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

  • Mouna Maamar1Email author,
  • Zoubida Tazi-Mezalek1,
  • Hicham Harmouche1,
  • Wafaa Mounfaloti1,
  • Mohammed Adnaoui1 and
  • Mohammed Aouni1
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] (Table1). 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 Table1 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 (Table1). 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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