Combination therapy with belimumab and low‐dose interleukin‐2 in a patient with anti‐MDA5 antibody dermatomyositis overlapping with systemic lupus erythematosus

A 42-year-old man presented with a 2-month history of a generalized scattered rash, accompanied by a 1-month history of polyarthralgia. Physical examination revealed enlargement of the right-sided axillary nodes and scattered red maculopapular rashes on the extended side of the metacarpophalangeal of both hands, the forehead, the inner canthus, under the nose, both auricles, and back. Periungual erythema and dark red punctate rash were also observed on the digits of the fingers. The rash did not elevate above the skin surface and did not fade upon pressure. Laboratory parameters indicated decreased levels of white blood cells at 2.40 × 109/L and normal creatine phosphokinase levels. The patient's creatinine was 77 μmol/L, and urinalysis was positive for urine protein. Serum inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate, were within normal limits, while complement 3 (C3) was aberrantly low (0.63 g/L; reference range: 0.90–1.80 g/L). Multiple antibodies were positive, including antinuclear antibody (ANA, 1:640; reference range: <1:40), anti-Smith antibody, anti-U1-ribonucleoprotein (anti-U1RNP) antibody, antiribosomal RNP (anti-rRNP) antibody, and antinucleosome antibody (AnuA). These findings fulfilled the 2019 European League Against Rheumatism and the American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE). Additionally, serum antispecific myositis spectrum antibody detection was positive for antimelanoma differentiation-associated protein 5 (MDA5) and antitranscription intermediary factor (TIF)-1γ. Given the presence of anti-TIF-1γ antibodies, which are typically associated with malignancy-related dermatomyositis (DM), a thorough malignancy screening was conducted. A chest computed tomography (CT) showed bronchiolitis and solid nodules in both lungs and emphysema in the upper lobes of both lungs. Multiple slightly enlarged lymph nodes were found in the mediastinum, bilateral axillae, and bilateral subclavian region. To further evaluate for malignancy, a positron emission tomography/CT was performed (Supporting Information: Figure S1A), and a skin biopsy was obtained. Histopathological examination demonstrated hyperkeratosis of the epidermis, focal thickening of the granular layer, and irregular thickening of the stratum spinosum. Moreover, lymphocyte infiltration was scattered around the small blood vessels of the dermis and the cutaneous appendages. Despite the association between TIF-1γ positivity and malignancy, we prioritized the diagnosis of the anti-MDA5 antibody-associated DM based on the clinical context, the absence of definitive malignancy evidence, and the predominant presence of anti-MDA5 antibodies. Subsequently, a concurrent diagnosis of SLE was also confirmed. During the hospitalization, the patient initially received methylprednisolone pulse therapy (40 mg/day) for 3 days, complemented by hydroxychloroquine (200 mg) and cyclosporine A (50 mg) twice daily. As disease activity worsened and infection risk emerged, treatment was adjusted to belimumab (720 mg monthly) and low-dose interleukin-2 (IL-2, 100 million IU twice a day). Belimumab, as a monoclonal antibody that inhibits the B-cell activating factor, was selected for its efficacy in reducing disease activity in SLE by targeting B-cell-mediated autoimmunity. Low-dose IL-2 was included in the treatment regimen due to its ability to selectively expand regulatory T cells while avoiding the activation of effector T cells that can exacerbate autoimmunity. Low-dose IL-2 has been shown to restore regulatory T-cell function and reduce the risk of infection in autoimmune diseases, making it a suitable complement to belimumab in this complex case. At 12 months posttreatment, the patients showed significant clinical improvement. The rash and arthritis resolved, hematological parameters normalized, antibody levels reduced, and complement levels recovered (Supporting Information: Figure S1B). Specifically, serum ANA had decreased from 1:640 to 1:80, and the concentration of AnuA had decreased from 35.52 RU/mL to 1.22 RU/mL. Simultaneously, the levels of C3 presented a striking increase from 0.57 g/L to 1.11 g/L. The treatment also resulted in a reduction of B cell subsets and an elevation of regulatory T cells, indicating a favorable immunological response. A follow-up chest computed tomography at week 24 revealed a resolution of bronchiolitis with shrunken lymph nodes compared to the initiation. It is noted that the corticosteroid dosage was tapered from 50 mg to 7.5 mg daily after 6 months of treatment. DM patients with anti-MDA5 antibodies were considered to have a life-threatening condition for which effective therapies are currently lacking. Research on anti-MDA5 antibody DM overlapping with SLE has broadened our understanding, suggesting that these two diseases might share common pathophysiological pathways, including the dysregulation of the immune system and the production of autoantibodies.1 Current research focuses on targeted therapies that can modulate the immune response, reduce inflammation, and potentially improve disease activities for patients with overlapping DM and SLE features, including belimumab2 and low-dose IL-2.3 The combination of belimumab, an inhibitor of the B-cell activating factor, and low-dose IL-2, known for regulating T-cell balance, provides a novel therapeutic approach. Furthermore, anti-TIF-1γ antibodies are indeed well-documented markers associated with an increased risk of malignancy in DM.4 Our previous research reported similar cases of anti-MDA5 positivity co-occurring with other antibodies.5 Additionally, while the possibility of a false positive for any antibody cannot be entirely excluded, the presence of multiple myositis-specific antibodies certainly requires further investigation. Despite normal tumor markers and no overt malignancy signs, the initial assessment ruled out the need for invasive diagnostics like additional organ biopsies. Nonetheless, acknowledging the persistent risk posed by anti-TIF-1γ, we have initiated a comprehensive monitoring program. It encompasses regular check-ups, repeated imaging, and tumor marker reassessments to promptly detect any malignancy onset. Jing He conceived and designed the project. Jing He, Xia Zhang were in charge of participant management. Ruiling Feng conducted data acquisition and data analysis. Ruiling Feng and Jing He drafted and revised the first manuscript. All the authors have revised and approved the manuscript submission. This study was supported by grants from the National Key R&D Program of China, Grant/Award Number: 2022YFE0131700 and 2022YFC3602000, the National Natural Science Foundation of China Grant/Award Number: 82071813 and 82271835, and Beijing Nova Program Grant/Award Number: 20220484206. The authors declare no conflict of interest. Written informed consent was obtained from the patient for publication of the case. Data used in this article are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.