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Abstract
Background Acute exacerbation of interstitial lung disease (AE-ILD) is a severe complication with a poor prognosis. No clinical trials have supported the use of rituximab in AE-ILD associated with connective tissue disease.
Methods We present a series of four cases in which administration of rituximab was associated with appropriate clinical, radiological and functional progress.
Results The four patients were alive 30 days after discharge following their exacerbation.
Conclusions Given the speed of action, safety and efficacy profile observed for rituximab, we believe that this agent should be further investigated in clinical trials so that it could be included in the daily clinical management of this severe condition.
- Rituximab
- Treatment
- Autoimmune Diseases
- Pulmonary Fibrosis
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Key messages
Acute exacerbation of interstitial lung disease associated with connective tissue disease (AE-ILD-CTD) is a serious complication with a poor short-term prognosis, and management is based on corticosteroids and broad-spectrum antibiotics, without clinical trials to support other options.
Rituximab has been shown to be effective in the treatment of severe or progressive ILD-CTD; however, its role in AE-ILD-CTD has only been evaluated in case reports, with no information on its effect on the entities described in our study.
In our case series, an adequate clinical, radiological and functional response was evidenced after the administration of rituximab in acute exacerbation of interstitial lung disease associated with rheumatoid arthritis, scleroderma, primary Sjögren’s syndrome and antisynthetase syndrome.
The results obtained with rituximab position it as a promising alternative for the treatment of this condition in our clinical practice.
Introduction
Acute exacerbation of interstitial lung disease (AE-ILD) is a serious complication that worsens the prognosis.1 Most studies focus on acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), and the criteria to define AE-IPF have been extended to other interstitial lung diseases (ILDs).1 2 These criteria are as follows: previous or concurrent diagnosis of idiopathic pulmonary fibrosis, worsening of dyspnoea within the previous month, new areas of consolidation and/or bilateral ground-glass opacities in a pattern of usual interstitial pneumonia on a high-resolution CT (HRCT) scan of the chest, and finally exclusion of alternative diagnoses.3 AE-ILD associated with connective tissue disease (AE-ILD-CTD) usually manifests early, mainly with inflammation, in comparison with AE-IPF.1 4 Twelve months after AE-ILD-CTD, mortality is high and survival low, similar to the prognosis for AE-IPF.5 6 Today, management is based on high-dose corticosteroids with or without immunosuppressants and broad-spectrum antibiotics according to expert opinion.5 7 8 Rituximab is a monoclonal antibody that selectively targets the B-lymphocyte CD20 antigen and has been associated with fewer adverse effects than cyclophosphamide when administered as rescue treatment in patients with severe or progressive ILD-CTD.9 In a recent study, induction therapy with rituximab was associated with a greater tendency towards complete remission compared with cyclophosphamide in patients diagnosed with granulomatosis with polyangiitis.10 However, the effect of rituximab on AE-ILD-CTD has only been evaluated in case reports, with no evidence reported for rheumatoid arthritis (RA), antisynthetase syndrome (ASSD) or scleroderma. In the following case series, we describe the effect of rituximab on survival 30 days after AE-ILD-CTD.
Methods
We included four patients diagnosed with ILD associated with RA, scleroderma, primary Sjögren’s syndrome (pSS) and ASSD who suffered an AE-ILD meeting the criteria for AE-IPF. The laboratory work-up included a complete blood count, coagulation testing, arterial blood gas analysis, sputum culture and PCR for respiratory virus detection. HRCT of the chest showed areas of consolidation or ground-glass opacity overlapping with an ILD pattern. Thirty days after discharge, patients were assessed with chest HRCT, spirometry and diffusing capacity of the lung for carbon monoxide. All four patients received 1000 mg of intravenous (IV) rituximab on day 0 and day 14.
Results
Patient 1
A 79-year-old woman diagnosed with RA under treatment with methotrexate was evaluated in the emergency room (ER) due to progressive dyspnoea accompanied only by dry cough. Examination revealed a baseline oxygen saturation (SaO2) of 70%, a breathing rate of 30 per minute and a heart rate of 120 beats per minute (bpm). Auscultation revealed diffuse bilateral crackles. Neither lower extremity oedema nor jugular venous congestion was observed. The laboratory work-up revealed leucocytosis with neutrophilia. Given the suspicion of AE-ILD-CTD, we ordered a chest HRCT scan (figure 1A,B) and the patient was admitted to the intensive care unit. The severity of the patient’s clinical situation led us to initiate treatment with methylprednisolone 250 mg/day IV for 3 days, meropenem and diuretics. As the patient was not a candidate for intubation, high-flow nasal cannula oxygen therapy was started, with a subsequent saturation value of 92%. The patient’s clinical condition worsened 72 hours after admission with an atrial fibrillation and heart failure that responded poorly to treatment. After approval by the multidisciplinary committee, treatment with rituximab was started with a favourable response in ILD and the associated heart condition. Oxygen therapy was reduced until discharge (SaO2, 95%). At the monthly check-up, the patient’s radiological findings and lung function values had improved (figure 1C).
(A) The initial CT scan revealed interlobular and intralobular septal thickening with traction bronchiolectasis and no evident honeycombing (red arrows). Note the basal and peripheral predominance, although with involvement of the ventral portion of the upper lobes (arrowheads), consistent with diffuse interstitial lung disease associated with connective tissue disease. Note also the presence of a large hiatus hernia (star). (B) The high-resolution CT scan performed during the acute exacerbation shows bilateral pleural effusion, bibasilar consolidation and small areas of pseudonodular consolidation in the right apex overlying the abovementioned interstitial pattern. (C) After therapy with rituximab, the volume of the effusion decreased and the areas of consolidation resolved.
Patient 2
A 74-year-old man diagnosed with ILD secondary to ASSD on treatment with mycophenolate attended the ER owing to worsening of dyspnoea and marked weakness in the right leg that prevented him from walking. Physical examination revealed an SaO2 of 89%, a breathing rate of 15 per minute and a heart rate of 90 bpm. The laboratory work-up revealed slightly raised transaminase levels, with no other findings of interest. The chest HRCT findings are shown in figure 2A. Given the diagnosis of AE-ILD-CTD, we started therapy with methylprednisolone 250 mg/day IV for 3 days, rituximab and a broad-spectrum antibiotic. The patient’s clinical picture improved considerably. He did not require oxygen therapy at discharge and walked without difficulty. Assessment at the outpatient clinic 30 days later revealed a relevant improvement in radiological findings (figure 2B). PFT findings remained unchanged.
(A) Chest CT before therapy with rituximab. Note the peripheral peribronchovascular patchy ground-glass areas which were associated with septal thickening (circle) and architectural distortion in the form of subtle traction bronchiectasis (arrows), indicating a fibrosing component. The line of subpleural sparing is highly suggestive of non-specific interstitial pneumonia (arrowhead). (B) Chest CT after therapy with rituximab. Note the clear improvement in ground-glass opacities and septal thickening, with residual areas of reticulation and bronchiectasis secondary to the abovementioned fibrosing component. (C) High-resolution chest CT before therapy with rituximab revealed an interstitial pattern consisting of reticulation with ground-glass opacities (star) associated with varicose traction bronchiectasis (arrowheads), mainly affecting the subpleural and basilar areas and suggestive of fibrotic non-specific interstitial pneumonia. Note also the bibasilar consolidations (arrows) and the presence of oesophageal dilatation in the context of scleroderma (circle). (D) The areas of consolidation resolved with rituximab, with only the basilar interstitial pattern remaining.
Patient 3
A 60-year-old woman diagnosed with scleroderma undergoing treatment with mycophenolate attended the ER with a 7-day history of productive cough with greenish sputum and dyspnoea on moderate exertion. Physical examination revealed an SaO2 of 93%, a respiratory rate of 18 per minute, a heart rate of 80 bpm and bibasilar crackles. The laboratory work-up revealed leucocytosis with neutrophilia and a C reactive protein value of 10.50 mg/dL. The chest HRCT findings are shown in figure 2C. Based on the suspicion of respiratory infection, we started treatment with a broad-spectrum antibiotic. The expectoration resolved, although dyspnoea persisted despite treatment. Subsequent ultrasound evaluation by the cardiology department revealed no signs of pulmonary hypertension or structural heart disease. Suspicion of AE-ILD-CTD secondary to respiratory infection led us to add rituximab followed by resolution of respiratory symptoms. The radiological findings at 1 month were favourable, as were the PFT values (figure 2D).
Patient 4
A 56-year-old woman under assessment for possible pSS reported dry cough and dyspnoea on moderate exertion that had first appeared some weeks earlier. The laboratory work-up (with assessment of autoimmunity) revealed normal findings, as did PFT. The chest HRCT findings are shown in figure 3A. Given the non-specific radiological pattern, we performed transbronchial cryobiopsy, which led to iatrogenic complete right pneumothorax requiring a chest drain. After more than 72 hours, lung re-expansion was incomplete and the patient continued to require supplementary oxygen. Therefore, a new chest HRCT confirmed the suspicion of procedure-induced AE-ILD-CTD and the patient was prescribed methylprednisolone 250 mg/day IV for 3 days, rituximab and broad-spectrum antibiotic therapy (figure 3B). Pneumothorax and respiratory insufficiency had resolved completely within 7 days. One month after discharge, the patient was diagnosed with pSS, the PFT results were normal and the HRCT scan revealed a significant improvement (figure 3C,D).
(A) Baseline high-resolution CT scan showing a diffuse, heterogeneous pattern consisting of ground-glass areas (circle) and radiolucent areas (star), that is, a mosaic attenuation pattern. (B) After cryobiopsy, we observed pneumothorax (arrows), consolidations and atelectasis caused by compression of the parenchyma and postprocedural haemorrhagic changes (arrowheads), as well as an iatrogenic pneumatocele in the medial segment of the right lower lobe (star). (C) Inspiratory chest CT scan after therapy with rituximab. Note the overall improvement in the patchy ground-glass opacities. However, diffuse mosaic attenuation persisted, eventually requiring an expiratory study to be performed. (D) Expiratory chest CT after therapy with rituximab. Note the persistence of hypodense geographical images corresponding to pulmonary lobules with air trapping (stars), indicating some degree of airway compromise.
Discussion
No clinical trials have been performed on the management of AE-ILD. Treatment of this condition is based on the recommendations established for AE-IPF.8 We observed an appropriate clinical, radiological and functional response after administration of rituximab in AE-ILD-CTD in different conditions. In our study, rituximab was effective both at the onset of a severe condition and as rescue therapy after the failure of other agents. It was also effective in the control of AE-ILD secondary to transbronchial cryobiopsy and may have had a positive impact on pulmonary re-expansion in persistent air leak pneumothorax. The effect of rituximab on AE-ILD-CTD has only been evaluated in case reports. The drug proved effective in the treatment of sudden-onset ILD in a patient diagnosed with pSS.11 In acute exacerbation of corticosteroid-refractory hypersensitivity pneumonitis and idiopathic lymphoid interstitial pneumonia, rescue therapy with rituximab enabled critically ill patients to be extubated.12 13 In one case series, rituximab proved useful as rescue therapy in patients with corticosteroid-refractory organising pneumonia.14 Finally, combined treatment with plasmapheresis, rituximab and IV immunoglobulin was associated with a rapid reduction in the need for oxygen therapy in patients with AE-IPF.15 Our literature review showed rituximab to be effective in improving or stabilising respiratory function and sometimes the radiological pattern in ILD-CTD.9 However, we were unable to identify studies that evaluated the effect of rituximab in AE-ILD associated with ASSD, scleroderma and RA. In our case series, we observed a positive effect on the survival of patients with AE-ILD-CTD. All four patients were alive 30 days after the acute exacerbation, with markedly improved radiological and functional findings. In our experience, rituximab acts rapidly, especially in critically ill patients, and enables long-term remission to be maintained, with fewer adverse events than cyclophosphamide.9 10 Our study is limited by the fact that it is a case series. However, the notable outcomes and safety profile achieved with rituximab in AE-ILD-CTD make this drug an important therapeutic option that warrants evaluation in clinical trials.
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Footnotes
Contributors FLR: writing—original draft preparation, writing—review and editing, project administration, conceptualisation, validation. BP-C: conceptualisation, visualisation, original draft preparation. DG-C, FM-G, JALG-A: conceptualisation, resources. CD-R, MNM-L, ML-B, BR-M, SR-G, YM-H: conceptualisation. IC: conceptualisation, writing—review and editing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.