Refractory antibody-mediated rejection after high-emergency lung transplantation for dermatomyositis with anti-MDA5 antibody: a case report

Abstract

This case report describes a female with amyopathic anti-MDA5+ dermatomyositis who underwent emergency double lung transplantation due to rapidly progressive interstitial lung disease. Following transplantation, she developed acute antibody-mediated rejection (AMR). Despite multiple rounds of immunosuppressive therapy, her condition continued to deteriorate, and her donor-specific anti-human leukocyte antigen antibody levels increased markedly. An experimental treatment, imlifidase—an immunoglobulin G endopeptidase—was employed as a rescue therapy. This case highlights the complexity of posttransplant management of AMR and emphasizes the need for dedicated clinical trials to provide additional data.

HIGHLIGHTS

This case report illustrates the challenge of managing antibody-mediated rejection (AMR) following emergency lung transplantation in a patient with anti-MDA5 dermatomyositis. Despite aggressive immunosuppressive therapy, AMR proved refractory, necessitating the use of imlifidase as a rescue strategy. The case underscores the difficulty in managing refractory AMR, highlighting the absence of established guidelines or data to inform therapeutic decisions.

INTRODUCTION

Lung transplantation (LT) is often considered the only viable treatment option for rapidly progressive interstitial lung disease (RP-ILD) after the failure of recommended triple therapy [1]. Antibody-mediated rejection (AMR), a complication occurring after LT, is characterized by the presence of antibodies directed toward donor human leukocyte antigen (HLA) and specific lung histological features [2]. In the absence of specific guidelines, a multimodal approach typically includes plasma exchange (PLEX), anti-CD20 antibody, and intravenous immunoglobulin (IVIg), yet associated mortality rates remain high, between 50% and 70% at 2 years [2,3].

CASE REPORT

Informed consent was obtained from the patient’s guardian for publication of this case report. We report the case of a 25-year-old female with no prior medical history. She presented with amyopathic anti-MDA5+ dermatomyositis (DM) characterized by RP-ILD. Her initial presentation was fully described in a previous report [4]. Unfortunately, her condition progressed to refractory hypoxemia, necessitating her placement on the high-emergency lung transplant waiting list with venovenous extracorporeal life support (ECLS) in the Paris-Bichat lung transplant program. She received a double lung transplant on November 18, 2021. During the perioperative period, she received five units of red blood cells, five units of frozen plasma, one platelet concentrate, and four liters of crystalloid fluids. No preformed donor-specific anti-HLA antibodies (DSA) were detected, and the prospective crossmatch was negative. Induction therapy consisted of pulsed steroids (1,000 mg at day 1 [D1], followed by 125 mg at hour 12 [H12], H24, and H36). Further immunosuppressive therapy included oral steroids (initial dosage of 0.5 mg/kg per day, gradually tapered to 0.25 mg/kg per day at 3 months post-LT, then to 0.15 mg/kg per day at 6 months, stabilizing at 7.5 mg per day by 1 year post-LT), mycophenolate mofetil (2 g per day), and tacrolimus (initial target residual concentration of 10–14 ng/mL). The postoperative course was uneventful, and she was transferred to the pneumology unit on day 10.

On day 15, routine screening for anti-HLA antibodies revealed two DSAs: anti-HLA DQ2 (mean fluorescence intensity [MFI], 2,300) and anti-HLA targeting the DQ2.5 DQ beta/alpha combination (MFI, 8,700) (Fig. 1). At the 1-month follow-up, her anti-DQ2 and anti-DQ2.5 DSA levels had increased. Her first post-LT forced expiratory volume in 1 second (FEV1) was 1.21 L (33%). Chest computed tomography (CT) showed bilateral posterobasal consolidations (Fig. 2A). Transbronchial biopsy (TBB) revealed very discrete acute inflammatory lesions (widening of interalveolar septa and sparse septal neutrophils without capillaritis), consistent with AMR without evidence of acute cellular rejection (International Society for Heart and Lung Transplantation [ISHLT] grade A0Bx). C4d staining was not available. Comprehensive diagnostic work-up ruled out other diagnostic possibilities. Probable AMR was diagnosed. Treatment was initiated with pulsed methylprednisolone (250 mg/day for 3 days) and eight rounds of PLEX. Clinical and biological responses were favorable. Treatment continued with monthly IVIg (2 g/kg over 2 days) for 3 months.

Fig. 1.

Trends in DSA (MFI) over time. HLA, human leukocyte antigen; DSA, donor-specific anti-HLA antibody; MFI, mean fluorescence intensity; M, month; PLEX, plasma exchange; IVIg, intravenous immunoglobulin.

Fig. 2.

Trends in FEV1 over time and axial thoracic computed tomography images demonstrating parenchymal changes. Computed tomography scan at (A) M1, (B) M4, (C) M6, and (D) M8. (E) Graph showing trends in FEV1 over time. FEV1, forced expiratory volume in 1 second; M, month.

At month 4 (M4), FEV1 remained stable, but the patient exhibited a marked increase in DSA levels and the emergence of diffuse ground-glass opacities on CT (Fig. 2B and E). TBB indicated acute lung injury characterized by septal and perivascular inflammatory cells (predominantly mononuclear cells, occasionally neutrophils or eosinophils). Immunohistochemical staining for C4d was inconclusive. Further analysis showed that these DSAs (DQ2 and DQ2.5) at MFI 6,400 and 9,200 were C1q-binding antibodies. The overall presentation was consistent with A2 cellular rejection accompanied by acute lung injury, possibly related to AMR. Treatment consisted of five sessions of PLEX combined with pulsed steroids (15 mg/kg [600 mg] daily for 3 days). Functional and radiological improvements were observed. However, due to persistently elevated DSA levels, additional therapy was initiated: infusion of alemtuzumab (30 mg), IVIg (2 g/kg), and C1 esterase inhibitor (human) (20 UI/kg, administered as 800 UI on D1–D3, followed by 20 UI/kg twice weekly), due to C1q binding.

Despite this support, the patient required oxygen at M5, and her FEV1 decreased to 1.07 L (28%). Chest CT showed bilateral ground-glass opacities and pulmonary consolidation. The DSA MFI continued to increase. We initiated a new immunosuppressive regimen consisting of three steroid pulses (600 mg each) combined with 16 PLEX sessions. However, this treatment yielded neither clinical improvement nor reduction in DSA. Given the refractory AMR, we opted to add a course of the proteasome inhibitor carfilzomib (20 mg administered on D1, D2, D8, D9, D15, and D16), PLEX every 2 days, and monthly IVIg [5].

Clinical deterioration marked by increased oxygen requirements, in conjunction with worsening abnormalities on CT (Fig. 2C), necessitated the patient’s transfer to the intensive care unit (ICU). Although retransplantation was considered, it was contraindicated due to severe malnutrition (body mass index of 13 kg/m²) and the underlying immunologic condition. At M7 in the ICU, the patient still exhibited no improvement despite ongoing treatment with carfilzomib and PLEX. Consequently, we initiated a further series of immunosuppressive treatments: first, three steroid pulses, followed by a dose of imlifidase (immunoglobulin G endopeptidase, 11 mg intravenously). Following this, we observed a rapid and significant decrease in DSA MFI associated with transient radiological improvement, although levels returned to baseline by day 3.

After 65 sessions without clinical or biological efficacy, PLEX was discontinued. Another course of carfilzomib combined with C1 esterase inhibitor (human) was administered according to the previous protocol. Her clinical condition continued to deteriorate, accompanied by escalating oxygen requirements (Fig. 2D). Despite prophylaxis, the patient experienced multiple adverse effects of treatment, including recurrent nosocomial pneumonia, cytomegalovirus and Epstein-Barr virus replication, renal failure, cytopenia, and thrombotic microangiopathy. Considering the numerous infectious complications and her overall clinical status, carfilzomib and C1 esterase inhibitor (human) were discontinued. Unfortunately, the outcome was unfavorable, and she died of acute respiratory failure 12 months after LT.

DISCUSSION

We report a fatal case of refractory AMR in a patient transplanted for anti-MDA5+ RP-ILD. Anti-MDA5 DM with RP-ILD has been reported to have an ICU mortality of up to 80% [6,7]. Despite the availability of new treatments such as Janus kinase inhibitors [1,8], ECLS is frequently required. Bay et al. [9] described 15 patients who required ECLS, five of whom underwent LT through a high-urgency allocation procedure; the other 10 had fatal outcomes. All transplanted patients were alive at the end of the study.

A European cohort study reported survival and prognostic factors in LT recipients with ILD associated with idiopathic inflammatory myositis [10]. Five-year survival after transplantation resembled those for other indications. Of the 64 patients studied, 13 had anti-MDA5+ RP-ILD. The primary factor associated with poorer survival was a history of muscle involvement, which our patient did not exhibit. However, she presented with several factors linked to poor prognosis: previous immunosuppressive exposure, poor nutritional status, and high-urgency LT allocation procedure. In this cohort, the rate of rejection, including AMR, was similar to that observed in transplant registries for all causes. This study supports using ECLS as a bridge to transplantation for patients with DM, even if they are not yet on the LT waiting list.

The management of acute AMR in LT is not standardized, with existing studies being few, uncontrolled, and retrospective [3,11–13]. Other lung and kidney transplant teams were consulted to determine the appropriate treatment sequence. Confronted with refractory AMR, we targeted various components of humoral immunity: antibody levels with PLEX and endopeptidase, immunomodulation with IVIg, T and B lymphocytes with alemtuzumab, plasma cells with proteasome inhibitors, and the complement system with anti-C1 esterase. This case also highlights questions regarding induction protocols. According to the 33rd Report from the ISHLT Registry, approximately 50% of patients transplanted between 2006 and 2016 received induction therapy [14]. Most lung transplant centers use basiliximab, an interleukin (IL)-2 receptor antagonist, while polyclonal antithymocyte globulin and alemtuzumab are alternative options. We chose to avoid induction therapy and used only methylprednisolone, considering the patient’s heightened risk of infection due to previous immunosuppressive treatment and ECLS. In retrospect, our strategy proved inadequate, either because it was initiated too late or because it did not comprehensively target the immune response. For instance, anti-IL-6 receptor antibodies could have been used to target both innate and adaptive immunity [15].

In this case, relapse of DM was deemed unlikely, given the absence of detectable anti-MDA5 antibody and lack of extrarespiratory clinical manifestations. Notably, this patient developed two antibody-mediated immune pathologies, one before transplantation and one afterward. Nevertheless, we found no evidence in the literature linking AMR with autoimmune diseases, even in other types of organ transplants.

In conclusion, we present various treatment strategies for managing refractory humoral rejection, informed by pathophysiological rationale, which ultimately failed in this patient. Dedicated clinical trials or registries are necessary to systematically document practice patterns and efficacy, informing evidence-based guidelines.