Melanoma Differentiation-associated Gene 5-Positive Rapidly Progressive Interstitial Lung Disease Successfully Treated with Tofacitinib

Abstract

Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody-positive dermatomyositis is associated with rapidly progressive interstitial lung disease (RP-ILD). We encountered a man in his 40s who presented with a history of a fever and dry cough. Based on laboratory tests and computed tomography scans of his chest, he was diagnosed with anti-MDA-5 antibody-positive dermatomyositis with RP-ILD refractory to antimicrobial agents. Although the patient was treated with glucocorticoids, calcineurin inhibitors, intravenous cyclophosphamide, and plasma exchange, ventilatory management was still required. The patient survived additional therapy with tofacitinib; however, he developed a catheter-related pulmonary embolism as a complication.

Introduction

Clinical amyopathic dermatomyositis, a dermatomyositis with negligible muscle symptoms, is frequently associated with rapidly progressive interstitial lung disease (RP-ILD) that is refractory to treatment and has a poor prognosis with a reported mortality rate of 25-35% (1,2). The melanoma differentiation-associated gene 5 (MDA-5) antibody has been reported to be a specific diagnostic marker of this condition (3,4).

The treatment for anti-MDA-5 antibody-positive dermatomyositis associated with RP-ILD is not well established. Recent studies have reported the efficacy of triple therapy with glucocorticoids, calcineurin inhibitors, and intravenous cyclophosphamide (IVCY) (2,5,6). The efficacy of plasma exchange (PE) in treatment-resistant anti-MDA-5 antibody-positive dermatomyositis with RP-ILD has also been reported (7). However, previous studies have noted the progression of respiratory failure without any response to triple therapy or PE (8).

Janus kinase (JAK) inhibitors, which act on the JAK signal transducer and transcription activator pathways and block several cytokine pathways, are effective against anti-MDA-5 antibody-positive dermatomyositis with RP-ILD (9,10). Tofacitinib, a JAK inhibitor, suppresses cytokines, such as type I interferon, type II interferon, and interleukin-2 (11). Chen et al. reported the usefulness of adding tofacitinib to glucocorticoids in mild cases of anti-MDA-5 antibody-positive dermatomyositis with RP-ILD (9). Kurasawa et al. reported that three Japanese patients with anti-MDA-5 antibody-positive dermatomyositis and RP-ILD, who were unresponsive to triple therapy, survived after being treated with tofacitinib (10). In contrast, a large randomized controlled trial (RCT) of patients with rheumatoid arthritis (RA) reported that JAK inhibitors increased the risk of deep vein thrombosis and pulmonary embolism in a dose-dependent manner (12).

In this report, we describe a patient with MDA-5-positive RP-ILD who was effectively treated with tofacitinib but later developed pulmonary embolism.

Case Report

A man in his 40s presented with a fever and dry cough for 9 days prior to admission. As his symptoms did not improve, he was treated with azithromycin for 3 days before admission; however, his symptoms worsened.

On the day of admission, dyspnea appeared, and chest computed tomography (CT) showed bilateral diffuse ground-glass shadows. The patient was 179 cm tall and weighed 80 kg. On admission, his body temperature was 36.8 °C, blood pressure was 132/80 mmHg, SpO₂ was 89% (mask, 8 L), and respiratory rate was 20 breaths/min. The patient had a heliotrope rash, scratch dermatitis, periungual erythema, and fine crackles bilaterally at the base of the lungs. No abnormalities were observed in the head and neck, heart, abdomen, limb joints, or neuromuscular system.

A laboratory examination revealed an alveolar-to-arterial oxygen difference of 272 mmHg, partial pressure of oxygen in the arterial blood of 53 mmHg, and respiratory failure. Other findings included creatine kinase, 336 U/L; Krebs von den Lungen, 6,576 U/mL; lactate dehydrogenase, 353 IU/L; anti-MDA antibody, 2,285 U/mL; anti-Ro52 antibody negativity, ferritin, 1,097 ng/dL; lupus anticoagulant 1.3, immunoglobulin G anti-cardiolipin antibody, 4 U/mL; and anti-cardiolipin β 2-glycoprotein 1 antibody 1.3 U/mL. Chest CT of the patient showed diffuse alveolar damage with extensive non-regional ground-glass shadows mainly on the pleural side of all lung fields (Fig. 1). The patient was diagnosed with anti-MDA-5 antibody-positive dermatomyositis with RP-ILD, refractory to antimicrobial agents, based on skin rashes that were characteristic of dermatomyositis and a high serum titer of anti-MDA-5 antibody. A high ferritin level suggests cytokine storm.

Figure 1.

High-resolution computed tomography scan of the chest on Day 1 of admission. Bilateral patchy distribution with ground glass shadows is observed.

From the first to the third day, the patient was administered 1,000 mg/day of intravenous methylprednisolone, and from the first day, oral sulfamethoxazole (400 mg) and trimethoprim (80 mg) were administered for chemoprophylaxis of pneumocystis pneumonia. On the Day 4 of admission, the patient was administered 80 mg (1 mg/kg/day) of oral prednisolone and tacrolimus (TAC) (target trough, 10-15 ng/mL). However, the patient developed respiratory muscle fatigue and respiratory failure for which mechanical ventilation was performed. On Day 5, 1,000 mg (500 mg/m²) of IVCY and PE was started. On Day 9, the respiratory condition worsened, and ferritin levels were elevated (1,299 ng/dL), which was considered to be due to the exacerbation of ILD. The patient was treated again with methylprednisolone 1,000 mg/day for 3 days, and 10 mg/day of tofacitinib was administered. Chemoprophylaxis with micafungin, acyclovir, and levofloxacin was initiated to prevent the infection.

On Day 10, the patient developed mediastinal emphysema; however, the respiratory condition gradually improved, and the was extubated on Day 14. On Day 17, after removal of the internal jugular vein catheter, the patient's oxygen level suddenly decreased, and he was reintubated. Contrast-enhanced CT showed pulmonary embolism (Fig. 2) with worsened interstitial shadows (Fig. 3) and no venous thrombosis in the lower extremities. A laboratory examination revealed the following findings: D-dimer, 1.18 μg/mL; fibrin degradation products, 2.66 μg/mL; fibrinogen, 76 mg/dL; activated partial thromboplastin time, 46.6 seconds; and prothrombin time-international normalized ratio, 1.57.

Figure 2.

Emergency computed tomography scan of the chest on Day 17. Thrombus in the right pulmonary artery is observed.

Figure 3.

Emergency computed tomography scan of the chest on Day 17. Worsening of interstitial shadows is observed.

On Day 20, 500 mg/day of methylprednisolone for 3 days and rivaroxaban anticoagulant therapy were started. As the patient's respiratory condition improved, the glucocorticoid dose was reduced on Day 21, and the patient was successfully extubated on Day 22. PE was terminated on Day 32. On Day 43, chest CT performed to evaluate the effect of triple therapy with PE, and tofacitinib showed marked improvement in the lung field shadows (Fig. 4). Tofacitinib was discontinued on Day 46 because triple therapy was sufficient to maintain improvement in the interstitial pneumonia. Thereafter, the interstitial pneumonia did not worsen, and the patient was discharged on Day 77 after the fifth dose of IVCY and TAC at 10 mg/day. The prednisolone dose was then reduced to 35 mg/day. On Day 130, mycophenolate mofetil was initiated as a glucocorticoid-sparing agent. One year later, the patient was in remission with TAC 4 mg/day, mycophenolate mofetil 2,500 mg/day, and prednisolone 11 mg/day. The clinical course of the patient in the hospital is shown in Fig. 5.

Figure 4.

High-resolution computed tomography scan of the chest on Day 43. Improvement in lung field shadows is observed.

Figure 5.

The clinical course of the patient. P/F ratio: arterial partial pressure of oxygen/fraction of inspired oxygen, MDA-5: melanoma differentiation-associated gene 5

Discussion

The efficacy of tofacitinib in refractory anti-MDA-5 antibody-positive dermatomyositis with RP-ILD was reported earlier (9,10) and may have been effective in this case. Anti-MDA-5 antibody-positive dermatomyositis with a poor prognosis of RP-ILD is indicated by a ferritin level ≥1,000 ng/mL, ground-glass shadows in the lung field, and poor oxygenation (2,7,10), all of which were noted in this case; the prognosis was thus considered poor. Mechanical ventilation is necessary for effective respiratory management in such cases. Although PE with triple therapy was started earlier, the patient was refractory to the treatment; hence, tofacitinib was used. The synergistic effect of tofacitinib and triple therapy may be implicated in the effective treatment of anti-MDA-5 antibody-positive dermatomyositis with RP-ILD, as the patient's respiratory status gradually stabilized over time and extubation was achieved.

However, the patient in this case might have developed pulmonary embolism due to tofacitinib. Tofacitinib has been associated with thrombosis in RA patients (13,14). Recently, a large RCT showed a significant increase in venous thrombosis due to treatment with JAK inhibitors (12). The JAK/signal transduction and activator of transcription (STAT) signaling pathway, the target of JAK inhibitors, phosphorylates tyrosine residues and activates downstream signaling proteins involved in signal transduction to regulate important processes such as immune response, growth, development, and cell death (15). Cytokines produced by the JAK/STAT signaling pathway, such as IL-6 and IL-11, enhance intracellular signaling through platelets and collagen, and are involved in thrombus formation. In contrast, IL-4, IL-10, IL-13, and IL-22 are involved in antithrombotic effects. Thus, cytokine imbalance caused by JAK inhibitors may lead to thrombus formation (16). Adverse events of thrombosis are mainly reported in RA (12,14); however, thrombosis in anti-MDA-5 antibody-positive dermatomyositis with RP-ILD has not been previously reported.

According to the Padua score (17), a risk score for venous thrombosis in hospitalized patients, our patient had thrombotic risks, such as decreased activity, glucocorticoid treatment, and rheumatic disease. In this case, the Padua score was 5 points, and a score of ≥4 is considered to indicate a high risk of venous thrombosis. In this case, tofacitinib might have been involved in thrombus formation along with these risk factors. Indications for anticoagulation therapy might be considered, but close attention to potential side effects, such as anticoagulation alveolar hemorrhaging and idiopathic fibrosis, is required (18,19).

In conclusion, the synergistic effect of tofacitinib with triple therapy may have been responsible for effectively treating anti-MDA-5 antibody-positive dermatomyositis with RP-ILD, since the patient's respiratory status gradually stabilized over time and extubation was achieved successfully. Thrombosis prophylaxis may also be considered when tofacitinib is used. Although tofacitinib is an established drug for the treatment of RA, it has not been indicated for dermatomyositis. Therefore, in this case, the use of tofacitinib as a treatment for dermatomyositis was novel.

The authors state that they have no Conflict of Interest (COI).