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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 34-37

Severe Refractory Pulmonary Sarcoidosis: Case Report and a Review of Newer Therapeutic Options


Metro Centre for Respiratory Diseases, Metro Multispecialty Hospital, Noida, Uttar Pradesh, India

Date of Web Publication3-Jan-2018

Correspondence Address:
Rahul K Sharma
Metro Centre for Respiratory Diseases, Metro Multispecialty Hospital, Sector 11, Noida, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jacp.jacp_11_17

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  Abstract 


Patients with sarcoidosis who fail to improve on corticosteroids pose a therapeutic challenge for clinicians, because there is a lack of consensus guidelines to manage these patients with other therapeutic options. Herein, we report one such patient with severe progressive sarcoidosis and review the alternative treatment options in patients with sarcoidosis who progress over corticosteroid therapy.

Keywords: Antimetabolites, biologicals, corticosteroids, immunomodulator therapy, severe sarcoidosis


How to cite this article:
Khera R, Sharma RK, Prajapat D, Talwar D. Severe Refractory Pulmonary Sarcoidosis: Case Report and a Review of Newer Therapeutic Options. J Assoc Chest Physicians 2018;6:34-7

How to cite this URL:
Khera R, Sharma RK, Prajapat D, Talwar D. Severe Refractory Pulmonary Sarcoidosis: Case Report and a Review of Newer Therapeutic Options. J Assoc Chest Physicians [serial online] 2018 [cited 2019 Nov 14];6:34-7. Available from: http://www.jacpjournal.org/text.asp?2018/6/1/34/217313




  Introduction Top


The treatment of sarcoidosis requires a two-step evaluation, that is, whom to treat and how to treat. Indications for starting treatment in patients with sarcoidosis are clear, with corticosteroids being the first line of therapy. No clear consensus exists regarding the use of second-line drugs (antimetabolites) or when to switch to biologicals.[1] With the advent of newer potential targets against various cytokines involved in the immunopathogenesis of sarcoidosis, more options are being explored in clinical trials.[2] However, because what constitutes severe or refractory disease is not clear, considerable confusion exists regarding the appropriate timing to utilise these therapeutic options, which has serious impact on the mortality and morbidity for this disease worldwide.[3] Herein, we present a case with severe sarcoidosis refractory to corticosteroids, review the various therapeutic options available beyond corticosteroids and highlight the need for protocolised guidelines for the early use of these therapeutic alternatives.

Case Summary

A 33-year-old, non-smoker male, with no known co-morbidities, was brought to emergency with progressive breathlessness for the past 3 years, increasing over the last 3 months, along with significant weight loss (10 kg). There was no history of fever or any other illness. On examination, the following were observed: pulse rate − 148/min, blood pressure (BP) − 140/80 mmHg, respiratory rate − 38/min and room air oxygen saturation (SpO2) − 78% with no clubbing or pedal edema. Chest auscultation revealed bilateral inspiratory crackles. Rest of the general and systemic examination was normal. He was put on high-flow oxygen via venturimask (FiO2 60%). Routine blood investigations revealed the following: haemoglobin − 14.5 gm/dl, total leucocyte count − 11,200/cm3 (predominantly neutrophilic), platelet count − 2.5 L/cumm and C-reactive protein − 89 IU/dl. Liver and kidney functions along with echocardiography were within normal limits. Chest X-ray revealed bilateral confluent shadows [[Figure 1]a] with a 2-year-old X-ray film, which was suggestive of bilateral hilar and right paratracheal lymphadenopathy [[Figure 2]a]. Sputum Acid bast bacilli (AFB) stain was negative and GeneXpert assay did not detect Mycobacterium tuberculosis. Sputum pyogenic and fungal cultures showed no growth. Also a negative autoimmune profile [including rheumatoid factor, anti-ccp (cyclic citrullinated peptide), ANA (antinuclear antibody), ENA (Extractable nuclear antigens), ANCA (Anti-neutrophil cytoplasmic antibodies) and myositis profile] ruled out the presence of any autoimmune disease associated with interstitial lung disease. Viral markers (including hepatitis B, C and human immunodeficiency virus, HIV) were negative, and the level of procalcitonin was 0.04 mg. Serum angiotensin converting enzyme levels were 62 IU/L. High-resolution CT thorax showed bilateral symmetrical alveolar opacities, indicating diffuse alveolar damage with interstitial septal thickening and perilymphatic nodules [[Figure 1]c]. He was treated with parenteral antibiotics and methylprednisolone and improved gradually. He was discharged after 7 days on oral prednisolone 60 mg/day with domiciliary home oxygen.
Figure 1: (a) X-ray chest showing bilateral confluent shadows. (b) Two-year-old chest X-ray showing bilateral hilar and right paratracheal lymphadenopathy consistent with sarcoidosis. High-resolution CT thorax showing bilateral symmetrical alveolar opacities, suggestive of diffuse alveolar damage. (c) High-resolution CT thorax showing bilateral symmetrical alveolar opacities, indicating diffuse alveolar damage. (d) Repeat HRCT chest performed after 4 weeks showing improvement in the lung parenchymal lesions

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Figure 2: (a) and (b) Positron Emission Tomography–Computed Tomography (PET–CT) scan showing enlarged lymph nodes with increased Fludeoxyglucose (FDG) uptake in bilateral paratracheal, and subcarinal lymph nodes, multiple inter- and intralobular interstitial thickening with increased FDG uptake and ground glass haze involving parenchyma of both the lungs. (c) PET–CT scan at 16th week (8 weeks after first PET–CT) showing FDG uptake in both the lower lobes (active disease) along with the development of some fibrosis in the lower lobe. (d) High-resolution computed tomography (HRCT) thorax at 18th week showing an increase in fibrosis with the appearance of honeycombing in bilateral lung parenchyma

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Repeat HRCT chest performed after 4 weeks showed improvement in the lung’s parenchymal lesions [[Figure 1]d], and prednisolone dose was tapered to 40 mg/day. However, there was a worsening of his breathlessness and pulmonary infiltrates at 7 weeks requiring readmission and pulse methylprednisolone therapy (1 g/day for 3 days). He was again started on oral prednisolone with azathioprine 100 mg/day, which was stopped due to the development of significant transaminitis.

Considering the high risk associated with fiberoptic bronchoscopy and lymph node/transbronchial lung biopsy, the patient underwent PET–CT scan, which revealed the presence of bilateral lower lobe parenchymal ground glass haze, multiple FDG-avid enlarged mediastinal lymph nodes and multiple small FDG-avid irregular nodules along the fissures and sub-pleural regions in both the lungs (perilymphatic distribution) overall consistent with extensive sarcoidosis [[Figure 2]a and [Figure 2]b]. His lung functions revealed the following: forced vital capacity (FVC) − 0.74 L (16%) and forced expiratory volume in one second (FEV1)–0.7 L (19%). Fine needle aspiration cytology (FNAC) of the right supraclavicular lymph node was performed, which revealed the presence of well-formed non-caseating granuloma. His results of the Mantoux test as well as tuberculosis (TB) Gold test were negative. Video-assisted thoracoscopic surgery (VATS) biopsy was deferred by the thoracic surgeon due to high risk for post-operative complications. In view of the worsening symptoms, 10 mg of methotrexate once a week and oral hydroxychloroquin 200 mg twice daily were added to the regimen. However, the patient continued to worsen over the next 6 weeks requiring an increase in the dosage of steroids and two hospital admissions. Lung transplant was contemplated but donors were not immediately available.

In view of the worsening symptoms, a repeat PET scan was performed at 16 weeks (8 weeks after first PET–CT), which showed still active disease in both the lower lobes along with the development of some fibrosis [[Figure 2]c]. In view of the rapid progression of the disease and non-response to steroids and antimetabolites, the patient was planned for infliximab therapy after documenting viral markers for Epstein-Barr Virus (EBV), Cytomegalovirus (CMV) and Herpes simplex virus (HSV) as negative. Two doses of infliximab were given 2 weeks apart and were tolerated well by the patient. Over the next 2 weeks, the patient felt better clinically though his oxygen requirement did not improve. His repeat HRCT thorax performed in the 18th week showed an increase in fibrosis with the appearance of honeycombing [[Figure 2]d]. The patient’s condition further deteriorated, with development of respiratory failure and requiring mechanical ventilation with high FiO2 settings. Awaiting response from the lung transplant center, extra corporeal membrane oxygenation (ECMO) and a third dose of infliximab were contemplated; however, because of continuous deterioration of his condition, his relatives refused further interventions, and the patient eventually succumbed to the illness.


  Discussion Top


Corticosteroids are the first line of therapy in symptomatic and progressive sarcoidosis. Though effective in the short-term control of symptoms, they have limited role in changing the long-term course of the disease.[4] The use of corticosteroid-sparing agents, for example, methotrexate, azathioprine, leflunomide and mycophenolate mofetil have improved the treatment options available to patients. However, all patients do not benefit from these therapies, and few develop serious adverse effects necessitating the termination of therapy.[5]

Acute, progressive and severe sarcoidosis is not uncommon, and our case highlights the presence of lacunae in the early diagnosis and management of such cases, which eventually become refractory leading to fatality. Because no clear definition of severe sarcoidosis exists, one needs to recognise such patients early to prevent significant morbidity and mortality.[6] There is no biomarker available to distinguish between active and burnt out disease in the lungs. Serum IL-2 receptor level has been reported as a predictor of survival but does not indicate activity.[7] HRCT chest cannot predict residual active disease in fibrotic lesions in the lungs. Fluorodeoxyglucose PET has shown its utility in distinguishing between end-stage irreversible disease and residual activity that can potentially benefit from immunomodulatory therapy.[8]

Our patient had fulminant disease course rapidly progressing to irreversible fibrosis despite the use of corticosteroids and antimetabolites. The need for novel anti-sarcoidosis therapies has been felt for long, and newer biologicals targeting inflammatory cascade have been recently reported with some success.[9] For refractory sarcoidosis not responding to glucocorticoids or antimetabolites, targeted TNF-alpha-inhibitor drugs are the next step in treatment with latest evidence currently in favour of infliximab.[10] In our case, we tried infliximab though it might have been too late, because by then significant pulmonary fibrosis had taken place. Adalimumab as an alternative to infliximab has limited experience in sarcoidosis with equal safety and efficacy and, hence, is recommended in patients intolerant to infliximab therapy.[11] Thalidomide, pentoxifylline, apremilast, and abatacept are non-targeted tumor necrosis factor (TNF)-alpha inhibitory drugs considered third line due to inferior efficacy and side effects.[12],[13]

Levels of IL-12 and IL-23 cytokines have been shown to be elevated in the bronchoalveolar fluid and the skin lesions of sarcoidosis offering scope for further research.[14] Tildrakizumab, an interleukin (IL)-23 major sub-unit blocker, approved for treating psoriasis with promising results in rheumatoid arthritis and ankylosing spondylitis, has shown good results in preliminary experience with sarcoidosis.[15] Other experimental targeted therapies such as golimumab and etanercept, ustekinumab and p38 Mitogen-activated protein (MAP) kinases, however, failed to show effectiveness in sarcoidosis.[16],[17]Lung transplantation in chronic respiratory diseases has shown promising results and has been tried with improved survival in patients with advanced life-threatening pulmonary sarcoidosis.[18] However, limited availability and experience in India precludes its use in the present scenario.


  Conclusion Top


Rising mortality in the severe and refractory cases of sarcoidosis such as in our case strongly supports the need to develop therapies directed at modifying the course of disease. The growing use of newer biological-targeted therapies in other immunogenic diseases, for example, rheumatoid arthritis, Crohn’s disease and psoriasis, provides an opportunity to explore them in refractory sarcoidosis as well. Hence, the need of the hour is not only to introduce second-line drugs early, but also to have more clear guidelines as to what constitutes failure of an individual therapy and when to escalate without wasting much time so that the maximum benefits can be achieved from these agents.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wijsenbeek MS, Culver DA. Treatment of sarcoidosis. Clin Chest Med 2015;36:751-67.  Back to cited text no. 1
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2.
Chiarchiaro J, Chen BB, Gibson KF. New molecular targets for treatment of sarcoidosis. Curr Opin Pulm Med 2016;22:515-21.  Back to cited text no. 2
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Swigris JJ, Olsen AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger D et al. Sarcoidosis related mortality in the United States from1988 to 2007. Am J Respir Crit Care Med 2011;183:1524-30.  Back to cited text no. 3
    
4.
Baughman RP, Lowe EE. Medical therapy of sarcoidosis. Semin Respir Crit Care Med 2014;35:391-406.  Back to cited text no. 4
    
5.
Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: Results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 2000;17:60-6.  Back to cited text no. 5
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Ziegenhagen MW, Benner UK, Zissel G, Zabel P, Schlaak M, Müller-Quernheim J. Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med 1997;156:1586-92.  Back to cited text no. 7
    
8.
Keijsers RG, Verzijlbergen FJ, Oven WJ, van den Bosch JM, Ruven HJ, van Velzen-Blad H et al. 18F-FDG PET, genotype-corrected ACE and sIL2R in newly diagnosed sarcoidosis. Eur J Nucl Med Mol Imaging 2009;36:1131-7.  Back to cited text no. 8
    
9.
Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795.  Back to cited text no. 9
    
10.
James DG, Carstairs LS, Trowell J, Sharma OP. Treatment of sarcoidosis. Report of a controlled therapeutic trial. Lancet 1967;2:526-8.  Back to cited text no. 10
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Crommelin HA, van der Burg LM, Vorselaars AD, Drent M, van Moorsel CH, Rijkers GT et al. Efficacy of adalimumab in sarcoidosis patients who develop intolerance to infliximab. Res Med 2016;115:72-7.  Back to cited text no. 11
    
12.
Park MK, Fontana Jr, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J et al. Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2009;26:121-31.  Back to cited text no. 12
    
13.
Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR, Panaccione R et al. Abatacept for Crohn’s disease and ulcerative colitis. Gastroenterology 2012;143:62-9.e4.  Back to cited text no. 13
    
14.
Utz JP, Limper AH, Kalra S, Specks U, Scott JP, Vuk-Pavlovic Z et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124:177-85.  Back to cited text no. 14
    
15.
Judson MA, Baughman RP, Costabel U, Drent M, Gibson KF, Raghu G et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J 2014;44:1296-307.  Back to cited text no. 15
    
16.
Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 2011;66:144-50.  Back to cited text no. 16
    
17.
Schreiber S, Feagan B, D’Haens G, Colombel JF, Geboes K, Yurcov M et al. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: A randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4:325-34.  Back to cited text no. 17
    
18.
Morgenthau AS, Michael C, Lannuzzi M. Lung transplantation in sarcoidosis. Minerva Pneumol 2008;47:63-72.  Back to cited text no. 18
    


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