CONCISE REPORTS
Abatacept Therapy in Rheumatoid Arthritis With Interstitial Lung Disease Antonio Mera-Varela, MD, and Eva Pe´rez-Pampı´n, PhD
R
heumatoid arthritis (RA) is associated with a wide variety of pulmonary diseases, including nonspecific interstitial pneumonia, organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, and diffuse alveolar damage.1 Interstitial lung disease (ILD) contributes to morbidity and mortality in RA. High-resolution computed tomography shows that approximately 19% of patients have findings compatible with noninfectious lung disease. Prospective studies of ILD show that, if a common definition was established, the average prevalence would be 37%.2 Given the limits of current knowledge, deciding on biologic therapy in RA patients with preexisting ILD is not easy. Fatal exacerbation of RA-associated ILD or new-onset ILD is a complication of most conventional antiYtumor necrosis factor (TNF) agents, such as infliximab, etanercept, and adalimumab.3 Golimumab,4 certolizumab pegol,5 and tocilizumab6 have also been associated with ILD, and rituximab carries a warning in this sense.7 Only 1 biologic agent, abatacept, has not been associated with ILD. We present our experience with abatacept in 4 patients who developed ILD or whose ILD deteriorated while on antiYTNF-> therapy. They were 3 women and 1 man (aged 72Y75 years) with a mean history of RA of 18 years (range, 16Y21 years). Patient A was diagnosed with symmetric polyarthritis in 1991 (positive rheumatoid factor titer). She had received diseasemodifying antirheumatic drugs (DMARDs), including gold salts, chloroquine, and methotrexate, although her response was poor. Therefore, in 2001, she was prescribed infliximab, which was suspended owing to a reaction after her third infusion. She remained on treatment with leflunomide until 2004, when, as a result of persistent inflammatory activity, treatment was switched to etanercept (standard dose of 50 mg/wk), which she received for 42 months. She developed dry cough followed by dyspnea requiring admission to hospital. Test results showed that she had RA-associated ILD. Lung biopsy revealed usual interstitial pneumonia, and the patient initiated high-dose corticosteroids and cyclophosphamide for 6 months, after which time the acute symptoms resolved, although radiography showed persistence of ILD. The patient continued to take leflunomide, which failed to control the disease. Therefore, in 2008, she initiated therapy with abatacept, which she received for 46 months and continues to receive today. She has had no further episodes of respiratory
From the Department of Rheumatology, Hospital Clinico Universitario, Santiago de Compostela, Spain. Editorial assistance was provided by an agency and was funded by Bristol-Myers Squibb. The authors declare no conflict of interest. Correspondence: Antonio Mera-Varela, PhD, Department of Rheumatology, Hospital Clı´nico Universitario, Travesı´a de Choupana s/n, 15706 Santiago de Compostela, Spain. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 1076-1608/14/2008Y0445 DOI: 10.1097/RHU.0000000000000084
JCR: Journal of Clinical Rheumatology
&
insufficiency, and imaging studies have not revealed progression of the interstitial pattern. Patient B was diagnosed with seropositive RA in 1995, with evidence of ILD at the lung bases. She was treated successively with methotrexate, chloroquine, and leflunomide. Response to treatment was incomplete, and she continued to have marked inflammatory activity; therefore, etanercept was started in 2004. Until then, the pulmonary pattern had remained stable. She continued treatment with etanercept for 27 months, after which time it was suspended owing to onset of dyspnea and cough. Imaging studies revealed marked deterioration of ILD. She was then prescribed high-dose corticosteroids and cyclophosphamide, which she received for 6 months. Her joint symptoms persisted, and, in 2008, she was prescribed abatacept, which she continues to receive today. The results of imaging studies have remained unremarkable since that time. Patient C was diagnosed with seropositive RA in 1990. He had worked as a stonemason and suffered from silicosis. He was treated with gold salts, methotrexate, and chloroquine. In 1999, he was diagnosed with pulmonary tuberculosis and received a complete course of treatment for 1 year. Given the marked joint inflammation, infliximab was started in 2001, although it had to be discontinued after the second dose owing to an infusion reaction. At the same time, he was diagnosed with ILD; biopsy of the lung parenchyma revealed interstitial pneumonia and chronic bronchitis. In 2009, he was prescribed leflunomide, which was suspended owing to peripheral polyneuropathy. The patient was prescribed a 20-month course of abatacept, which he tolerated well, with no deterioration in lung function or radiological findings. The patient died of a cause not related to treatment (suicide). Patient D was diagnosed with seropositive RA in 1992 and was treated with gold salts, chloroquine, and methotrexate. Given the marked joint involvement, treatment was started with infliximab in 2002 and continued for 15 months with a good response. However, this drug was suspended owing to ILD with respiratory insufficiency requiring admission to hospital on several occasions. The patient was prescribed leflunomide, which failed to control RA. This drug was combined with abatacept in 2008, and the disease was well controlled. The patient continued to receive abatacept for 30 months; however, she moved to a different area and was lost to follow-up. In our cases, therapy with abatacept was monitored for a mean of 35 months (range, 20Y46 months), with no remarkable adverse events and no deterioration of respiratory function tests. Fatal exacerbation of RA-associated or new-onset ILD, idiopathic pulmonary fibrosis, and allergic pneumonitis have been described as complications with most conventional antiTNF agents.3 In the cases we report, unacceptable activity of joint disease led to prescription of anti-TNF agents, the only molecules authorized at that time in Spain. Prescription was aimed at improving not only joint damage, but also the systemic manifestations of RA not responding to DMARDs. This approach has evolved over the years, and anti-TNF agents are now prescribed with caution in patients with ILD.
Volume 20, Number 8, December 2014
www.jclinrheum.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
445
Mera-Varela and Pe´rez-Pampı´n
JCR: Journal of Clinical Rheumatology
The choice of the most appropriate biologic agent for specific patient subtypes is increasingly based on the presence of rheumatoid factor, antiYcitrullinated protein antibodies, previous tuberculosis, or susceptibility to frequent infections.8 The effect of abatacept on lung disease is controversial. Whereas basic science suggests a beneficial effect, other studies associate it with infection. Thus, although experimental and clinical observations show that abatacept inhibits lung inflammation9,10 and can play a curative role in patients with underlying chronic obstructive pulmonary disease, it also increases the risk of respiratory complications in form of severe infections with risk of death and is contraindicated in these cases, but there are no descriptions of the appearance of interstitial lung autoimmune disease in the scientific publications.11,12 At present, abatacept is the recommended biologic agent for patients at increased risk of nonpulmonary infection, including tuberculosis,13 and to the best of our knowledge, no cases of exacerbation or new onset of ILD have been reported with this drug. Therefore, we administered abatacept to control disease activity and potentially prevent exacerbation of ILD.
KEY MESSAGE Abatacept enables better control of RA in patients with ILD whose conventional DMARD therapy is unsuccessful. REFERENCES ¨ stor AJK, Chilvers ER, Sommerville MF, et al. Pulmonary 1. O complications of Infliximab therapy patients with rheumatoid arthritis. J Rheumatol. 2006;33:622Y628. 2. Wolfe F, Caplan L, Michaud K. Rheumatoid arthritis treatment and the risk of severe interstitial lung disease. Scand J Rheumatol. 2007;36:172Y178.
446
www.jclinrheum.com
&
Volume 20, Number 8, December 2014
3. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum. 2011;41:256Y264. 4. Hadjinicolau AV, Nisar MK, Bhagat S, et al. Non-infectious pulmonary complications of newer biological agents for rheumatic diseases -a systematic literature review. Rheumatology. 2011;50:2297Y2305. 5. Pearce F, Johnson SR, Courtney P. Interstitial lung disease following certolizumab pegol. Rheumatology (Oxford). 2012;51:578Y580. 6. Koike T, Harigai M, Inokuma S, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011;70:2148Y2151. 7. Wagner SA, Mehta AC, Laber DA. Rituximab-induced interstitial lung disease. Am J Hematol. 2007;82:916Y919. 8. Keyser FD. Choice of biological therapy for patients with rheumatoid arthritis: the infection perspective. Curr Rheumatol Rev. 2011;7:77Y87. 9. Israe¨l-Assayag E, Fournier M, Cormier Y. Blockade of T cell costimulation by CTLA4-Ig inhibits lung inflammation in murine hypersensivity pneumonitis. J Immunol. 1999;163:6794Y6799. 10. Neff K, Stack J, Harney S, et al. The use of abatacept in debilitating cavitating lung disease associated with rheumatoid arthritis, bronchocentric granulomatosis and aspergillosis. Thorax. 2010;65:545Y546. 11. Miller KL, Sawitzke AD, Doane J. Abatacept and serious respiratory infections in patients with previous lung disease. Clin Rheumatol. 2008;27:1569Y1571. 12. Furst DE, Keystone EC, Fleischmann R, et al. Updated consensus statement of biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis. 2011;70(suppl 1):i2Yi36. 13. Buch MH, Vital EM, Emery P. Abatacept in the treatment of rheumatoid arthritis. Arthritis Res Ther. 2008;10 (suppl 1):S5.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Abatacept Therapy in Rheumatoid Arthritis With Interstitial Lung Disease Antonio Mera-Varela, MD, and Eva Pe´rez-Pampı´n, PhD
R
heumatoid arthritis (RA) is associated with a wide variety of pulmonary diseases, including nonspecific interstitial pneumonia, organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, and diffuse alveolar damage.1 Interstitial lung disease (ILD) contributes to morbidity and mortality in RA. High-resolution computed tomography shows that approximately 19% of patients have findings compatible with noninfectious lung disease. Prospective studies of ILD show that, if a common definition was established, the average prevalence would be 37%.2 Given the limits of current knowledge, deciding on biologic therapy in RA patients with preexisting ILD is not easy. Fatal exacerbation of RA-associated ILD or new-onset ILD is a complication of most conventional antiYtumor necrosis factor (TNF) agents, such as infliximab, etanercept, and adalimumab.3 Golimumab,4 certolizumab pegol,5 and tocilizumab6 have also been associated with ILD, and rituximab carries a warning in this sense.7 Only 1 biologic agent, abatacept, has not been associated with ILD. We present our experience with abatacept in 4 patients who developed ILD or whose ILD deteriorated while on antiYTNF-> therapy. They were 3 women and 1 man (aged 72Y75 years) with a mean history of RA of 18 years (range, 16Y21 years). Patient A was diagnosed with symmetric polyarthritis in 1991 (positive rheumatoid factor titer). She had received diseasemodifying antirheumatic drugs (DMARDs), including gold salts, chloroquine, and methotrexate, although her response was poor. Therefore, in 2001, she was prescribed infliximab, which was suspended owing to a reaction after her third infusion. She remained on treatment with leflunomide until 2004, when, as a result of persistent inflammatory activity, treatment was switched to etanercept (standard dose of 50 mg/wk), which she received for 42 months. She developed dry cough followed by dyspnea requiring admission to hospital. Test results showed that she had RA-associated ILD. Lung biopsy revealed usual interstitial pneumonia, and the patient initiated high-dose corticosteroids and cyclophosphamide for 6 months, after which time the acute symptoms resolved, although radiography showed persistence of ILD. The patient continued to take leflunomide, which failed to control the disease. Therefore, in 2008, she initiated therapy with abatacept, which she received for 46 months and continues to receive today. She has had no further episodes of respiratory
From the Department of Rheumatology, Hospital Clinico Universitario, Santiago de Compostela, Spain. Editorial assistance was provided by an agency and was funded by Bristol-Myers Squibb. The authors declare no conflict of interest. Correspondence: Antonio Mera-Varela, PhD, Department of Rheumatology, Hospital Clı´nico Universitario, Travesı´a de Choupana s/n, 15706 Santiago de Compostela, Spain. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 1076-1608/14/2008Y0445 DOI: 10.1097/RHU.0000000000000084
JCR: Journal of Clinical Rheumatology
&
insufficiency, and imaging studies have not revealed progression of the interstitial pattern. Patient B was diagnosed with seropositive RA in 1995, with evidence of ILD at the lung bases. She was treated successively with methotrexate, chloroquine, and leflunomide. Response to treatment was incomplete, and she continued to have marked inflammatory activity; therefore, etanercept was started in 2004. Until then, the pulmonary pattern had remained stable. She continued treatment with etanercept for 27 months, after which time it was suspended owing to onset of dyspnea and cough. Imaging studies revealed marked deterioration of ILD. She was then prescribed high-dose corticosteroids and cyclophosphamide, which she received for 6 months. Her joint symptoms persisted, and, in 2008, she was prescribed abatacept, which she continues to receive today. The results of imaging studies have remained unremarkable since that time. Patient C was diagnosed with seropositive RA in 1990. He had worked as a stonemason and suffered from silicosis. He was treated with gold salts, methotrexate, and chloroquine. In 1999, he was diagnosed with pulmonary tuberculosis and received a complete course of treatment for 1 year. Given the marked joint inflammation, infliximab was started in 2001, although it had to be discontinued after the second dose owing to an infusion reaction. At the same time, he was diagnosed with ILD; biopsy of the lung parenchyma revealed interstitial pneumonia and chronic bronchitis. In 2009, he was prescribed leflunomide, which was suspended owing to peripheral polyneuropathy. The patient was prescribed a 20-month course of abatacept, which he tolerated well, with no deterioration in lung function or radiological findings. The patient died of a cause not related to treatment (suicide). Patient D was diagnosed with seropositive RA in 1992 and was treated with gold salts, chloroquine, and methotrexate. Given the marked joint involvement, treatment was started with infliximab in 2002 and continued for 15 months with a good response. However, this drug was suspended owing to ILD with respiratory insufficiency requiring admission to hospital on several occasions. The patient was prescribed leflunomide, which failed to control RA. This drug was combined with abatacept in 2008, and the disease was well controlled. The patient continued to receive abatacept for 30 months; however, she moved to a different area and was lost to follow-up. In our cases, therapy with abatacept was monitored for a mean of 35 months (range, 20Y46 months), with no remarkable adverse events and no deterioration of respiratory function tests. Fatal exacerbation of RA-associated or new-onset ILD, idiopathic pulmonary fibrosis, and allergic pneumonitis have been described as complications with most conventional antiTNF agents.3 In the cases we report, unacceptable activity of joint disease led to prescription of anti-TNF agents, the only molecules authorized at that time in Spain. Prescription was aimed at improving not only joint damage, but also the systemic manifestations of RA not responding to DMARDs. This approach has evolved over the years, and anti-TNF agents are now prescribed with caution in patients with ILD.
Volume 20, Number 8, December 2014
www.jclinrheum.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
445
Mera-Varela and Pe´rez-Pampı´n
JCR: Journal of Clinical Rheumatology
The choice of the most appropriate biologic agent for specific patient subtypes is increasingly based on the presence of rheumatoid factor, antiYcitrullinated protein antibodies, previous tuberculosis, or susceptibility to frequent infections.8 The effect of abatacept on lung disease is controversial. Whereas basic science suggests a beneficial effect, other studies associate it with infection. Thus, although experimental and clinical observations show that abatacept inhibits lung inflammation9,10 and can play a curative role in patients with underlying chronic obstructive pulmonary disease, it also increases the risk of respiratory complications in form of severe infections with risk of death and is contraindicated in these cases, but there are no descriptions of the appearance of interstitial lung autoimmune disease in the scientific publications.11,12 At present, abatacept is the recommended biologic agent for patients at increased risk of nonpulmonary infection, including tuberculosis,13 and to the best of our knowledge, no cases of exacerbation or new onset of ILD have been reported with this drug. Therefore, we administered abatacept to control disease activity and potentially prevent exacerbation of ILD.
KEY MESSAGE Abatacept enables better control of RA in patients with ILD whose conventional DMARD therapy is unsuccessful. REFERENCES ¨ stor AJK, Chilvers ER, Sommerville MF, et al. Pulmonary 1. O complications of Infliximab therapy patients with rheumatoid arthritis. J Rheumatol. 2006;33:622Y628. 2. Wolfe F, Caplan L, Michaud K. Rheumatoid arthritis treatment and the risk of severe interstitial lung disease. Scand J Rheumatol. 2007;36:172Y178.
446
www.jclinrheum.com
&
Volume 20, Number 8, December 2014
3. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum. 2011;41:256Y264. 4. Hadjinicolau AV, Nisar MK, Bhagat S, et al. Non-infectious pulmonary complications of newer biological agents for rheumatic diseases -a systematic literature review. Rheumatology. 2011;50:2297Y2305. 5. Pearce F, Johnson SR, Courtney P. Interstitial lung disease following certolizumab pegol. Rheumatology (Oxford). 2012;51:578Y580. 6. Koike T, Harigai M, Inokuma S, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011;70:2148Y2151. 7. Wagner SA, Mehta AC, Laber DA. Rituximab-induced interstitial lung disease. Am J Hematol. 2007;82:916Y919. 8. Keyser FD. Choice of biological therapy for patients with rheumatoid arthritis: the infection perspective. Curr Rheumatol Rev. 2011;7:77Y87. 9. Israe¨l-Assayag E, Fournier M, Cormier Y. Blockade of T cell costimulation by CTLA4-Ig inhibits lung inflammation in murine hypersensivity pneumonitis. J Immunol. 1999;163:6794Y6799. 10. Neff K, Stack J, Harney S, et al. The use of abatacept in debilitating cavitating lung disease associated with rheumatoid arthritis, bronchocentric granulomatosis and aspergillosis. Thorax. 2010;65:545Y546. 11. Miller KL, Sawitzke AD, Doane J. Abatacept and serious respiratory infections in patients with previous lung disease. Clin Rheumatol. 2008;27:1569Y1571. 12. Furst DE, Keystone EC, Fleischmann R, et al. Updated consensus statement of biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis. 2011;70(suppl 1):i2Yi36. 13. Buch MH, Vital EM, Emery P. Abatacept in the treatment of rheumatoid arthritis. Arthritis Res Ther. 2008;10 (suppl 1):S5.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
