López-Soto and Lopez [15]
Spain
25/Female
Yes
HS
Yes
No
Yes
NR/NR
NR
6.46
NR
BM smear Autopsy
Spain
23/Male
Yes
S
No
No
Yes
NR/90
NR
40
NR
BM smear
LAB 3 mg/kg/day for 10 Cured days LAB 3 mg/kg/day for 5 days þ single additional dose on day 10 LAB 3 mg/kg/day for 5 days þ single additional dose on day 10 LAB 200 mg/kg/day for 5 days Antimony (interrupted) LAB þ Allopurinol Sodium stibogluconate 600 mg/day for 25 days Meglumine antimonite 60 mg/kg/day in three daily doses Stibogluconate þ meglumine antimonite Meglumine antimonite 20 mg/kg/day for 20 days
Cured
Cured
Cured
Cured Cured
Died (pneumococcal septic shock) Died (disseminated VL) Cured
Abbreviations: CRP: C-reactive protein (mg/L); ESR: erythrocyte sedimentation rate (mm/h); P: pancytopenia; γ: gamma globulins (g/L); HS: hepatosplenomegaly; H: hepatomegaly; S: splenomegaly; BM: bone marrow; LAB: liposomal amphotericin B; NR: not reported.
I.U. Santana et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
Origin
Study
Table 2 Clinical and laboratory criteria for previous diagnosis of SLE Age at SLE diagnosis
Skin
Joint
Hemolytic anemia
Leukopenia
Thrombocytopenia
Renal
Serositis
Neurologic
APS
Immunologic
Hypocomplementemia
Others
Moore and Brown [6] Celant et al. [7]
35
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
43
Malar rash Vasculitis
Arthralgia
No
Yes
No
No
No
No
Anti-RNP Anti-Ro
Yes
Fever Lymphadenopathy
Ossandon et al. [8]
25
Malar rash
Arthralgia
No
Yes
No
Lupus nephritis class IV Lupus nephritis class IV
Yes
No
No
Yes
Fever
Lupus nephritis class IV NR
No
No
No
ANA Anti-dsDNA Anti-Ro Anti-La ANA Anti-dsDNA
Yes
Alopecia
NR
NR
Yes
NR
NR
Lupus nephritis class IV
No
No
Yes
NR at the time of SLE diagnosis ANA
NR
Anti-dsDNA Anti-platelet ANA
Skin biopsy compatible with SLE Mixed cryoglobulinemia NR
Mild splenomegaly
Ravelli et al. [9]
13
Malar rash
Arthritis
No
No
No
Perez Silvestre et al. [10]
26
NR
NR
NR
NR
NR
Granel et al. [11]
37
Livedo reticularis
Arthralgia
No
No
No
Wallis and Clark [12] Braun et al. [13]
32
Rash on face and trunk Malar rash
No
No
Yes
Yes
Nephritis
Yes
No
No
48
No
Arthralgia
No
No
No
No
No
No
No
ANA Anti-dsDNA
NR
FernándezGuerrero et al. [14] López-Soto and Lopez [15]
NR
No
Yes (not specified)
No
No
No
Yes (not No specified)
Yes
No
NR
NR
23
Photosensitivity
No
No
No
No
No
No
No
ANA Anti-dsDNA
Yes
Yes
Yes
Fever Pulmonary fibrosis Myalgia Cardiac involvement (not specified)
I.U. Santana et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
Study
NR
Abbreviations: APS: antiphospholipid syndrome; ANA: antinuclear antibody; anti-dsDNA: anti-double stranded DNA antibody; SLE: systemic lupus erythematosus; NR: not reported.
5
6
Table 3 Characteristics of VL-infected patients leading to inappropriate suspicions of SLE Origin
Age/gender
Fever
HS
Renal
Joint
P
CRP/ESR
C3/C4
γ
Immunologic
AntiLeishmania antibodies
Diagnosis
Treatment
Outcome
Tunccan et al. [16]
Turkey
26/Female
Yes
HS
No
Arthritis
Yes
19.9/65
Normal
Elevated
ANA ASMA
Yes
BM smear BM biopsy Liver biopsy Serology Liver biopsy Histology of spleen Culture PCR BM smear (5) Serology (1)
LAB 4 mg/kg/day for 5 days þ single dose on day 10 þ weekly dose for 4 weeks
Cured
LAB 4 mg/kg/day for 5 days þ single dose on day 10 þ weekly dose for 4 weeks
Cured
LAB (6)
Cured (6)
AMA
Arlet et al. [17]
France
55/Female
Yes
HS
Yes
Arthralgia
Yes
54/NR
Normal
Normal
RF ANA
Yes
Anti-dsDNA
Anti-CCP Sakkas et al. [18]
Greece
28/Female
NR
S (6)
NR
NR
Yes (6)
Elevated CRP (6)
Normal or NR
Elevated (6)
17/Female 56/Male 54/Male 71/Male 79/Female Voulgari et al. [19]
Greece
50/Male
Yes
S
No
Arthralgia
Yes
56/50
NR
Elevated
Castellino et al. [20]
Italy
36/Female
Yes
S
No
Arthralgia
Yes
2.9/93
NR
NR
Voulgarelis et al. [21]
Greece
37/Female
Yes (2)
S (2)
Yes (1)
Arthralgia (2)
Yes (3)
80/50
74/23
Elevated (3)
75/70 NR/93
Normal 136/9
NR
Low (2)
62/Female 50/Male Liberopoulos et al. [22]
Greece
43/Female 72/Female 24/Male 80/Female 29/Female
Yes (5)
S (4)
No
Arthralgia (1)
Yes (2)
Elevated (3)
ANA (5) dCoombs (5) ASMA (4) RF (4) Anti-dsDNA (1) Anti-CL IgM (1) Anti-ANCA (1) ANA Anti-Sm LA VDRL dCoombs RF ANA Anti-dsDNA LA dCoombs ANA (3)
dCoombs (1) RF (1) VDRL (1) ANA (5) RF (3) CG (2) dCoombs (1) iCoombs (1) c-ANCA (1) ASMA (1) Anti-thyroid (1)
NR
Yes
BM biopsy Serology
Sodium antimony gluconate for 4 weeks
Cured
NR
BM smear
LAB
Cured
NR
BM smear
LAB 4 mg/kg/day for 5 days þ single dose on day 10 (2); Antimony for 4 weeks (1)
Cured (3)
Yes (5)
BM smear (5)
NR
Cured (5)
Abbreviations: CRP: C-reactive protein (mg/L); ESR: erythrocyte sedimentation rate (mm/h); P: pancytopenia; γ: gamma globulins (g/L); HS: hepatosplenomegaly; H: hepatomegaly; S: splenomegaly; BM: bone marrow; PCR: polymerase chain reaction; LAB: liposomal amphotericin B; ANA: antinuclear antibody; anti-dsDNA: anti-double stranded DNA antibody; a-CL: anti-cardiolipin antibody; dCoombs: direct Coombs’ test; iCoombs: indirect Coombs’ test; a-ANCA: atypical anti-neutrophil cytoplasmic antibodies; c-ANCA: cytoplasmic anti-neutrophil cytoplasmic antibodies; ASMA: anti-smooth muscle antibody; anti-Sm: anti-Sm antibody; LA: lupus anticoagulant test; VDRL: venereal disease research laboratory test; RF: rheumatoid factor; AMA: anti-mitochondrial antibodies; CG: Cryoglobulins; anti-CCP: anti-cyclic citrullinated peptide antibody; NR: not reported. The numbers in brackets indicate the numbers of reported cases in each series.
I.U. Santana et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
Study
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diagnosis of concomitant or isolated VL in endemic areas for this infection. Oppositely, arthritis was described only in one patient infected with VL; therefore, when present, it may suggest an inflammatory cause. Also, the lack of response to steroids, the normal levels of C3 and C4, and abnormal liver function tests suggest a possible infectious origin. Renal abnormalities were described only in two patients infected with VL. There are evidences suggesting that renal involvement may be seen in patients infected with VL, presenting a wide spectrum of renal disorders [27–29]. The autoantibodies that are more prevalent in patients infected with VL, without the diagnostic criteria for SLE, were ANA (94%), RF (55%), and positive direct Coombs’ test (50%). These results also reinforce the need for caution when analyzing immunological tests out of an appropriate clinical context, even for tests generally considered highly specific, such as the anti-dsDNA (16%). A Brazilian study evaluating 45 patients with VL showed the following prevalence of autoantibodies: 24.4%, RF; 17.8%, IgG anti-cardiolipin; 6.7%, IgM anti-cardiolipin; 4.5%, anti-dsDNA; 4.4%, ANA; and 1.1%, anti-La [24]. The same study found positive serum levels of anti-Leishmania antibodies in 100% of the patients. A Greek study evaluating 16 patients infected with VL observed the following prevalence of autoantibodies: 88%, ANA; 63%, RF; 25%, ASMA; 25%, perinuclear ANCA; 25%, anti-extractable nuclear antigens antibody; 13%, IgG anti-cardiolipin; 13%, direct Coombs’ test; 13%, anti-Ro; 6%, indirect Coombs’ test; 6%, anti-thyroid peroxidase antibody; 6%, anti-myeloperoxidase; and 6%, anti-Sm. They also reported the presence of cryoglobulins in 50% of patients and a decreased serum level of C3 (13%) and C4 (50%). No laboratory autoimmune manifestations were detectable in all the patients who were reevaluated 3 months after specific treatments [25]. In a previous study evaluating 30 patients with a VL infection, we observed a significant prevalence of the following autoantibodies by ELISA: 53%, anti-beta 2 glycoprotein I; 6%, IgG anti-cardiolipin; and 3%, IgM anti-cardiolipin [30]. The prevalence of autoantibodies showed large variations among the studies, which should be investigated in further research addressing genetic and population characteristics and differences between the leishmaniasis strains. From our review, it was noted that the diagnosis of VL can be often difficult, requiring multiple diagnostic approaches that can delay the introduction of specific treatment. It was also found that patients with SLE may have negative serology for Leishmania antigens, but a positive test, even in a low titer, should be valued. The diagnosis of VL is based on a combination of demographic, clinical, and laboratory findings and confirmatory parasitological tests. Parasitological tests remain the gold standard for the diagnosis of VL because of their high specificity [31] despite their relatively low sensitivity. Molecular methods, such as PCR targeting the DNA of kinetoplast or ribosomal RNA genes, can considerably increase the sensitivity of the technique for microbiologic diagnosis [32]. Microscopy and culture techniques should also be performed because they could increase specificity and allow drug resistance evaluation. However, in endemic areas, the identification of protozoa in microbiologic analysis does not necessarily indicate active disease, as Leishmania may persist in tissues in asymptomatic patients or in most immunosuppressed patients following successful treatments. Presently, many serologic methods for the detection of antibodies against Leishmania are available and are useful for epidemiologic studies and for VL diagnosis in immunocompetent individuals from non-endemic areas [33]. In contrast, serologic investigations can be negative in patients with asymptomatic VL infection [34] at the early stages of the disease or in immunosuppressed patients [35,36] and fail to indicate active disease or progression of asymptomatic patients in endemic areas [37,38]. Notably, in immunosuppressed patients, even low titers of
7
these antibodies may have diagnostic value when combined with appropriated clinical manifestations. The results of this study also highlight a high fatality rate in cases of VL infection in SLE patients (23% of deaths, despite specific treatment), in accordance with what is observed in the literature for other types of immunosuppression. The treatment of leishmaniasis classically involves the use of pentavalent antimony or amphotericin B. In HIV-infected patients, the treatment can present therapeutic failure rates as high as 50%; the mortality in East Africa is as high as 15–33% [39,40]. These co-infected patients present a high rate of disease relapse (approaching 90%) in those who are not receiving highly active antiretroviral therapy (HAART) [41]. Also, HAART is apparently only partially protective [42]. Similarly, other immunocompromising conditions may present high rates of therapeutic failure [14]. For this group of patients, new therapeutic regimens should be evaluated, these include miltefosine, paramomycin, and the combination of drugs, as well as the use of preventive treatment and secondary prophylaxis [43].
Conclusion In endemic areas for VL, the diagnosis or exacerbation of SLE may be problematic. However, there are some characteristics that could help to distinguish each other: 1. Massive splenomegaly is not a common sign in SLE. 2. Arthritis is not a common clinical feature of VL. 3. High values of CRP are not common in SLE patients unless in the presence of infections. 4. Complement serum levels may be decreased during an SLE flare, but they usually are normal in VL. 5. SLE patients with VL may present negative anti-Leishmania antibodies, but a positive test (at even low titers) should be valued.
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