To the Editor: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies. Disease prevalence is 20 to 70 per 100,000 among adults, and 1.89 to 25.7 per 100,000 among children.[1,2] The pathogenesis of SLE is associated with immune disorders, especially involving the activation of B and T cells, which can lead to abnormal antibodies with nuclear and cytosolic antigens from apoptotic cells of the immune complexes (ICs) removing the damaged cells, and excessive activation of the complement system, thus causing damage to target organs, such as the kidneys and lungs.[3,4]

With pulmonary involvement in SLE patients, various comorbidities may occur, including pleurisy and diffuse alveolar hemorrhage (DAH). DAH, first described in 1904, is a rare, serious, and potentially life-threatening complication of SLE.[1] DAH can also occur in other diseases, including antiphospholipid syndrome, connective tissue diseases, infective endocarditis, and other infections.[5] The prevalence of SLE-DAH in adults ranges from 0.5% to 5.7%, with a female-to-male ratio of approximately 6:1, and a higher prevalence in young females. The mean age of onset is 27 years, approximately 35 months after SLE onset.[1] In children with SLE, DAH incidence is approximately 0.8% to 4.9%; however, the mortality rate is over 30%,[2,6] emphasizing the need for timely diagnosis and appropriate choice of treatment, and for simultaneously researching new potential treatments to reduce mortality, by clinicians.

SLE-DAH pathogenesis is illustrated in Figure 1. Its development may be related to macrophage and neutrophil recruitment to the lungs at the early stage. Systemic inflammation involving the pulmonary vasculature, caused by overactive autoimmune responses and cytokine storms, is thought to be the main cause of DAH, which may be related to the overactivation of the complement pathway [Figure 1]. The pathological manifestations are mainly autoantibody-mediated pulmonary capillaritis, mild alveolar hemorrhage, and diffuse alveolar injury.[5] Mild bleeding may be related to mononuclear cell (Mc) infiltration of the alveolar wall. Additionally, the excessive complement pathway is closely related to the B cell activation, and can also activate neutrophils, forming neutrophil cell traps and secreting cytokines, also related to DAH [Figure 1].

Figure 1:

Pathogenesis of SLE-DAH. In SLE-DAH, increased alveolar wall cell apoptosis can lead to RBC infiltration into the alveolar space, which may lead to bleeding; however, the source of apoptotic cells is unclear and alveolar epithelial cells, Mc, and MQ may phagocytose apoptotic cells and RBCs. During inflammation, bone marrow-derived MQs are recruited to the alveoli and differentiate into proinflammatory M1-type MQs and IgM/C3-induced apoptotic cells, bind to C3b receptors 3 and 4 on MQs, accelerating the development of DAH. In SLE, excessive B cell activation can produce numerous autoantibodies in response to antigens (such as vascular endothelial cells of phospholipids, etc.), the formation of ICs, and excessive activation of complement, making up the immune response that can result in the endothelial cell damage, pulmonary capillary inflammation, increased permeability, and infiltration of RBC into alveolar cavities, causing DAH. Hyperactivation of pulmonary complement leads to the production of anaphylaxis toxins and effector cell activating mediators, particularly C5a. C5a attracts and activates NEs and releases inflammatory mediators, including proteolytic enzymes, chemokines (such as CXCL2), and cytokines (such as TNF-α), which worsen alveolar damage and capillary leakage. Also, C5a can bind to C5a receptors on NEs, activating them to form NETs. NETs are fibrous networks protruding from activated NE cell membranes that accelerate inflammatory processes by releasing histones, active lyases, and various cytokines into the extracellular space. Ab: Antibody; CXCL2: Chemokine ligand 2; DAH: Diffuse alveolar hemorrhage; ICs: Immune complexes; IFN: Interferon; Ig: Immunoglobulin; IL: Interleukin; Mc: Mononuclear cell; MQ: Macrophages; NE: Neutrophil; NET: Neutrophil extracellular trap; RBCs: Red blood cells; SLE: Systemic lupus erythematosus; TNF: Tumor necrosis factor.

SLE-DAH diagnosis requires careful history, symptom assessment, and physical examination. A combination of laboratory tests, lung imaging, and bronchoalveolar lavage fluid analysis will provide evidence for diagnosis. It also needs to be differentiated from other diseases (including diastolic dysfunction, deep fungal infections, end-stage chronic kidney disease with uremia, etc.). The diagnostic flow is illustrated in Supplementary Figure 1, https://links.lww.com/CM9/B415.

SLE-DAH has a high mortality rate, especially acute macroscopic bleeding requiring prompt treatment. Glucocorticoids (GCs) are the main treatment for SLE-DAH, and it is recommended to use large doses immediately after diagnosis to exclude infection, as well as to treat underlying diseases.[5] It can reduce acute inflammatory responses by inhibiting inflammatory cells and cytokines. However, it is often fatal in immunocompromised patients. Therefore, the effectiveness of high-dose GC for DAH treatment remains controversial. Treatment of SLE-DAH using cyclophosphamide (CTX) has been shown to improve survival.[7] In children with SLE-DAH, a regimen of high-dose methylprednisolone pulse combined with CTX is recommended.[8]

B-cell activation is thought to play an important role in SLE pathophysiology. Rituximab (RTX) is a chimeric monoclonal antibody targeting cluster of differentiation 20 (CD20) that reduces the serum levels of antibodies, immune complexes (ICs), and cytokines by specifically targeting the elimination of CD20+ B cells. In one study, all SLE-DAH patients were treated with RTX, and the follow-up time was 12 to 58 months. All patients survived, with no recurrence in three patients having a history of DAH recurrence.[9] Therefore, RTX could be used as a drug for SLE-DAH.

Intravenous immunoglobulin (IVIG) has immunomodulatory effects, including inhibition of B-cell proliferation, antibody production, growth factors, and cytokines, and can exert anti-inflammatory effects by inhibiting the complement system. In a recent literature review of treatment strategies for DAH patients, it was found that a patient with DAH and pulmonary infection had no recurrence of DAH after adding IVIG once a month to the treatment regimen of daily GC.[10] These results indicate that IVIG combined with other therapies is effective in SLE-DAH treatment.

ICs and pathological antibodies may cause SLE-DAH capillaritis. Therapeutic plasma exchange (TPE) removes ICs, antibodies, and cytokines, and has been used as an adjunct therapy in patients who do not respond to high-dose GC and CTX therapy. The 1-year survival rate of DAH patients treated with TPE is higher than that of patients treated with GC pulse therapy, whether combined with immunosuppressive agents or not.[11] However, few studies have reported that TPE treatment increases mortality.[12]

Recombinant hereditary factor VIIa (FVIIa) has a good hemostatic effect in patients with life-threatening intractable hemorrhage. FVIIa stops bleeding by forming the FVIIa-tissue factor complex, which activates factor X leading to thrombin production and clot formation. In a recent comprehensive review of 111 DAH cases, the patients were treated with systemic or intrapulmonary rFVIIa. In patients receiving systemic rFVIIa, single or repeated doses of 35 to 200 μg/kg were used, with an average of 250 μg/kg per episode. However, patients receiving intrapulmonary rFVIIa had almost complete hemostasis at 50 μg/kg per episode, which was not significantly different from systemic administration, and no thromboembolic events were reported. In children, intrapulmonary FVIIa administration can successfully induce pulmonary hemostasis and reduce the risk of systemic complications, indicating that it can be an effective treatment strategy for children and adults with DAH.[5]

Mesenchymal stem cells (MSCs) are pluripotent cells that differentiate into various mesenchymal lineages. MSCs exert immunomodulatory effects by inhibiting the proliferation and activation of T, B, and other immune cells. Human umbilical cord-derived MSCs have been used as a single-push intravenous infusion in a trial series, resulting in improved oxygen saturation and complete suppression of lung infiltration after 2 to 3 weeks.[1] Other studies have found that human umbilical cord MSC-exosomes reduce SLE-DAH-induced inflammation and alveolar hemorrhage by increasing the proportion of M2 macrophages.[13] Based on these results, MSCs and human umbilical cord MSC-exosomes may provide new prospects for DAH treatment.

Currently, SLE-DAH pathogenesis remains unclear. For patients suspected to have DAH, it is necessary to undergo the relevant examination to confirm the diagnosis and exclude other diseases with similar manifestations. GC and CTX are the most commonly used treatment methods for SLE-DAH. In addition to treating the primary disease, hemostatic management is crucial. For non-responders, MSCs and human umbilical cord MSC-exosomes are new therapeutic strategies to consider. SLE-DAH treatment has mainly been reported in individual cases; therefore, individualized treatment is required.

Conflicts of interest

None.

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