Case Report: Crosstalk between systemic lupus erythematosus and sickle cell syndromes—two cases from eastern India

Introduction

Sickle cell hemoglobinopathies are common genetic disorders that are widely prevalent in certain parts of eastern India (1, 2). Systemic lupus erythematosus (SLE) is an autoimmune entity characterized by multisystem involvement and variable manifestations. Both diseases have certain clinical features in common, such as episodes of joint pain, renal manifestations, and acute chest syndrome, which can pose diagnostic challenges for lupus in patients with these hemoglobinopathies. These common features may represent some common intersecting pathogenic pathways in these diseases. Hence, early diagnosis may sometimes be delayed in such endemic areas (3, 4). This report describes two cases of sickle cell trait (SCT) with seropositivity for lupus-related autoantibodies. The coexistence of SLE and SCT remains a field of active research.

Case presentation

Case 1

A 17-year-old woman with known sickle cell trait presented with a low-grade fever, cough associated with hemoptysis for 2 weeks, chest discomfort, and dyspnea for 3 days. There was no history suggestive of rashes or joint pain. Her medical history included cervical lymphadenopathy. Lymph node biopsy showed only reactive lymphadenitis . Physical examination revealed a pulse rate of 112/min, blood pressure of 136/86 mmHg, respiratory rate of 30/min, and oxygen saturation of 90%. Respiratory examination showed bilateral crepitations and wheezing in all lung fields. Over time, her oxygen saturation dropped to 84%. She was treated with intravenous systemic antibiotics, nebulization, and intravenous fluids. Laboratory investigations revealed an erythrocyte sedimentation rate (ESR) of 151 mm with anemia. Urinalysis revealed 3+ proteinuria. A chest x-ray revealed bilateral patchy infiltrates (Figure 1). Further examination revealed rashes on both feet, along with bilateral cervical lymphadenopathy and an oral ulcer. A peripheral smear showed features suggestive of hemolysis with target cells. The direct Coombs test was positive, and serum ferritin was elevated. Antinuclear antibodies (ANA) and double-stranded DNA (dsDNA) were positive (3+; mixed pattern) with a titer of ≥1:80. Splenomegaly was noted in an ultrasound of the abdomen. A computed tomography scan of the thorax revealed ground glass opacities, bilateral pleural effusions on the right side, and mediastinal and axillary lymphadenopathy (Figure 2). Sputum culture, acid-fast bacilli, and cartridge-based nucleic acid amplification test (CBNAAT) were negative. The 24-h urine protein was 3,521 mg. perinuclear ANCA (p-ANCA) and cytoplasmic ANCA (c-ANCA), tests were negative. The patient received pulse methylprednisolone, followed by oral prednisolone and hydroxychloroquine. Her condition gradually improved, and she was discharged in stable clinical condition. A renal biopsy obtained after discharge showed class 4 lupus nephritis. The case fulfilled the ACR/EULAR 2019 criteria for the diagnosis of SLE (5) (Table 1).

Table 1. Progress chart: case 1.

Case 2

A 20-year-old woman presented with a low-grade fever, multiple small joint pains of 1.5 months, and lower leg swelling, along with abdominal and facial puffiness of 1 month. The joint pain was additive in nature and associated with early morning stiffness lasting approximately 2–3 h. The swelling was not associated with any alteration in urine output or frothy urine. She also reported intermittent abdominal pain. Her medical history included repeated blood transfusions for anemia and a sickle cell abnormality, although no documentation was available. Physical examination revealed malar rashes, hyperpigmented rashes over the upper chest, and oral ulcers (Figures 3, 4). Her scalp hair was sparse, and she had pallor and pitting pedal edema. Laboratory evaluation showed a hemoglobin level of 6.7 g/dl, serum albumin of 3 g/dl, and a urine albumin-to-creatinine ratio of 100 mg/g creatinine. The direct Coombs test was 3+, and serum C3 was low. The 24-h urine protein was 840 mg. An abdominal ultrasound revealed no abnormalities. However, the anti-dsDNA test was positive with 2+ intensity. She developed a bloodstream infection with methicillin-resistant Staphylococcus aureus, for which intravenous antibiotics were administered. High-performance liquid chromatography revealed an HbA2 level of 3.4% and an HbF level of less than 0.8%, suggestive of sickle cell trait. Renal biopsy was deferred as the patient wished to get discharged and reviewed at follow-up. The case fulfilled the ACR/EULAR 2019 criteria for the diagnosis of SLE (5). The patient was discharged on oral corticosteroids. Her joint pain improved considerably, along with the resolution of pedal edema and facial puffiness (Tables 1, 2).

Table 2. Progress chart: case 2.

uACR, urine albumin-creatinine ratio.

Discussion

We have presented two cases of sickle cell trait coexisting with SLE. Both of them have antibodies to ANA and anti-dsDNA. The coexistence of these conditions is of great importance, as autoimmune diseases are infrequently reported in the literature (6). Owing to the fact that sickle cell hemoglobinopathies are commonly reported in this part of the country, such cases highlight the importance of recognizing such associations. Usually, the presence of SCT is evident long before SLE is diagnosed (7). In these two cases, the diagnosis of sickle cell trait was made long before the onset of SLE. Both patients were young at the time of SLE diagnosis, as was reported in other literature work (7). In the first case, the patient presented with acute respiratory symptoms, which is in stark contrast to other reported cases where sickle cell patients presented with SLE symptoms like joint pain, swelling, and renal manifestations (3, 7). In contrast, the second case aligned with the more common presentation of SLE as reported elsewhere (8).

Articular manifestations were the most common presentation in such combinations of diseases, followed by serositis and renal involvement. Skin involvement was not frequently observed, which may be an uncommon observation compared to SLE alone (9).

Although the association of ANA positivity with sickle cell disease (SCD) has been described, very few cases have been reported with the SCT variant (3, 7). Patients with sickle cell disease have abnormalities of the alternate pathway of the complement system, which may make them susceptible to the development of autoimmune conditions (10).

Patients with sickle cell hemoglobinopathies and SLE present with hypocomplementemia, which leads to a failure in the activation of the alternate pathway (10). This results in reduced clearance of antigens, inciting autoimmunity. Sickle cell hemoglobinopathies have broad symptomatology, and ANA positivity alone cannot justify a diagnosis of SLE. Because ANA positivity has been found in approximately 50% of cases of sickle cell hemoglobinopathies, clinicians should not rely on this criterion alone (10). Therefore, when SLE is suspected, anti-dsDNA testing should be considered. Immune complexes are formed in such hemoglobinopathies, and this process can lead to the activation of autoimmunity.

Complement activation is intrinsic to sickle cell hemoglobinopathies, even in steady-state conditions, due to the exposure of phosphatidylserine and free heme released during intravascular hemolysis (10). The role of B regulatory cells may be key in the pathogenesis of the possible crosstalk between SLE and SCT. There is both a decrease and functional impairment of B regulatory cells in sickle cell syndromes with SLE, resulting in an imbalanced immune response (11).

Published literature suggests that SCT may not be a completely benign state or an actual disease condition but may posit itself as a risk factor for worse outcomes that herald from the interplay between the two (12–14). The sickle gene herein is envisaged to confer an increased susceptibility to infections like bloodstream infections, autoimmune hemolytic anemia, and lung infections.

Evidence suggests that sickle cell trait may potentially increase the risk of hypercoagulability. In addition, the literature supports that SLE itself is an independent risk factor for both arterial and venous thromboembolism (13). In situ, thrombus or hypercoagulability is known to promote microbial adhesion and colonization and thus is a potent risk factor for infection (15). Hence, SLE patients with SCT may be at higher risk for adverse clinical outcomes.

To date, only a few cases of SLE in individuals with sickle cell trait have been reported in the scientific literature (6). However, it is important to mention that there is no established evidence of a cause–and-effect relationship between sickle cell trait and SLE. Although the limitation of generalizability remains, a heightened awareness of sickle-associated complications may lead to a reduction of complications in such populations within the evolving SLE landscape.

Certain common genes have been implicated in sickle cell syndrome and SLE. The bone morphogenetic protein( BMP) pathway gene is involved in sickle vasculopathy and renal complications, like albuminuria and glomerular hyperfiltration, in sickle cell syndrome. Similarly, BMP single-nucleotide polymorphisms (SNPs) are associated with susceptibility to SLE and its pathogenesis. It has also been found that certain other genes, namely, human leukocyte antigen (HLA) and genes located on chromosomes 2 and 6, are involved in the pathogenesis of both SLE and sickle cell disease (16–19).

Although there are case series and case reports documenting lupus nephritis in patients with sickle cell syndrome, large epidemiological studies are lacking to convincingly state that lupus nephritis has a high prevalence in patients with SCT and SLE (20).

This report highlights that sickle cell trait may be one of the crucial risk factors for SLE. The decline in kidney function in individuals with sickle cell syndromes (SCD and SCT) is greater than in healthy individuals (21). Clinicians should be aware of this knowledge of the association for appropriate management. Awareness of such associations is important for the prognosis of the cases. In areas with a high prevalence of sickle cell syndromes, the diagnosis of SLE needs to be carefully considered based on clinical signs and symptoms.

Conclusion

This report highlights the importance of the appropriate use of diagnostic tests in the setting of sickle cell syndrome and SLE. Early intervention is the key to favorable outcomes. Large clinicoepidemiological studies are required to further explore the relationship between autoimmune diseases and sickle cell syndromes.

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