Systemic lupus erythematosus associated with sickle-cell disease: a case report and literature review

  • Mouna Maamar1Email author,

    Affiliated with

    • Zoubida Tazi-Mezalek1,

      Affiliated with

      • Hicham Harmouche1,

        Affiliated with

        • Wafaa Mounfaloti1,

          Affiliated with

          • Mohammed Adnaoui1 and

            Affiliated with

            • Mohammed Aouni1

              Affiliated with

              Journal of Medical Case Reports20126:366

              DOI: 10.1186/1752-1947-6-366

              Received: 3 August 2012

              Accepted: 28 September 2012

              Published: 26 October 2012

              Abstract

              Introduction

              The occurrence of systemic lupus erythematosus has been only rarely reported in patients with sickle-cell disease.

              Case presentation

              We describe the case of a 23-year-old North-African woman with sickle-cell disease and systemic lupus erythematosus, and discuss the pointers to the diagnosis of this combination of conditions and also present a review of literature. The diagnosis of systemic lupus erythematosus was delayed because our patient’s symptoms were initially attributed to sickle-cell disease.

              Conclusions

              Physicians should be alerted to the possible association of sickle-cell disease and systemic lupus erythematosus so as not to delay correct diagnosis and initiation of appropriate treatment.

              Keywords

              Sickle-cell disease systemic lupus erythematosus

              Introduction

              Sickle-cell disease (SCD) is a prevalent genetic disorder that includes sickle-cell anemia (the homozygous and most common form of SCD (SS)), sickle-cell hemoglobin C (SC) and sickle-cell β thalassemia (S/β thal) [1]. The protean clinical features of SCD result from chronic variable intravascular hemolysis and microvascular ischemia, leading to damage in multiple organs [2]. The occurrence of connective tissue diseases, in particular systemic lupus erythematosus (SLE), has only been rarely reported in patients with SCD [2]. The incidence of SLE in patients with SCD is not known because most of the published studies are case reports. Due to similar clinical manifestations, diagnosis of SLE in patients with SCD may be difficult and is often delayed. We report the case of a patient who developed symptoms initially attributed to SCD, but on further investigation underlying SLE was revealed.

              Case presentation

              A 23-year-old North-African woman with no family history of SCD was admitted to our department of internal medicine with symptoms of anemia, bone pain, arthralgia and fever. Her symptoms had been developing for six weeks with alteration of her general condition and abdominal pain. On physical examination our patient was pale, she had a temperature of 39.5°C, her blood pressure was 130/75mmHg and heart rate was 100 beats/minute. The patient had slight splenomegaly, pain on pressure in the long bones and arthritis in her knees.

              Blood test results showed normocytic anemia at 6.6g/dL with a high reticulocyte count (230,000 cells/mm3), hyperleukocytosis with granulocytosis (leukocyte count 16,500 cells/mm3, polymorphonuclear cells 9500 cells/mm3) and moderate thrombopenia (100,000 cells/mm3). Further investigations showed diminished haptoglobin (0.08mg/L), elevated lactate dehydrogenase (4670UI/L) indirect hyperbilirubinemia (21mg/L) with moderate cytolysis and cholestasis (aspartate aminotransferase 43U/L, alanine aminotransferase 65U/L, phenylalanine ammonia lyase 217U/L and γ-glutamyl transpeptidase 188U/L). Hemoglobin (Hb) electrophoresis test results showed Hb S at 50.3 percent, Hb C at 44 percent and Hb A1 at 0 percent, confirming a diagnosis of SCD (hemoglobin S/C).

              Our patient’s erythrocyte sediment rate was 110mm/first hour, her C-reactive protein level was 38mg/L (range <6mg/L), fibrinogen was 6.4g/L (24g/L) and serum protein electrophoresis showed a polyclonal IgG 24g/L (range 9 to 13g/L) with normal immunofixation. Results of a chest X-ray were normal. Abdominal ultrasonography, transthoracic and transesophageal echocardiography results were also normal. A thoraco-abdominal scan revealed numerous splenic infarctions. The results of a bone scan showed diffuse bone infarcts.

              Her symptoms were attributed to SCD and hence our patient received blood transfusions, antibiotics and analgesics, but with no improvement. Her fever and arthritis failed to respond to this treatment. Instead, the evolution of her condition was marked by the development of arthritis in her hands and relapse of anemia.

              Blood culture test results were negative, and the result of a tuberculin skin test was an 8mm induration. There was no BK virus found in repeated sputum and urine examinations, and procalcitonin test results were negative.

              Serology test results for human immunodeficiency virus, hepatitis B, hepatitis C, brucellosis and typhoid fever were all negative. Cytobacteriological urine analysis revealed no bacteria but microscopic hematuria (670 cells/mm3) and leukocyturia (50 cells/mm3). Proteinuria results were negative.

              The results of a Coombs test performed on admission were strongly positive for IgG. Immunological investigations revealed a positive anti-nuclear antibody (1/2600) result, and a positive anti-Sm result. Anti-DNA antibody tests were negative. A test for anti-extractable nuclear antigen antibodies (anti-ENA) was negative. C3 levels and C4 levels were normal (respectively, 0.95g/L and 0.3g/L). Tests for anti-phospholipid antibodies were negative. A diagnosis of SLE associated to SCD was established, with five of the diagnostic criteria of the American College of Rheumatology being met. Steroids were administered as a pulse of methylprednisolone 1g/day for three days followed by oral prednisone at 1mg/kg/day with hydroxychloroquine. Her symptoms quickly improved. At her 18-month follow up, she was in clinical remission on prednisone 5mg per day and hydroxychloroquine; she had not experienced a sickle-cell crisis and her lupus is still quiescent.

              Discussion

              In the present report we described the case of a Moroccan woman with SCD and coexistent SLE. The overlap of SLE and SCD is of interest, but the limited number of patients that have been reported previously implies that the association is uncommon [3]. Only 40 similar cases have been reported in the literature over the last 50 years [216] (Table 1). The African/Afro-Caribbean/African-American population is predisposed to contracting both SCD and SLE, explaining the fact that most patients with this association are African women (70 percent in Table 1 and 73 percent in the series by Michel et al.). All reported cases were relatively young at the time of lupus diagnosis (mean age 23 years, range eight to 57 years). All of them had SCD several years before SLE. Articular involvement is the most frequent lupus-related symptom, present in 84 percent of cases, followed by serositis (36 percent), and glomerulonephritis class III or IV (11 percent). Cutaneous manifestations are not frequently mentioned. Positive anti-nuclear antibody (ANA) results were found in 34 cases. Prognosis was favorable in 80 percent of cases (Table 1). Patients with SCD present with a defective activation of the alternate pathway of the complement system; this is the reason why these patients are at increased risk of capsulate bacteria infection, such as from pneumococci [15]. Some authors have suggested the hypothesis that this defect may lead to immune complex disorders secondary to failure to eliminate antigens, predisposing these patients to autoimmune diseases, but this has not been confirmed in other studies [3, 11, 13]. The clinical features of SLE and SCD have certain elements in common. Diverse manifestations such as polyarthritis, anemia, fever, visceral pain, renal, cardiovascular and pulmonary involvement are common in both conditions. Owing to the overlap of clinical features in the two diseases it may easy to confuse them, as occurred with our patient.
              Table 1

              Summary of previous case reports of SCD and SLE[216]

              Lead author/year/reference

              Sex/origin

              Age of SCD onset

              Age of SLE onset

              SLE features

              Immunologic features

              Hemoglobin type

              Treatment

              Outcome

              Cherner 2010 [3]

              F/Afro-Caribbean

              13

              21

              Arthritis, fever

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Malar rash

              Anti-CCP+

               

              Methotrexate

               
                  

              Gut vasculitis

              Anti-RNP+

               

              Rituximab

               
                   

              ACL+

               

              Cyclophosphamide

               

              Cherner 2010 [3]

              F/Afro-Caribbean

              7

              41

              Skin rash

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Renal disease (biopsy not performed)

              Anti-DNA+

                 
                   

              Anti-Ro+

                 

              Appenzeller 2008 [4]

              F/African-American

              NA

              16

              Fever, arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Photosensitivity

              Anti-SM+

               

              Azathioprime

               
                  

              Cardiomyopathy

                  
                  

              Pericarditis

                  

              Appenzeller 2008 [4]

              F/African-American

              15

              21

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Pleuritis

              Anti-DNA+

              SS

              Hydroxychloroquine

               
                  

              Lymphadenopathy

              Anti-Sm+

                 

              Appenzeller 2008 [4]

              F/African-American

              NA

              57

              Arthritis

              Anti-Sm+

              SS

              Prednisone

               
                  

              Photosensitivity

                

              Hydroxychloroquine

              Clinical improvement

                  

              Discoid lesions

                  
                  

              Raynaud’s phenomenon

                  

              Michel 2008 [2]

              F/NA

              NA

              30

              Arthritis

              ANA+

              SS

              Prednisone

              Deceased

                  

              Pericarditis

              Anti-DNA+

                 
                  

              Pleuritis

              Anti-SSA+

                 
                  

              GN class II

                  

              Michel 2008 [2]

              M/NA

              NA

              40

              Arthritis

              ANA+

              SS

              Prednisone

              Remission

                  

              Discoid lesions

                

              Hydroxychloroquine

               
                  

              Thrombocytopenia

                  

              Michel 2008 [2]

              F/NA

              NA

              32

              Thrombocytopenia

              ANA+

              SC

              Hydroxychloroquine

              Remission

                   

              Anti-DNA+

                 

              Michel 2008 [2]

              F/NA

              NA

              35

              Arthritis

              ANA+

              SS

              Prednisone

              Deceased

                  

              Cutaneous vasculitis

              Anti-DNA+

               

              Hydroxychloroquine

               
                  

              Raynaud’s phenomenon

              Anti-Sm+

               

              Methotrexate

               
                  

              GN class II

              Anti-SSA+

                 
                   

              Anti-RNP

                 

              Michel 2008 [2]

              F/NA

              NA

              27

              Arthritis

              ANA+

              SS

              Prednisone

              Remission

                   

              Anti-DNA+

               

              Hydroxychloroquine

               

              Michel 2008 [2]

              F/NA

              NA

              25

              Arthritis

              ANA+

              SS

              Prednisone

              Remission

                  

              GN class III

              Anti-DNA+

               

              Hydroxychloroquine

               
                  

              Jaccoud arthropathy

              ACL+

                 
                  

              Major depression

                  

              Michel 2008 [2]

              M/NA

              NA

              26

              Arthritis

              ANA+

              SC

              Hydroxychloroquine

              Clinical improvement

                   

              Anti-DNA+

                 
                   

              Anti-RNP+

                 
                   

              ACL+

                 

              Michel 2008 [2]

              F/NA

              NA

              28

              Arthritis

              ANA+

              SS

              Prednisone

              Persistent renal disease

                  

              GN class IV

              Anti-DNA+

               

              Hydroxychloroquine

               
                  

              Bullous lupus

              Anti-Sm+

               

              Dapsone

               
                   

              Anti-RNP+

                 

              Michel 2008 [2]

              F/NA

              NA

              32

              Arthritis

              ANA+

              SS

              Prednisone

              Remission

                  

              Kikuchi’s disease

              RF+

                 
                  

              Autoimmune hepatitis

                  

              Michel 2008 [2]

              F/NA

              NA

              40

              Arthritis

              ANA+

              SS

              Hydroxychloroquine

              Clinical improvement

                  

              Discoid lupus

              ANA+

                 
                  

              Venous thrombosis

              Anti-Ro+

                 
                   

              ACL

                 

              Michel 2008 [2]

              F/NA

              NA

              38

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                     

              Hydroxychloroquine

               

              Michel 2008 [2]

              F/NA

              NA

              17

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Thrombocytopenia

              Anti-Ro+

               

              Hydroxychloroquine

               
                   

              Anti-La+

                 
                   

              ACL+

                 

              Michel 2008 [2]

              F/NA

              NA

              35

              Pedal and peri-orbital edema

              ANA+

              SC

              Prednisone

              Dialysis

                  

              Ascites and renal failure

              Anti-DNA+

               

              Cyclophosphamide

               
                  

              GN class IV

                  

              Oqunbiyi 2007 [6]

              M/African

              NA

              8

              Malar rash

                

              Prednisone

              Clinical improvement

                  

              Arthritis

                

              Hydroxychloroquine

               
                  

              Seizures

                  
                  

              Fever

                  

              Khalide 2005 [7]

              F/NA

              16

              24

              Heart failure

              Anti-DNA+

              SC

              Prednisone

              Clinical improvement

                  

              Renal failure

              Anti-Sm+

                 
                  

              Pericarditis

              Lupus anticoagulant+

                 
                  

              Pulmonary emboli

                  
                  

              Polyneuropathy

                  
                  

              Generalized seizures

                  

              Khalide 2005 [7]

              M/NA

              NA

              16

              Discoid rash

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Polyarthritis

              Anti-DNA+

               

              Hydroxychloroquine,

               
                  

              Partial seizures

                

              azathioprine

               

              Khalide 2005 [7]

              M/NA

              NA

              23

              Skin rash

              ANA+

              SS

              Hydroxychloroquine

              Lost to follow up

                  

              Pleuritis

              ACL+

                 
                  

              Arthritis

                  
                  

              Raynaud’s phenomenon

                  

              Khalide 2005 [7]

              F/NA

              NA

              28

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Oral ulcers

              Anti-DNA+

                 
                  

              GN class III

              ACL

                 

              Saxena 2003 [8]

              M/African-American

              NA

              9

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Fever

              Anti-DNA+

               

              Cyclophosphamide

               
                  

              Acute chest syndrome

              Anti-SSA+

                 
                  

              Pericarditis

                  
                  

              Seizures

                  

              Saxena 2003 [8]

              F/African-American

              NA

              7

              Fever

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Arthritis

              Anti-DNA+

               

              Cyclophosphamide

               
                  

              Alopecia

                

              Azathioprine

               
                  

              GN class II

                  

              Saxena 2003 [8]

              F/African-American

              NA

              11

              Fever

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Arthritis

                

              Cyclophosphamide

               
                  

              Skin rash

                  
                  

              Seizures

                  
                  

              Cardiomegaly

                  

              Saxena 2003 [8]

              F/African-American

              NA

              14

              Seizures

              ANA+

              SS

              Prednisone

              Septic shock due to pneumococcal bacteremia

                  

              Malar rash

              Anti-DNA+

               

              Cyclophosphamide

               
                  

              Splenomegaly

                

              Azathioprine

               
                  

              Arthritis

                

              Plasmapheresis

               
                  

              Pericarditis

                

              Splenectomy

               

              Saxena 2003 [8]

              M/African-American

              NA

              17

              Malar rash

              ANA+

              SS

              Prednisone

              Hemodialysis dependent

                  

              Alopecia

                

              Cyclophosphamide

               
                  

              Pericarditis

                  
                  

              Cardiomegaly

                  
                  

              GN class V

                  

              Shetty 1998 [9]

              F/Afro-Carribbean

              Nine months

              10

              Arthritis

              LE cells in pericardial effusion

              SS

              Prednisone

              Clinical improvement

                  

              Pulmonary infiltrate

                  
                  

              Pericarditis

                  
                  

              Myocarditis

                  

              Pham 1997 [10]

              F/Afro-Caribbean

              NA

              18

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Nephrotic syndrome

              Anti-DNA

                 

              Katsanis 1987 [11]

              F/Afro-Caribbean

              NA

              16

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Malar rash

              Anti-DNA+

               

              Hydroxychloroquine

               
                  

              Photosensitivity

              Anti-Sm+

                 
                  

              Pleuritis

                  
                  

              Pericarditis

                  
                  

              Renal class II

                  

              Katsanis 1987 [11]

              F/Afro-Caribbean

              NA

              15

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Pleuritis

              Anti-DNA borderline

              SC

              Prednisone

              Clinical improvement

              Warrier 1984 [12]

              F/Afro-Caribbean

              NA

              11

              Malar rash

              ANA+

                 
                  

              Alopecia

              Anti-DNA+

                 
                  

              Arthralgia

              Anti-ENA+

                 
                  

              Seizures

                  
                  

              Hepatosplenomegaly

                  

              Luban 1980 [13]

              F/African-American

              NA

              8

              Discoid lesions

              Positive LE

              SC

              Prednisone

              Clinical improvement

                  

              Pericarditis

              ANA+

                 
                  

              Myocarditis

                  

              Luban 1980 [13]

              F/African-American

              NA

              14

              Fever

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Renal disease

              Positive LE

                 

              Karthikeyan 1978 [14]

              F/African

              4

              15

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Raynaud’s phenomenon

              Positive LE cell test

                 
                  

              Photosensitivity

                  

              Wilson 1976 [15]

              F/African-American

              30

              40

              Arthritis

              Positive LE cells

              SS

              Prednisone

              Deceased

                  

              Pleuritis

                  
                  

              Libman-Sacks endocarditis

                  

              Wilson 1976 [15]

              F/African-American

              Four months

              16

              Arthritis

              ANA+

              SS

              Prednisone

              Clinical improvement

                  

              Hepatitis

              Anti DNA +

                 
                  

              Pneumonitis

                  

              Wilson 1976 [16]

              F/African-American

              NA

              27

              Arthritis

              Histopathologic evidence for SLE on post-mortem examination

              SS

              No treatment for SLE

              Deceased

                  

              Malar rash

                  
                  

              Pulmonary congestion

                  
                  

              Hepatomegaly

                  
                  

              Nephrotic syndrome

                  
                  

              Cerebral and subarachnoid hemorrhage

                  

              ACL=anti-cardiolipin antibodies; ANA=anti-nuclear antibodies; anti-ENA=anti-extractable nuclear antigen antibodies; GN=glomerulonephritis; NA=not available; RF=rheumatoid factor; anti-RNP=anti-ribonucleoprotein antibodies; SCD=sickle-cell disease; SLE=systemic lupus erythematosus; anti-SSA=anti-Sjögren syndrome antigen A antibodies.

              Further, the frequency and titers of antibodies in SCD have been reported as relatively higher than in population controls, making the diagnosis more challenging in clinical practice [17].

              Toly-Ndour et al. reported that 50 percent of 88 patients with SCD had positive anti-nuclear antibody results and 20 percent had titers greater than one in 200, but only one patient developed rheumatoid arthritis five years later and no patients developed SLE [18]. In this series, patients treated with hydroxyurea had ANA-positive results less frequently than non-treated patients (P=0.053) [18].

              Large prospective epidemiological studies are necessary to determine whether the prevalence of immune complex diseases is increased in patients with SCD.

              Conclusions

              This report illustrates the importance of considering associated diseases when clinical findings are unexplained by SCD alone, or are unresponsive to the conventional treatment. Early diagnosis and the initiation of appropriate treatment may decrease morbidity and mortality in these patients.

              Consent

              Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

              Declarations

              Authors’ Affiliations

              (1)
              Department of Internal Medicine, Ibn Sina Hospital

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              © Maamar et al.; licensee BioMed Central Ltd. 2012

              This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.