The clinical characteristics of the Patient were analyzed. Clinical data, including age, sex, initial symptoms, lab tests and therapy were collected. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki with approval from the ethics committee of Sun Yat-sen Memorial Hospital, Sun Yat-Sen University [Ethical number: SYSKY-2023-1134-01]. Written informed consent was obtained from the Patient or her parents.
Patient’ medical report
In August 2022, a 12-year-old girl from Maoming, Guangdong, was readmitted to our institution with the primary complaint of a three-year history of Systemic Lupus Erythematosus (SLE) and a 16-day duration of anemia. She initially presented to our hospital at 8 years and 5 months old with symptoms of skin rashes and arthralgia, her diagnostic evaluations yielded a high anti-nuclear antibody (ANA) titer of 1:1280, positive anti-double-stranded DNA (anti-ds-DNA), and positive anti-ribosomal, anti-Smith, anti-ribonucleoprotein, and anti-nucleosome antibodies. Complement levels were substantially reduced (C3: 0.225 g/L, C4: 0.031 g/L), with a complete blood count revealing leukopenia (WBC: 2.98 ×10^9/L), hemoglobin of 116 g/L, and platelets at 183 × 10^12/L. A renal ultrasound exhibited effusions and synovial thickening in the left ankle and knee, without evidence of proteinuria or hematuria. The patient met the 2017 ACR criteria for SLE diagnosis and received treatment with cyclophosphamide (CTX) (10 mg/kg/day for two days, biweekly for a total of eight doses) and methylprednisolone (0.5 g/day for three days), which normalized the erythrocyte sedimentation rate (ESR) and 24-hour urinary protein levels. All immunologic markers including ANA, anti-ds-DNA, and complement levels returned to normal, alongside a negative urine microalbumin test. Maintenance therapy with mycophenolate mofetil was commenced, with the patient maintaining an SLE Disease Activity Index (SLEDAI) score of 0 at follow-up.
At the age of 10 years and 5 months, the patient's medications, including mycophenolate mofetil, prednisone, and hydroxychloroquine, were discontinued and replaced with methotrexate. However, at 12 years of age, blood tests revealed anemia with hemoglobin levels ranging from 54 to 72 g/L and an elevated ESR (27 mm/h). Further serological examinations demonstrated positive results for anti-nuclear antibodies, anti-ds-DNA antibodies, anti-nuclear U1-nRNP antibodies, Smith antibodies, anti-nucleosome antibodies, and anti-nucleolar antibodies. Complement C3 was 0.65 g/L, and erythropoietin levels were elevated at 652.0 mIU/mL. A positive direct Coombs test led to the diagnosis of "SLE complicated with immune hemolytic anemia." Intravenous immunoglobulin (1 g/kg) was administered without yielding any response. Bone marrow examination revealed active bone marrow hyperplasia with reduced proliferation of the red giant cell lineage (Fig. 1A-1B) and free-type homogeneous bodies accounting for 1%. Bone marrow biopsy demonstrated significant inhibition of erythroid hyperplasia (Fig. 1C-1D), leading to the consideration of pure red cell aplastic anemia (PRCA). Lymphocyte subgroup analysis indicated elevated proportions of CD20 + B cells. Subsequently, the patient received methylprednisolone pulse therapy and cyclosporine, but her hemoglobin levels failed to improve, necessitating blood transfusions. Rituximab (375 mg/m^2/week × 4 doses) was then administered, leading to gradual improvements in hemoglobin levels. Subsequent management included the sequential use of mycophenolate mofetil (20–30 mg/d) (as shown in Fig. 2). The patient returned to the hospital at the age of 12 years and 3 months, exhibiting anti-nuclear antibodies (++), negative ds-DNA, anti-Smith antibodies (-), anti-ribosome antibodies (+), and anti-nucleosome antibodies (+). Blood cell analysis indicated white blood cell count 6.61 ×10^9/L, hemoglobin 124 g/L, and platelet count 254 ×10^9/L. Complement levels C3 (0.785 g/L) and C4 (0.198 g/L) were within normal range, and lymphocyte subpopulation analysis showed CD19 + 0.13% and CD20 + 0.00%. Urinary analysis showed negative results for proteinuria and red blood cells, and ESR was normal. The SLEDAI score was 0.
Literature Review and Discussion
The underlying pathophysiological mechanisms that contribute to the concurrent manifestation of SLE and PRCA are not well-understood. It has been postulated that the autoantibodies in SLE may either directly target bone marrow progenitor cells or interfere with erythropoietin, through either humoral or cellular immune responses [7]. Additionally, T lymphocyte dysfunction is suggested to be implicated, evidenced by the restoration of erythroid colony-forming units in the bone marrow upon T-cell depletion [22].
A thorough review of 63 documented cases detailing the co-presence of SLE and PRCA was carried out, utilizing data from Pubmed, Wanfang, and CNKI databases covering a span from 1966 to 2022. The data revealed a predominant occurrence in middle-aged and young female cohorts (Table 1) [1–6, 9–13, 15–23, 25–32, 34–36, 38–40, 42–44, 46]. It was observed that PRCA often manifests subsequent to the SLE diagnosis, with around 20% of patients being diagnosed concurrently with both conditions, and a smaller portion presenting with PRCA preceding the SLE diagnosis [28]. The case under examination in our study is of particular interest as the patient developed SLE in her school-age years and maintained stability over two years post induction and maintenance therapy. Nevertheless, a relapse of her condition, marked by the onset of PRCA, ensued following the cessation of her treatment, underscoring the potential for PRCA to emerge in pediatric patients with SLE.
Table 1
Literature review of the PRCA with SLE complication
| Year | Sex | Age at SLE diagnosis (years) | Age at PRCA diagnosis (years) | Other organs involvement | Treatment | Ref |
| 2022 | M | 9 | 9 | Kidney | CS + CYC→CsA + Testosterone→MMF + MP pulse | [1] |
| 2021 | M: 3 F: 20 | 31.9 ± 14.5 | 38.5 ± 13.2 | Cutaneous, Joints, Liver | CS + IVIG, HCQ, CSA, MMF, RTX, AZA, MTX, CYC | [2] |
| 2021 | F | 27 | 27 | Cutaneous | CS | [5] |
| 2017 | M | 19 | 19 | Kidney | IVIG + CS + MMF | [6] |
| 2014 | F | 54 | 47 | Joint, Thyroid | CS | [7] |
| 2014 | F | 45 | 55 | Joint | HSCT | [8] |
| 2014 | F | 32 | 52 | NM | CS + CYC + IVIG + rhEPO | [9] |
| 2007 | NA | NM | NM | NM | CS + CsA | [10] |
| 2006 | F | 33 | 33 | Cutaneous, Kidney | CS + CSA | [11] |
| 2005 | F | 26 | 26 | NM | CS + Tripterygium glycosides | [12] |
| 2005 | F | 29 | 34 | NM | CS→CYC→CsA→MMF | [13] |
| 2005 | F | 6 | 6 | NM | NM | [14] |
| 2005 | F:2 | 31, 31 | 41, 31 | NM | CS + EPO, CS + CSA | [15] |
| 2003 | F | 38 | 38 | Cutaneous | CS | [16] |
| 2003 | F | 42 | 50 | NM | HCQ + CS→CsA + CS | [17] |
| 2002 | F | 31 | 31 | Cutaneous | CS、HCQ | [18] |
| 2002 | F | 26 | 31 | Cutaneous, Joint | CS→AZA + plasmapheres | [19] |
| 2001 | F | 19 | 19 | Joint | CS | [20] |
| 2000 | F | 21 | 21 | Cutaneous, Joint | CsA→AZA | [21] |
| 1999 | F: 2 | 21, 28 | 21, 28 | Cutaneous, Muscle Liver, Thyroid | IVIG、HCQ | [22] |
| 1997 | F | 28 | 28 | Liver | NM | [23] |
| 1996 | F | 69 | 69 | Cutaneous, Joint | NSAIDs、CS | [24] |
| 1995 | F: 2 | 22.5, 40 | 22, 33 | Cutaneous; Joint | HCQ + CS; CS + CsA | [4] |
| 1995 | F | 50 | 40 | Kidney, heart, lungs | NSAID→AZA→CYC | [25] |
| 1995 | F | 32 | 32 | NM | IVIG + CS→EPO | [26] |
| 1994 | M | 32 | 43 | Kideny, | EPO | [27] |
| 1993 | F | 22 | 22 | NM | CS→IVIG | [28] |
| 1993 | F | 28 | 28 | NM | CS | [29] |
| 1988 | M | 78 | 78 | Joints, Lung | drug discontinued, rhEPO (Procainamideinduced lupus) | [30] |
| 1987 | F | 33 | 33 | Joints | CS | [31] |
| 1987 | F | 24 | 24 | Cutaneous | CS | [32] |
| 1985 | F | 22 | 22 | Digest tract | CS | [33] |
| 1982 | F | 58 | 58 | Thyroid | CS | [34] |
| 1981 | F | 14 | 14 | Cutaneous, Kindney | CS + CYC | [35] |
| 1978 | F | 56 | 56 | Joints | CS | [36] |
| 1973 | F | 43 | 53 | Kidney, Joints | CS | [37] |
| 1973 | F | 43 | 50 | Thymoma, Endocarditisof aortic valve cusps | CS | [38] |
| 1968 | F | 38 | 41 | Cutaneous | CS (Dead) | [39] |
| Note: AZA, Azathioprine; CS, corticosteroid; CSA, cyclosporine A; CYC, cyclophosphamide; HCQ, Hydroxychloroquine; HSCT, hematopoietic stem cell transplantation; IVIG, Intravenous immunoglobulin; MMF, Mycophenolate mofetil; MTX, methotrexate; rhEPO, Recombinant human erythropoietin; RTX, Rituximab. |
Literature indicates that the clinical manifestations of SLE with PRCA largely overlap with those of SLE without PRCA, though leukopenia and thrombocytopenia are more prevalent in the former. Pleurisy is less common in patients with concurrent PRCA [46], and instances of renal and central nervous system involvement, as well as serositis, appear to be infrequent [26, 46]. Contrasting these observations, recent reports have identified renal complications characterized by significant proteinuria in this patient population [5, 22, 26, 27, 32]. A positive Coombs' test and autoimmune hemolytic anemia have also been documented in a subset of SLE with PRCA cases [40, 46]. In the case discussed herein, the initial symptoms were dermatological and articular, with severe anemia manifesting during a relapse. Subsequent examinations confirmed PRCA and autoimmune hemolytic anemia, corroborating that the latter is a recurring complication in SLE patients with PRCA.
Management of PRCA typically commences with red blood cell transfusions and extends to include treatments such as glucocorticoids, immunosuppressants, erythropoietin, and plasma exchange [46]. Prednisone is effective for most patients, and the adjunctive use of cyclosporine with glucocorticoids can enhance remission rates and diminish the risk of relapse [40]. Reports from China indicate that severe SLE can precipitate PRCA early in the disease course, with comprehensive remission achievable through combined treatment with intravenous immunoglobulin, glucocorticoids, and mycophenolate mofetil [27]. It is noteworthy that medications prescribed for SLE, including hydroxychloroquine, mycophenolate mofetil [3, 8, 45], and azathioprine, have been implicated in the development of PRCA, with symptoms often ameliorating upon cessation of these drugs [8, 45]."
Rituximab, a chimeric monoclonal antibody that targets CD20 on B cells [37], has been incorporated into the therapeutic regimen for systemic lupus erythematosus (SLE) for more than two decades [24]. Despite the paucity of data on its efficacy in the pediatric population [41], rituximab has demonstrated substantial effectiveness in conjunction with disease-modifying antirheumatic drugs (DMARDs) in the management of refractory lupus nephritis [14]. It also serves as a secondary treatment option for certain refractory autoimmune hematologic conditions [33]. Prior research indicates that rituximab is beneficial for SLE patients with concomitant pure red cell aplasia (PRCA) [28]. In the case detailed within this study, the patient underwent multiple transfusions of red blood cells, which initially did not yield a positive outcome. Treatment with intravenous immunoglobulin and cyclosporine, instituted due to autoimmune hemolytic anemia, did not result in clinical improvement. It was the administration of rituximab that precipitated a progressive enhancement in hemoglobin levels. The treatment plan was augmented with a sequential mycophenolate mofetil regimen, as depicted in Fig. 2. These observations support the potential role of rituximab in treating SLE associated with PRCA, especially in scenarios where conventional treatments such as intravenous immunoglobulin, glucocorticoids, and cyclosporine are ineffective. Nonetheless, these preliminary conclusions necessitate validation through larger-scale investigations.