Tocilizumab Treatment in a Patient of Refractory Anti-EJ Positive ASyS: A Case Report

Abstract

Anti-synthetase syndrome (ASyS) is an autoimmune disease characterized by the presence of autoantibodies to aminoacyl-tRNA synthetases accompanied with various organ involvements, including the lung, joints, and skin. The ASyS-related interstitial lung disease (ILD) can be seen in the vast majority of patients. The extent of lung involvement has a significant impact on patient prognosis; the occurrence of rapid-progressive ILD could prominently increase mortality. The mainstay of treatment is prednisone in combination with conventional synthetic disease-modifying anti-rheumatic drugs or some biologic disease-modifying anti-rheumatic drugs (DMARDs). Tocilizumab (TCZ), a recombinant humanized anti-interleukin (IL)-6 receptor monoclonal antibody, has also been used to treat some systemic autoimmune rheumatic diseases associated with ILD. Although the most recent American College of Rheumatology (ACR) Guideline for the Treatment of Interstitial Lung Disease conditionally recommends against the use of TCZ as a treatment option for people with idiopathic inflammatory myopathy (IIM)-ILD progression despite initial ILD treatment, the treatment effect of TCZ in ASyS patients remains obscure, particularly for refractory cases with anti-non-Jo1 antibodies. This report describes a case of Chinese ASyS patients with anti-EJ-positive antibodies who presented with typical proximal muscle weakness, elevated creatine kinase, and ILD with non-specific interstitial pneumonia (NSIP) pattern, along with typical skin involvement such as mechanic’s hand. The patients were resistant to various treatments, including rituximab (RTX), but benefited from TCZ. In this case, TCZ shows good therapeutic efficacy in a fatal acute exacerbation of ILD with a hyperinflammatory status, resulting in a relative remission of the disease flare and full preservation of lung function with a positive long-term treatment outcome.

Introduction

Anti-synthetase syndrome (ASyS) is an autoimmune condition characterized by the presence of aminoacyl-tRNA-synthetases (ARS) autoantibodies, and an array of presentations including interstitial lung disease (ILD), myositis, fever, and rash. The ASyS-related ILD can be seen in the vast majority of patients, with the highest proportion seen in patients with anti-non-Jo1 antibodies. ¹ The extent of lung involvement has a significant impact on patients’ prognosis; the occurrence of rapid-progressive ILD in the course of disease could increase mortality. The ASyS can be further divided into 2 categories according to the profile of ARS antibodies, ie, anti-Jo1 and anti-non-Jo1, for the latter, such as anti-EJ, PL7, PL12, OJ, KS, HA, and ZO. The treatment for ASyS involves typically glucocorticosteroids in combination with immunosuppressants. ² More targeted agent, rituximab (RTX) for example, has demonstrated its efficacy in anti-Jo1 positive ASyS. ³ However, refractory cases, especially for those anti-non-Jo1 ASyS, pose a big clinical challenge. Here, we present a Chinese patient with refractory anti-EJ positive ASyS who was successfully treated with tocilizumab (TCZ) after failure of several treatments including RTX.

Case Report

A 39-year-old woman presented with intermittent fever, symmetrical proximal muscle weakness, mechanic’s hands, and Raynaud’s phenomenon, who was diagnosed as having anti-EJ positive ASyS for 4 years. Pulmonary high-resolution computed tomography (HRCT) imaging showed a non-specific interstitial pneumonia (NSIP) pattern, accompanied with irregular reticular opacities and traction bronchiectasis. The patient’s pulmonary function test showed a restrictive pattern, with predicted forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) values of 62.4% and 62.5%, respectively. In addition, her predicted diffusing capacity for carbon monoxide (DLCO) was 43.2%. Her peak creatine kinase (CK) level was 1145 (reference <135 U/L).

Initially, her symptoms were controlled with a combination of mycophenolate and intravenous methylprednisolone at a daily dose of 80 mg. However, when prednisone tapered to 20 mg/d, she experienced flare of disease. Other immunosuppressive regimens—such as cyclosporine, methotrexate (MTX), and tofacitinib—were prescribed sequentially, but multiple relapses occurred during glucocorticoid tapering. Finally, RTX was introduced, in combination with MTX and prednisone.

After 6 months, her oral prednisone was 12.5 mg/d, and then the patient experienced another relapse starting with a flu-like symptom. On examination, the patient was febrile with a temperature of 39°C, a pulse rate of 125 bpm, and her oxygenation index dropped to 81, necessitating high-flow oxygen support. Her absolute lymphocyte count was 0.56 × 10⁹/L and her B-cell count was at a trough of 21.9 cells/µL. Her C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) increased to 300 mg/L and 48 mm/h, respectively. Her CK level slightly increased to 193 (reference <135 U/L), accompanied by myalgia. In addition, the level of KL-6 (Krebs von den Lungen-6 antigen) increased from a baseline of 1000 to 2465 U/L, which has been identified as a potential biomarker for determining the severity of ILD. Her ferritin was within the normal range, and her IL-6 was 14.93 pg/mL (reference <5.3 pg/mL). The HRCT revealed diffuse bilateral ground-glass opacities and consolidation. A pulmonary function test could not be performed due to severe respiratory failure.

Metagenomic next-generation sequencing of blood and sputum ruled out infections, including SARS-CoV-2. Given the ongoing acute exacerbation of ILD and hyperinflammatory status, we initiated the treatment with intravenous methylprednisolone at 160 mg/d for 3 days and intravenous TCZ, which was given at a dose of 480 mg, followed by 320 mg 2 weeks later, and then administered at 400 mg (8 mg/kg) every 4 weeks for 9 months (Figure 1A). Nintedanib was also prescribed, and compound sulfamethoxazole was used for the prophylaxis against Pneumocystis jirovecii. The patient’s critical condition stabilized, and her ESR and CRP normalized on the third day of TCZ infusion. Figure 1B illustrates her HRCT before and after the treatment, whereas the pulmonary function gradually recovered to baseline at a predicted FVC of 65.9% and FEV1 of 71.0%. Her oral dose of prednisolone was successfully tapered to 10 mg/d. At her 1-year follow-up, the patient’s overall condition had significantly improved, rendering her to perform routine domestic duties as a house wife.

Figure 1.

(A) The sequence of immunosuppressant administration and process of prednisone reduction. (B) Chest HRCT before and after (i) baseline pulmonary condition; (ii) acute relapse with RP-ILD, HRCT shows bilateral ground-glass opacities, diffuse exudation, and consolidation; (iii) 1 month after relapse with RP-ILD; (iv) 1 year after relapse with RP-ILD, HRCT shows significant improvement in the pulmonary after 1 year of TCZ treatment.

Discussion

Refractory ASyS can be difficult to treat due to its tendency to relapse and poor response to conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Progressive ILD, an important symptom of ASyS, can be highly dangerous and life-threatening. Interleukin (IL)-6 has been suggested to play a pivotal role in the inflammation-fibrosis interface of certain ILD.^4,5 Tocilizumab, an humanized anti-IL-6 receptor monoclonal antibody, has been shown to preserve lung function, slowing decline in FVC in SSc-ILD patients, and improve the prognosis of severe COVID-19 patients. ⁵ According to the latest American College of Rheumatology (ACR) guideline, for people with systemic autoimmune rheumatic disease (SARD)-ILD progression despite first ILD treatment, cyclophosphamide, mycophenolate, RTX, and nintedanib as treatment options were conditionally recommend. However, based on the treatment experience of our center, as in ASyS-ILD patients who are resistant to these aforementioned therapies, TCZ could be as a salvage treatment option to control the hyperinflammatory state and help patient through the critical acute respiratory failure. Our previous report suggested that a subtype of ASyS with hyperinflammatory features, ie, recurrent fever, rapid-progressive ILD, and high inflammatory markers, is prone to be refractory to conventional immunosuppressants. ⁶ On the contrary, as this case demonstrated, such ASyS patients with anti-non-Jo1 serologies may benefit from TCZ treatment. Despite chimeric antigen receptor (CAR) T-cell therapy, which recognize CD19+ B cells, was reported to be potentially effective in refractory forms of ASyS, ⁷ the expensive price and unaccessibility make it quite daunting for patients. As these refractory forms of disease have anti-non-Jo1 serologies, TCZ should be considered.

Conclusion

Anti-synthetase syndrome is a disease characterized by the presence of adaptive immune response against various tRNA synthetases, resulting in a range of clinical manifestations. Currently, there is no universal treatment available that can address all these multifaceted manifestations. However, TCZ has shown potential effectiveness in treating refractory ASyS patients with multiple organ involvement, particularly those with progressive ILD and hyperinflammatory state. This is the first report of the effect of TCZ in refractory ASyS patients with anti-EJ antibody. It provides a new perspective for the treatment of these patients. Further research on a larger scale is expected.