Abstracts
Objective
To report a case of coexisting systemic lupus erythematosus (SLE) and sickle cell disease (SCD) with a review of the literature on the topic.
Methodology
Case report and literature review of the association between SLE and SCD through scientific articles in health sciences databases, such as LILACS, MEDLINE/Pubmed and Scielo, until May 2012. Descriptors used: 1. Sickle cell anemia; 2. Sickle cell disease; 3. Systemic lupus erythematosus; 4. Hemoglobinopathies.
Results
The authors describe an association between SLE and SS hemoglobinopathy in an eight-year-old female patient presentingarticular, hematologic and neuropsychiatric manifestations during clinical evolution. Forty-five cases of association between SLE and SCD are described in literature, mostly adults (62.2%), women (78%) and with the SS phenotype in 78% of the cases, and diverse clinical manifestations. Compared with our patient, articular, hematologic and neuropsychiatric manifestations were present in 76%, 36% and 27% of the cases, respectively.
Conclusion
SLE and SCD are chronic diseases that have several clinical and laboratory findings in common, meaning difficult diagnosis and difficulty in finding the correct treatment. Although the association between these diseases is not common, it is described in literature, so it is imperative that physicians who treat such diseases be alert to this possibility.
Sickle cell anemia; Sickle cell disease; Systemic lupus erythematosus; Hemoglobinopathies
Objetivo
Relatar um caso de coexistência de lúpus eritematoso sistêmico (LES) e doença falciforme (DF) com revisão da literatura sobre o tema.
Metodologia
Relato de caso e pesquisa da associação entre LES e DF na literatura, através de artigos científicos nas bases de dados de ciências da saúde, como LILACS, MEDLINE/Pubmed e Scielo, até maio de 2012. Descritores utilizados: 1. anemia falciforme; 2. doença falciforme; 3. lúpus eritematoso sistêmico; 4. hemoglobinopatias.
Resultados
Os autores descrevem a associação de LES e hemoglobinopatia SS em paciente do sexo feminino, oito anos, apresentando manifestações articulares, hematológicas e neuropsiquiátricas durante a sua evolução clínica. Na literatura são descritos 45 casos de associação entre LES e DF, sendo a maioria em mulheres (78%) adultas (62,2%), apresentando fenótipo SS em 78% dos casos e com manifestações clínicas variadas. Comparando com a nossa paciente, manifestações articulares, hematológicas e neuropsiquiátricas, estiveram presentes em 76%, 36% e 27% dos casos, respectivamente.
Conclusões
LES e DF são doenças crônicas que apresentam diversos achados clínicos e laboratoriais em comum, implicando em dificuldades diagnósticas e na correta condução terapêutica dessas doenças. A associação entre essas enfermidades não é comum, mas está descrita na literatura, por isso é importante que médicos que cuidam dessas enfermidades estejam atentos para tal possibilidade.
Anemia falciforme; Doença falciforme; Lúpus eritematoso sistêmico; Hemoglobinopatias
Introduction
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with an incidence of 1.9 to 5.6 per 100,000 inhabitants,11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr Clin N Am. 2005;52:443-67. while sickle cell disease (SCD) is one of the most common hereditary diseases, affecting mainly black individuals.22 Loureiro MM, Rozenfeld S, Portugal RD. Acute clinical events in patients with sickle cell disease: epidemiology and treatment. Rev Bras Hematol. Hemoter. 2008;30:95-100. SCD is characterized by a mutation in the hemoglobin beta chain with formation of abnormal hemoglobin (HbS), responsible for microcirculation obstruction, ischemia, tissue necrosis and systemic organ dysfunction.22 Loureiro MM, Rozenfeld S, Portugal RD. Acute clinical events in patients with sickle cell disease: epidemiology and treatment. Rev Bras Hematol. Hemoter. 2008;30:95-100.
The coexistence of SCD and SLE is rarely described in literature, even in predominantly black populations, in which the prevalence of both conditions is higher.33 Luban NL, Boeckx RL, Barr O. Sickle cell anemia and SLE. J Pediatr. 1980;96:1120. Wilson et al. were the first to report this association.44 Wilson FM, Clifford GO, Wolf PL. Lupus erythematosus associated with sickle cell anemia. Arthritis Rheum. 1964;7:443-9. Perhaps the defective activation of the alternative complement pathway in sickle cell patients and the increased risk of infections caused by encapsulated bacteria predispose this group to develop an autoimmune disease.55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus erythematosus in patients with sickle cell disease. Clin Rheumatol. 2008;27:359-64.
The clinical features of SCD and SLE may show similar manifestations, such as the presence of fever, anemia, articular, renal, neurological and cardiopulmonary involvements and, consequently, diagnostic difficulties. Sickle cell patients showing atypical symptoms or refractory response to conventional treatment should be investigated for the possibility of coexistence of diseases.66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus and sickle hemoglinopathies: a report of two cases and review of the literature. Am J Hematol. 1987;25:211-4.
In view of the uncommon occurrence of this association, the authors describe an early childhood case and review the previously reported cases until May 2012.
Methodology
Case report and literature review of the association between SLE and SCD through scientific articles in health sciences databases, such as LILACS, MEDLINE/Pubmed and Scielo until May 2012. Descriptors used: 1. Sickle cell anemia; 2. Sickle cell disease; 3. Systemic lupus erythematosus; 4. Hemoglobinopathies.
Case report
Female patient diagnosed with SS hemoglobinopathy since birth, showing recurring, mild painful vaso-occlusive crises responsive to traditional hydration and analgesia. She has never received blood transfusions. At the age of nine, pain symptoms intensified, mainly characterized by repeated crises of acute and asymmetric polyarthritis of the knees, wrists, elbows and ankles, initially attributed to SCD. The clinical picture evolved with the development of photosensitivity, asthenia and intermittent fever, with an episode of generalized tonic-clonic seizure associated with transient left hemiparesis. Laboratory tests: hemoglobin, 7.9 g/dL; hematocrit, 25%; WBC, 12.000/mm3; platelet count, 374.000 mm3 (160-400.000); hemoglobin electrophoresis HbS 98.7% and HbA2 1.26%; positive antinuclear antibody (ANA) 1:320 (homogeneous pattern); positive anti-dsDNA antibody; erythrocyte sedimentation rate, 68 mm (<20); C-reactive protein, 71 units (< 6); rheumatoid factor, anti-Sm, anti-SSA, anti-SSB, were all negative as were viral serology. Serum C3, C4 and CH50 levels were normal as were renal and liverfunctions. Cranial magnetic resonance imaging revealed an area of hypoperfusion in the right temporal lobe. The study of the cerebrospinal fluid was normal. The patient had a sibling with sickle cell anemia who died at the age of two from acute myocardial infarction, and has two maternal aunts diagnosed with cutaneous lupus. She was diagnosed with SLE according to American College of Rheumatology (ACR) criteria,77 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. and the possibility of involvement of the central nervous system (CNS) by both diseases (SLE and SCD) was discussed. The patient received prednisone 2 mg/kg/day, hydroxychloroquine 5 mg/kg/day and blood transfusions in order to reduce HbS < 30%. Due to the possibility that the neurological manifestation was secondary to SCD we chose not to associate another immunosuppressive agent. There was significant reduction in joint pain, no progression of the neurological condition and improvement of hematological indices (HbS 60%; Hb 8.5 g/dL). Patient remains asymptomatic, taking hydroxychloroquine and prednisone 5 mg/day.
Discussion
Epidemiology of SLE and SCD
The coexistence of SCD and SLE is rarely described in the literature, probably due to the small number of cases. Because of the overlapping of symptoms of both diseases, particularly those related to the CNS, establishing a differential diagnosis between the diseases is unquestionably difficult. Until April 2012, 45 patients with SCD and SLE had been reported in the MEDLINE database (Table 1). Thirty-five (78%) of these patients were female, while 10 (22%) were male. The majority of patients are adults (62.2%), with a mean age of 23 years-old at diagnosis (variation: 4 to 63). This resembles the age group of SLE patients proposed by Manzi, in which the disease developed during the ages of 15 to 45.88 Manzi S. Lupus update: perspective and clinical pearls. Cleve Clin J Med. 2009;76:137-42. SLE developed in patients aged ≤16 in only 37.7% of the cases described. Among patients with SCD and SLE, 33 (78%) had the SS phenotype. Due to the coexistence of severe complications, life expectancy of these individuals can potentially be reduced when compared to that of individuals who are diagnosed with one of the diseases.99 Kaloterakis A, Filiotou A, Haziyannis S. Sickle cell/β°-thalassemia and systemic lupus erythematosus. Lupus. 1999;8:778-81. Treatment has also become a great challenge, since there are no controlled and randomized trials (that address the impact of SCD) of immunosuppressive drugs often used in SLE.
Probable etiology for coexistence of SCD and SLE
The infectious complications of SCD patients have a multifactorial etiology:
splenic atrophy, reduced phagocytic capacity, defective opsonization,
reduced production of antibodies and alternative complement pathway
components. Some authors have proposed that the deficiency of factors of the
alternative pathway complement and recurring infections caused by
encapsulated bacteria could be the link between the immune complex disease
and hemoglobin S.1010 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.
11 Wilson WA, Decelauer K, Morgan AG. Sickle cell anemia, complement,
and systemic lupus erythematosus. Arthritis Rheum. 1979;22:803.-1212 Warrier RP, Sahney S, Walker H. Hemoglobin sickle cell disease and
systemic lupus erythematosus. J Natl Med Assoc. 1984;76:1030-1. However, there had been no reduction
of alternative complement pathway components in this report or in others
described in the literature.66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,1313 Karthikeyan G, Wallace SL, Blum L. SLE and sickle cell disease.
Arthritis Rheum. 1978;21:862-3.
Articular manifestations
Articular disease were present in 35 patients (76%) with SLE and SCD,
corresponding to the most common manifestation.55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin Rheumatol.
2008;27:359-64.,66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,99 Kaloterakis A, Filiotou A, Haziyannis S. Sickle
cell/β°-thalassemia and systemic lupus erythematosus. Lupus.
1999;8:778-81.
10 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.-1111 Wilson WA, Decelauer K, Morgan AG. Sickle cell anemia, complement,
and systemic lupus erythematosus. Arthritis Rheum. 1979;22:803.,1313 Karthikeyan G, Wallace SL, Blum L. SLE and sickle cell disease.
Arthritis Rheum. 1978;21:862-3.
14 Kanodia KV, Vanikar AV, Goplani KR, Gupta SB, Trivedi HL. Sickle
cell nephropathy with diffuse proliferative lupus nephritis: a case report.
Diagn Pathol. 2008;3:9.
15 Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros F, et
al. Characteristics and outcome of connective tissue diseases in patients with
sickle-cell disease: Report of 30 Cases. Semin Arthritis Rheum.
2008;38:228-40.
16 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92.
17 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.
18 Shetty AK, Baliga MR, Gedalia A, Warrier RP. Systemic lupus
erythematosus and sickle cell disease. Indian J Pediatr.
1998;65:618-21.
19 Eissa MM, Lawrence JM 3rd, McKenzie L, Little FM, Mankad VN, Yang
YM. Systemic lupus erythematosus in a child with sickle cell disease. South Med
J. 1995;88:1176-8.
20 Shaw HE, Osher RH, Smith JL. Amaurosis fugax associated with SC
hemoglobinopathy and lupus erythematosus. Am J Ophthalmol.
1979;87:281-5.
21 Cherner M, Isenberg D. The overlap of systemic lupus erythematosus
and sickle cell disease: report of two cases and a review of the literature.
Lupus. 2010;19:875-83.-2222 Oqunbiyi AO, George AO, Brown O, Okafor BO. Diagnostic and treatment
difficulties in systemic lupus erythematosus coexisting with sickle cell
disease. West Afr J Med. 2007;26:152-5. The
difficulty in diagnosing the coexistence of these two diseases is due to the
fact both have articular manifestations. Hence, SCD patients’ joint
complaints are interpreted as vaso-occlusive crises, delaying the diagnosis
of SLE.66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,1717 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71. In this study, the patient presented
with a clinical picture of an asymmetric, additive, non-deforming
polyarthritis unresponsive to analgesia and with prolonged evolution. Such
characteristics diverge from standard SCD arthritis, which is usually
short-term, monoarticular, acute and recurrent.1616 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92. Thus, general practitioners, pediatricians,
hematologists and rheumatologists should be alert to the SCD patients with
unsatisfactory response to hydration, analgesia and articular involvement
pattern change in relation to the initial picture, and consider the
possibility of association with other diseases, including SLE.33 Luban NL, Boeckx RL, Barr O. Sickle cell anemia and SLE. J Pediatr.
1980;96:1120.,66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,1717 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.
Hematological manifestations
Hematological disorders are common in both SCD and SLE. Table 1 shows patients with anemia,
leukopenia or thrombocytopenia. In this review, 16 patients (36%) met at
least one of these criteria.33 Luban NL, Boeckx RL, Barr O. Sickle cell anemia and SLE. J Pediatr.
1980;96:1120.,55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin Rheumatol.
2008;27:359-64.,66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,99 Kaloterakis A, Filiotou A, Haziyannis S. Sickle
cell/β°-thalassemia and systemic lupus erythematosus. Lupus.
1999;8:778-81.,1010 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.,1212 Warrier RP, Sahney S, Walker H. Hemoglobin sickle cell disease and
systemic lupus erythematosus. J Natl Med Assoc. 1984;76:1030-1.,1515 Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros F, et
al. Characteristics and outcome of connective tissue diseases in patients with
sickle-cell disease: Report of 30 Cases. Semin Arthritis Rheum.
2008;38:228-40.,1717 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.
18 Shetty AK, Baliga MR, Gedalia A, Warrier RP. Systemic lupus
erythematosus and sickle cell disease. Indian J Pediatr.
1998;65:618-21.-1919 Eissa MM, Lawrence JM 3rd, McKenzie L, Little FM, Mankad VN, Yang
YM. Systemic lupus erythematosus in a child with sickle cell disease. South Med
J. 1995;88:1176-8.,2121 Cherner M, Isenberg D. The overlap of systemic lupus erythematosus
and sickle cell disease: report of two cases and a review of the literature.
Lupus. 2010;19:875-83.
22 Oqunbiyi AO, George AO, Brown O, Okafor BO. Diagnostic and treatment
difficulties in systemic lupus erythematosus coexisting with sickle cell
disease. West Afr J Med. 2007;26:152-5.
23 White LE, Reeves JD. Polyarthritis and positive LE preparation in
sickle hemoglobinopathies: a report of two cases. J Pediatr.
1979;95:1003-4.-2424 Nossent JC, Swaak AJC. Prevalence and significance of haematological
abnormalities in patients with systemic lupus erythematosus. QJ Med.
1991;80:605-12. However,
hematological laboratory evaluation is not very specific and, separately, it
does not contribute to the clinical suspicion of coexistence of both
diseases.
In most cases, SLE anemia is initially normocytic and normochromic and, if persistent, evolves into microcytosis and hypochromia.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr Clin N Am. 2005;52:443-67. Hemolytic anemia is only found in 13% of the cases.2525 Di Nuzzo DVP, Fonseca SF. Anemia falciforme e infeccões. J Pediatr (Rio J). 2004;80:347-54. On the other hand, the decreased hemoglobin in SCD is more important, reaching levels that range from 6 g to 9 g/dL,2525 Di Nuzzo DVP, Fonseca SF. Anemia falciforme e infeccões. J Pediatr (Rio J). 2004;80:347-54. particularly in cases of sickle cell anemia (HbSS). Therefore, patients suffering from both diseases may show more severe anemia due to the overlapping of pathophysiological disorders.
Leukopenia is identified in 20% to 40% of cases of isolate SLE,11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr Clin N Am. 2005;52:443-67. including granulocytopenia andlymphopenia. These findingsare caused by autoantibodies and by the systemic involvement of the disease. In SCD, predominantly leukocytosis and thrombocytosis are observed due to functional asplenia around the age of five.1616 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J Clin Rheumatol. 2005;11:86-92.
Neuropsychiatric manifestations
Cerebral infarction, intracranial hemorrhage, cognitive dysfunction and
seizures are neuropsychiatric disorders common to both SLE and SCD. The
prevalence of neurological disorders in SLE patients is estimated to be 50%,
with large variation among studies,2626 Bruns A, Meyer O. Neuropsychiatric manifestations of systemic lupus
erythematosus. Joint Bone Spine. 2006;73:639-45.
while in SCD it occurs in 25% of patients.2727 Adams RJ, Mckie VC, Hsu L, Files B, Vichinsky E, Pegelow C.
Prevention of a firs stroke by transfusions in children with sickle cell anemia
and abnormal results on transcranial doppler ultrasonography. N Engl J Med.
1998;339:5-11.,2828 Preul MC, Cendes F Just N, Mohr G. Intracranial aneurysms and sickle
cell anemia: multiplicity and propensity for the vertebrobasilar territory.
Neurosurgery. 1998;42:971-7. In SLE,
hemorrhage, thrombosis associated with antiphospholipid antibodies,
hypertension and thrombocytopenia relate to cerebrovascular accident,2929 Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The
prevalence of neuropsychiatric syndromes in systemic lupus erythematosus.
Neurology. 2001;57:496-500. while in SCD the formation of
aneurysms and the accumulation of drepanocytes in brain vessels promote
increased adhesion, intimal hyperplasia and limited endoluminal flow.3030 Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia.
Radiographics. 2001;21:971-94. In Table 1, one can see that 12 patients (27%) with SLE and SCD had
neuropsychiatric disorders, including seizures, psychosis, cognitive
disorders and cerebrovascular accident, and only two patients did not have
the SS phenotype.1010 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.
11 Wilson WA, Decelauer K, Morgan AG. Sickle cell anemia, complement,
and systemic lupus erythematosus. Arthritis Rheum. 1979;22:803.-1212 Warrier RP, Sahney S, Walker H. Hemoglobin sickle cell disease and
systemic lupus erythematosus. J Natl Med Assoc. 1984;76:1030-1.,1414 Kanodia KV, Vanikar AV, Goplani KR, Gupta SB, Trivedi HL. Sickle
cell nephropathy with diffuse proliferative lupus nephritis: a case report.
Diagn Pathol. 2008;3:9.,1616 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92.,1717 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.,2222 Oqunbiyi AO, George AO, Brown O, Okafor BO. Diagnostic and treatment
difficulties in systemic lupus erythematosus coexisting with sickle cell
disease. West Afr J Med. 2007;26:152-5.,2323 White LE, Reeves JD. Polyarthritis and positive LE preparation in
sickle hemoglobinopathies: a report of two cases. J Pediatr.
1979;95:1003-4.,3131 Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in
sickle cell disease. Kidney Int. 2000;57:1-8.
Presumably, individuals with both diseases, particularly of SS phenotype,
are more likely to develop cerebrovascular disease. However, identifying its
etiology is imperative for an effective treatment. Additional tests are
critical for this differentiation. Transcranial Doppler ultrasonography is a
valuable tool for assessing cerebral blood flow dynamic.3030 Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia.
Radiographics. 2001;21:971-94. The presence of antiphospholipid
antibodies associated with the increase of inflammatory markers may suggest
lupus etiology, requiring high doses of corticosteroids and additional
immunosuppressive agents.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr
Clin N Am. 2005;52:443-67.
Renal manifestations
Both SCD and SLE can cause progressive renal failure, particularly juvenile
SLE. Lupus nephritis is reported in 29% to 80% of juvenile cases, depending
on the specialty of the researchers, if rheumatologists or
nephrologists.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr
Clin N Am. 2005;52:443-67. The diagnosis of
SLE in sickle cell individuals could be neglected due to the overlapping of
signals that suggest renal disorder. Proteinuria, hematuria,
hyperfiltration, glomerulopathy, nephrotic syndrome and chronic renal
failure occur in both diseases. However, nephrotic syndrome is particularly
interesting since it occurs much more often in SLE than in SCD.44 Wilson FM, Clifford GO, Wolf PL. Lupus erythematosus associated with
sickle cell anemia. Arthritis Rheum. 1964;7:443-9. In Table 1, 21 patients (47%) developed renal disease attributed to
the development of the SLE.33 Luban NL, Boeckx RL, Barr O. Sickle cell anemia and SLE. J Pediatr.
1980;96:1120.,55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin Rheumatol.
2008;27:359-64.,66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,1010 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.,1111 Wilson WA, Decelauer K, Morgan AG. Sickle cell anemia, complement,
and systemic lupus erythematosus. Arthritis Rheum. 1979;22:803.,1313 Karthikeyan G, Wallace SL, Blum L. SLE and sickle cell disease.
Arthritis Rheum. 1978;21:862-3.
14 Kanodia KV, Vanikar AV, Goplani KR, Gupta SB, Trivedi HL. Sickle
cell nephropathy with diffuse proliferative lupus nephritis: a case report.
Diagn Pathol. 2008;3:9.
15 Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros F, et
al. Characteristics and outcome of connective tissue diseases in patients with
sickle-cell disease: Report of 30 Cases. Semin Arthritis Rheum.
2008;38:228-40.
16 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92.-1717 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.,1919 Eissa MM, Lawrence JM 3rd, McKenzie L, Little FM, Mankad VN, Yang
YM. Systemic lupus erythematosus in a child with sickle cell disease. South Med
J. 1995;88:1176-8.,2121 Cherner M, Isenberg D. The overlap of systemic lupus erythematosus
and sickle cell disease: report of two cases and a review of the literature.
Lupus. 2010;19:875-83.,2323 White LE, Reeves JD. Polyarthritis and positive LE preparation in
sickle hemoglobinopathies: a report of two cases. J Pediatr.
1979;95:1003-4. Sickle
cell nephropathy has a broad spectrum of pathological presentations.
Glomerular hyperfiltration, hemosiderin deposits, papillary necrosis,
cortical infarction, focal segmental glomerulosclerosis,
membranoproliferative glomerulonephritis with or without deposition of
immune complexes, tubular atrophy and interstitial fibrosis may occur.3030 Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia.
Radiographics. 2001;21:971-94. Due to the wide renal involvement
variety in SCD, renal biopsy becomes a useful diagnostic method for sickle
cell patients with suspected coexistence of SLE. Lupus renal involvement
targets glomeruli in most cases, with subendothelial immune deposits and
proliferation of mesangial cells.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr
Clin N Am. 2005;52:443-67.
The definition of the etiology of the renal involvement in patients with
both SCD and SLE has different implication with regard to morbidity,
mortality and treatment options.1616 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92.
Immunologic manifestations
Both SCD and SLE show important immunologic manifestations. Such involvement is mentioned in all case reports of coexistence of both diseases. The ANA may be present in the two diseases, being positive in almost 100% of SLE patients.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr Clin N Am. 2005;52:443-67. Approximately 20% of SCD patients have positive ANA with titers greater than 1:160;3232 Baethge BA, Bordelon TR, Mills GM, Bowen LM, Wolf RE, Bairnsfather L. Antinuclear antibodies in sickle cell disease. Acta Haematol. 1990;84:186-9. however, mechanisms related to the development of antibodies in such patients remain unknown.1616 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J Clin Rheumatol. 2005;11:86-92. Nonetheless, in the case of the association of both diseases, more specific autoantibodies, e.g. anti-dsDNA, anti-SM, anti-SSA and anti-SSB, should be ordered to support the diagnosis. Testing for antiphospholipid antibodies and lupus anticoagulant are also suggested, although these are also more commonly found in SLE than in SDC patients.2323 White LE, Reeves JD. Polyarthritis and positive LE preparation in sickle hemoglobinopathies: a report of two cases. J Pediatr. 1979;95:1003-4. Our patient presented with a positive ANA and anti-dsDNA. Anti-Sm, anti-SSA, anti-SSB were negative and C3, C4 and CH50 were within normal levels.
Serositis
Serositis is a clinical manifestation observed in both SCD (as a consequence
of vaso-occlusive crises) and SLE patients, present in 18 patients (42.8%)
of this review.33 Luban NL, Boeckx RL, Barr O. Sickle cell anemia and SLE. J Pediatr.
1980;96:1120.,55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin Rheumatol.
2008;27:359-64.,66 Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus erythematosus
and sickle hemoglinopathies: a report of two cases and review of the literature.
Am J Hematol. 1987;25:211-4.,99 Kaloterakis A, Filiotou A, Haziyannis S. Sickle
cell/β°-thalassemia and systemic lupus erythematosus. Lupus.
1999;8:778-81.
10 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.-1111 Wilson WA, Decelauer K, Morgan AG. Sickle cell anemia, complement,
and systemic lupus erythematosus. Arthritis Rheum. 1979;22:803.,1515 Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros F, et
al. Characteristics and outcome of connective tissue diseases in patients with
sickle-cell disease: Report of 30 Cases. Semin Arthritis Rheum.
2008;38:228-40.
16 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92.
17 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.
18 Shetty AK, Baliga MR, Gedalia A, Warrier RP. Systemic lupus
erythematosus and sickle cell disease. Indian J Pediatr.
1998;65:618-21.-1919 Eissa MM, Lawrence JM 3rd, McKenzie L, Little FM, Mankad VN, Yang
YM. Systemic lupus erythematosus in a child with sickle cell disease. South Med
J. 1995;88:1176-8.,2323 White LE, Reeves JD. Polyarthritis and positive LE preparation in
sickle hemoglobinopathies: a report of two cases. J Pediatr.
1979;95:1003-4. The
clinical similarities of these two diseases may delay the diagnosis of an
underlying connective tissue disorder; pericarditis in sickle cell patients
is a possible evidence of an active systemic autoimmune disease and/or an
infectious process.3333 Shetty AK, Kumar SR, Gedalia A, Warrier RP. Sickle cell anemia with
systemic lupus erythematosus: response to hydroxyurea therapy. J Pediatr Hematol
Oncol. 1998;20:335-7.
Skin manifestations
Cutaneous involvement is reported in 50% to 80% of SLE patients at diagnosis and in 85% of patients during the course of the disease.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr Clin N Am. 2005;52:443-67. Skin manifestations may include malar rash, photosensitivity, vascular skin lesions with nodules and ulceration, palmar/plantar erythema, Raynaud's phenomenon, annular erythema, alopecia and, less often, discoid lupus or lupus profundus.11 Benseler SM, Silverman ED. Systhemic lupus erythematosus. Pediatr Clin N Am. 2005;52:443-67. The characteristic cutaneous manifestation in SCD is the presence of lower-limb ulceration. The most common manifestation in patients with both SLE and SCD has not been reported yet.
The following cutaneous manifestations are described in Table 1: malar rash (26%), discoid
lesions (21%), photosensitivity (9.3%) and oral ulcers (6.9%).55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin Rheumatol.
2008;27:359-64.,99 Kaloterakis A, Filiotou A, Haziyannis S. Sickle
cell/β°-thalassemia and systemic lupus erythematosus. Lupus.
1999;8:778-81.,1010 Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G, Seijeant GR.
Systemic lupus erythematosus and sickle-cell anaemia. Br Med J.
1976;1:813.,1212 Warrier RP, Sahney S, Walker H. Hemoglobin sickle cell disease and
systemic lupus erythematosus. J Natl Med Assoc. 1984;76:1030-1.,1616 Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and therapeutic challenge. J
Clin Rheumatol. 2005;11:86-92.,1717 Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic lupus
erythematosus in children with sickle cell disease. J Pediatr Hematol Oncol.
2003;25:668-71.,1919 Eissa MM, Lawrence JM 3rd, McKenzie L, Little FM, Mankad VN, Yang
YM. Systemic lupus erythematosus in a child with sickle cell disease. South Med
J. 1995;88:1176-8.
20 Shaw HE, Osher RH, Smith JL. Amaurosis fugax associated with SC
hemoglobinopathy and lupus erythematosus. Am J Ophthalmol.
1979;87:281-5.
21 Cherner M, Isenberg D. The overlap of systemic lupus erythematosus
and sickle cell disease: report of two cases and a review of the literature.
Lupus. 2010;19:875-83.
22 Oqunbiyi AO, George AO, Brown O, Okafor BO. Diagnostic and treatment
difficulties in systemic lupus erythematosus coexisting with sickle cell
disease. West Afr J Med. 2007;26:152-5.-2323 White LE, Reeves JD. Polyarthritis and positive LE preparation in
sickle hemoglobinopathies: a report of two cases. J Pediatr.
1979;95:1003-4. These
features are uncommon in SCD patients and may facilitate the diagnosis of
association of the two diseases.55 Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin Rheumatol.
2008;27:359-64.
Conclusion
There is consensus among authors that physicians may face diagnostic difficulties when treating a SCD patient who develops SLE. These are different diseases, both with greater prevalence among blacks and sharing similar clinical manifestations during the course of the disease, delaying the diagnosis of a systemic autoimmune disease in these patients. Another confounding factor is that approximately 20% of SCD patients have a positive ANA at higher titers.3232 Baethge BA, Bordelon TR, Mills GM, Bowen LM, Wolf RE, Bairnsfather L. Antinuclear antibodies in sickle cell disease. Acta Haematol. 1990;84:186-9.
Due to microvascular occlusion and hemolytic anemia at variable levels, SCD patients will have clinical manifestations, such as severe localized or diffuse pain that may be associated with edema and erythema, as well as chest pain, pulmonary infiltrates, cardiomegaly, congestive heart failure, abdominal pain and other vaso-occlusive manifestations.22 Loureiro MM, Rozenfeld S, Portugal RD. Acute clinical events in patients with sickle cell disease: epidemiology and treatment. Rev Bras Hematol. Hemoter. 2008;30:95-100.
The limited number of cases published in the literature on the coexistence of SLE and SCD in the same individual does not allow stating if SCD patients are more likely to develop SLE.
According to the findings shown in this review, the presence of certain clinical features in SCD should alert pediatricians, hematologists and rheumatologists to the possibility of SLE diagnosis, particularly articular manifestations unresponsive to usual supportive measures, recurrent and refractory neuropsychiatric manifestations (especially if associated to the presence of antiphospholipid antibodies), presence of nephrotic proteinuria and, also, presence of leukopenia and/or thrombocytopenia. Renal biopsy and assessment of the specific antibodies for SLE could be very useful in these cases, just as positivity for other clinical manifestations, such as malar rash, photosensitivity, oral ulcers, alopecia and discoid lupus.
Prospective studies are required to clarify which mechanisms lead SCD individuals to develop SLE or if the coexistence of these two diseases is a mere coincidence.
Referências
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Publication Dates
-
Publication in this collection
Jan-Feb 2015
History
-
Received
08 May 2012 -
Accepted
14 May 2013