Heart & Lung 43 (2014) 84e86
Contents lists available at ScienceDirect
Heart & Lung journal homepage: www.heartandlung.org
Hemidiaphragm paresis and granulomatous pneumonitis associated with adalimumab: A case report Tarek Abdallah, MD *, Mokhtar Abdallah, MD, Chadi Saifan, MD, Dany El Sayegh, MD, Michel Chalhoub, MD, Louis Sasso, MD Staten Island University Hospital, Department of Medicine, Pulmonary and Critical Care Division, 475 Seaview Ave., Staten Island, NY 10305, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 July 2013 Received in revised form 6 October 2013 Accepted 7 October 2013 Available online 16 November 2013
Adalimumab is a fully human monoclonal anti-TNF-alpha antibody. Reported adverse effects have raised a number of safety concerns associated with their prolonged use. A case of granulomatous pneumonitis and hemidiaphragm paresis associated with adalimumab therapy for rheumatoid arthritis is described. In May 2012, a 57 year old male presented with dry cough, dyspnea and orthopnea after 4 months of treatment with adalimumab for rheumatoid arthritis. The patient received adalimumab from November 2011 to February 2012. A right hemidiaphragm elevation was shown on chest radiograph. A right hemidiaphragm paresis was shown on chest fluoroscopy. Bilateral lower lobe interstitial disease was shown on the chest HRCT scan. Open lung biopsy of the right lower lobe showed subacute granulomatous pneumonitis. In July 2013, the patient’s respiratory symptoms and the previous restrictive pattern on PFTs resolved. In a same patient, a rare association of hemidiaphragm paresis and granulomatous pneumonitis with adalimumab treatment is herein reported. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Pulmonary Interstitial lung disease Pharmacology (pulmonary)
Introduction Adalimumab is a fully human monoclonal anti tumor necrosis factor alpha antibody used in the treatment of rheumatoid arthritis. Reported adverse effects have raised a number of safety concerns. Adalimumab induced granulomatous pneumonitis has been reported.1 Phrenic neuropathy and diaphragm paralysis have been associated with adalimumab treatment.2 We report a 57 year old male with inactive Crohn’s disease for 6 years who presented in May 2012 with a worsening dry cough, dyspnea and orthopnea for 2 months. In November 2011, he was diagnosed with rheumatoid arthritis and was started on adalimumab. He discontinued adalimumab in February 2012 after the onset of his respiratory symptoms and no other therapy was started for rheumatoid arthritis. Chest radiograph showed an elevation of the right hemidiaphragm, a finding that was absent in 2008. Chest fluoroscopy showed right hemidiaphragm paresis. There was a worsening restrictive pattern on PFTs that fully resolved a year after discontinuing adalimumab. The open lung biopsy revealed subacute nonnecrotizing granulomatous pneumonitis. It is challenging to firmly prove the causal role of adalimumab, however the patient clinical course, the findings on PFTs, the findings on lung biopsy and the radiologic abnormalities, led us to believe that our patient symptoms were * Corresponding author. Tel.: þ1 347 703 6169. E-mail address: [email protected] (T. Abdallah). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2013.10.010
related to a unique combination of two rare adverse effects associated with adalimumab treatment; hemidiaphragm paresis and granulomatous pneumonitis. Case presentation In May 2012, a 57 year old male, non-smoker, presented to the pulmonary clinic with worsening dyspnea, orthopnea, dry cough and intermittent wheezing that started in February 2012. After an extensive rheumatological work up in November 2011, he received a diagnosis of rheumatoid arthritis which was treated with adalimumab subcutaneous injection 40 mg once a week. The patient attributed his respiratory symptoms to adalimumab and he discontinued the medication after receiving approximately adalimumab therapy for 4 months. His rheumatoid arthritis remained in remission. He was diagnosed in 2001 with Crohn’s disease that has been inactive since he underwent a partial ileocolic resection in 2006. He had systemic hypertension since 2009 that was controlled with quinapril. His past medical history and past surgical history were otherwise nonrelevant. He did not have a family history of lung disease or rheumatological disorder. He did not have a significant history of environmental or occupational exposure. His vital signs on physical exam were normal. His oxygen saturation on room air was normal. The auscultation and percussive findings were normal. His CBC and CMP were normal. A chest radiograph showed an elevated right hemidiaphragm. This finding was absent
T. Abdallah et al. / Heart & Lung 43 (2014) 84e86
85
Table 1 Serial Pulmonary function tests. Pulmonary function analysis
FVC (L) FEV1 (L) FEV1/FVC (%) TLC (L) DLCO, mL/mm Hg/min
Ref
3.66 2.71 74 5.03 22.1
Pre Meas
Pre% Ref
Pre Meas
Pre% Ref
Pre Meas
Pre% Ref
May 2012a
May 2012a
Sept 2012b
Sept 2012b
July 2013c
July 2013c
2.5 2.06 83 4.34 13.9
68 76
2.06 1.73 84 3.52 11.8
56 64
3.01 2.36 78 5.14 14.1
86 88
86 68
70 54
103 68
A mild response to bronchodilator was present only in July 2013. a Patient received adalimumab from November 2011 till February 2012, in May 2012 he presented to the pulmonary clinic. b In September 2012, after 2 months of therapy with prednisone, a worsening restriction was shown. c In July 2013, PFT’s were normal.
on the chest radiograph performed in 2008. PFTs showed mild restrictive pattern (Table 1). Pulmonary involvement in Crohn’s disease was suspected. The patient was treated with inhaled albuterol and inhaled budesonide. Two weeks later he returned to the clinic and did not report any improvement. Inhaled tiotropium was added, and a short course of prednisone was prescribed. In July 2012, he presented to the emergency department, complaining of severe dyspnea, orthopnea and wheezing. His oxygen saturation was 94% on room air. He had mild expiratory wheezing at lung bases. His blood work was normal. His chest radiograph showed a persistent right hemidiaphragm elevation, and no other abnormal findings. A conventional CT scan of the chest did not reveal interstitial lung disease. He did not have a thromboembolic lung disease. The patient was treated for possible exacerbation of a pulmonary involvement in Crohn’s disease. He received intravenous methylprednisolone for 3 days; he had a poor response, and he was discharged on inhaled albuterol, inhaled salmeterol/fluticasone, inhaled tiotropium and nebulized budesonide. He was also discharged on a maintenance dose of prednisone 60 mg daily. In August 2012, the patient remained symptomatic. The same treatment was continued. In September 2012, he presented to the pulmonary clinic with worsening dyspnea, orthopnea, and dry cough. His oxygen saturation was 95% on room air. His physical exam was normal. Chest radiograph showed a persistent right hemidiaphragm elevation. The repeat PFTs showed a significant worsening of his restrictive pattern (Table 1). An HRCT scan of the chest revealed bilateral lower lobe non-specific interstitial disease
Fig. 2. Right lower lobe biopsy showed subacute granulomatous pneumonitis.
(Fig. 1). In light of the worsening restrictive pattern on PFTs, the radiological findings and the lack of clinical improvement while receiving prednisone, the patient was referred for open lung biopsy. A slow taper of prednisone was continued. In October 2012, prior to open lung biopsy, the cardiothoracic surgeon investigated the overlooked right hemidiaphragm elevation. The chest fluoroscopy showed a right hemidiapghragm paresis. The open lung biopsy revealed subacute nonnecrotizing granulomatous pneumonitis with variable airspace organization compatible with pulmonary involvement in Crohn’s disease or idiosyncratic drug reaction (Fig. 2). The patient was discharged on the same inhaled regimen. It was complicated to distinguish in October 2012 if the biopsy findings were a pulmonary manifestation of his Crohn’s disease or related to adalimumab. During his follow up visits in January and February 2013, the patient did not report a significant improvement. The same treatment was continued. In July 2013, the patient presented for a follow up appointment at the pulmonary clinic, his respiratory symptoms resolved after a gradual amelioration that started in March 2013. His physical exam was normal. The right hemidiaphragm elevation was still present on the chest radiograph. However the PFTs were normal (Table 1). We did not repeat the chest fluoroscopy and the HRCT scan. The patient was continued on inhaled albuterol, tiotropium and salmeterol/fluticasone. Discussion
Fig. 1. Bilateral lower lobe interstitial disease on HRCT scan of the chest.
A potential association between TNF alpha inhibitors and demyelinating diseases has been suspected. In the FDA database review of demyelinating diseases, in 2001, nineteen cases were associated with the use anti TNF alpha inhibitors.3 Affected patients experienced confusion, ataxia, and paresthesia. Neurologic findings included facial nerve palsy, optic neuritis, hemiparesis, transverse myelitis, and GuillaineBarré syndrome.4 The biological neutralization of TNF-alpha has been suspected to induce demyelination.5 One case of phrenic neuropathy and diaphragm paralysis following adalimumab therapy for psoriasis was reported.2 The patient chest radiograph in 2008 did not show a right hemidiaphragm elevation. The only new relevant event since 2008 was the diagnosis of rheumatoid arthritis in November 2011 and the inception of adalimumab therapy. We were unable to find in the literature a causal relationship between rheumatoid arthritis or Crohn’s disease, and phrenic neuropathy or diaphragm myopathy. Although we did not
86
T. Abdallah et al. / Heart & Lung 43 (2014) 84e86
perform phrenic nerve electrodiagnostic or histopathologic studies, we believe that the new right hemidiaghragm elevation and paresis could be the result of a demyelinating right phrenic neuropathy. Granulomatous pneumonitis was associated with adalimumab and other TNF alpha inhibitors.1,6,7 A recent case of acute lung injury associated with adalimumab has also been reported.8 On the other hand, pulmonary involvement in patients with inflammatory bowel disease can occur.9 Hence, it is a challenge to confirm that the findings on lung biopsy are related to adalimumab. We will discuss facts that argue in favor of adalimumab causal role. Pulmonary involvement in Crohn’s disease is rare and patients usually have a concomitant active intestinal disease.10 Adalimumab is one of the first line treatments of intestinal Crohn’s disease.11 In responders who have pulmonary involvement, it is suggested as a treatment for the pulmonary manifestations of Crohn’s disease. If pulmonary involvement was present, we believe that it would be paradoxical and unusual for adalimumab to cause a flare up of the preexisting silent pulmonary disease. It is essential also to point out that our patient with history of intestinal Crohn’s disease since 2001, did not report any prior respiratory symptoms for 11 years except after treatment with adalimumab for 4 months. The temporal relationship between the inception of adalimumab treatment and the onset of symptoms was clear. In literature, the range of onset of respiratory symptoms after initiation of anti-TNF therapy for rheumatoid arthritis was 3 weeks to 51 months, with most occurring within 3 months.12,13 Our patient onset of respiratory symptoms fell in this range. Furthermore, parenchymal lung disease due to inflammatory bowel disease commonly improve with glucocorticoid therapy.14 Paradoxically, our patient treated with prednisone between July and September 2012 presented with worsening respiratory symptoms and clear deterioration of the PFTs that imposed the lung biopsy as a last diagnostic option after we performed the HRCT scan of the chest. This fact supports the causal role of adalimumab. In March 2013, a year after discontinuing adalimumab, the patient noticed a significant clinical improvement and in July 2013 his symptoms completely resolved and the PFTs were normal. The complete resolution of the restrictive pattern is another fact in favor of adalimumab causal role. The right hemidiaphragm elevation persisted on chest radiograph. A repeat chest fluoroscopy and a repeat HRCT scan of the chest can be helpful to document possible improvement of the right hemidiaphragm paresis and the parenchymal lung disease respectively. The patient is currently asymptomatic and those tests were not performed. We believe that within a year, the parenchymal injury resolved and the hemidiaphragm paresis might still be present but is not alone enough to cause the patient respiratory symptoms. It is necessary to rule out another medication engagement and a potential drug interaction. We were unable to find in literature an association between quinapril and granulomatous pneumonitis or diaphragm myopathy. In addition, the patient was on quinapril for 3 years prior to onset of his respiratory symptoms. We were also unable to find a report about interaction between quinapril and adalimumab that can support the suspicion of a drug interaction. It is also important to exclude an infectious etiology of the granulomatous lung disease. However, we did not suspect an infectious
etiology. On presentation, our patient did not report a productive cough, fever, chills or weight loss. In July 2012, based on the normal findings on the chest CT scan, we did not perform a bronchoscopy. In October 2012, tuberculous mycobacteria or fungal infection seemed unlikely because the lung biopsy did not show necrotizing granulomas. Our patient also improved without antimicrobial treatment. We did not perform special stains for mycobacteria, fungi or parasites but we do think infectious etiology must be carefully excluded according to the clinical presentation and patient risk factors. In light of the clear temporal relationship between the onset of respiratory symptoms and the inception of adalimumab treatment, the new right hemidiaphragm elevation and paresis which probably resulted from a demyelinating phrenic neuropathy, the deterioration despite prednisone therapy, the resolution of symptoms and the reversal of restrictive abnormalities on PFTs a year after discontinuing adalimumab, and after a thorough literature review, we attributed the patient findings to adalimumab.
Conclusion In summary, respiratory symptoms in patients receiving adalimumab must be an alarming sign. A pulmonary diagnostic work up must be initiated while weighing risk versus benefit of adalimumab therapy. Further investigation is needed to understand the mechanism of adalimumab adverse effects. We report in a same patient two rare adverse effects associated with adalimumab treatment: hemidiaphragm paresis and granulomatous pneumonitis.
References 1. Reid JD, Bressler B, English J. A case of adalimumab-induced pneumonitis in a 45-year-old man with Crohn’s disease. Can Respir J. 2011;18(5):262e264. 2. Alexopoulou A, Koskinas J, Soultati A, et al. Acute bilateral phrenic neuropathy following treatment with adalimumab. Clin Rheumatol. 2009;28(11):1337e 1340. 3. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during antitumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862e2869. 4. Manganelli S, Rossi M, Tuccori M, Galeazzi M. Guillain-Barre syndrome following adalimumab treatment. Clin Exp Rheumatol. 2012;30(4):592. 5. Magnano MD, Robinson WH, Genovese MC. Demyelination and inhibition of tumor necrosis factor (TNF). Clin Exp Rheumatol. 2004;22(5 suppl 35): S134eS140. 6. Khasnis AA, Calabrese LH. Tumor necrosis factor inhibitors and lung disease: a paradox of efficacy and risk. Semin Arthritis Rheum. 2010;40(2):147e163. 7. Thavarajah K, Wu P, Rhew EJ, Yelandi AK, Kamp DW. Pulmonary complications of tumor necrosis factor-targeted therapy. Respir Med. 2009;103(5):661e669. 8. Kohli R, Namek K. Adalimumab (Humira) induced acute lung injury. Am J Case Rep. 2013;14:173e175. 9. Bachmann O, Langer F, Rademacher J. Pulmonary manifestations of inflammatory bowel disease. Internist (Berl). 2010;51(suppl 1):264e268. 10. Ott C, Scholmerich J. Extraintestinal manifestations and complications in IBD. Nat Rev Gastroenterol Hepatol. 2013;10(10):585e595. 11. Girardin M, Manz M, Manser C, et al. First-line therapies in inflammatory bowel disease. Digestion. 2012;86(suppl 1):6e10. 12. Yousem SA, Dacic S. Pulmonary lymphohistiocytic reactions temporally related to etanercept therapy. Mod Pathol. 2005;18(5):651e655. 13. Hagiwara K, Sato T, Takagi-Kobayashi S, Hasegawa S, Shigihara N, Akiyama O. Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis. J Rheumatol. 2007;34(5):1151e1154. 14. Camus P, Piard F, Ashcroft T, Gal AA, Colby TV. The lung in inflammatory bowel disease. Medicine (Baltimore). 1993;72(3):151e183.
Contents lists available at ScienceDirect
Heart & Lung journal homepage: www.heartandlung.org
Hemidiaphragm paresis and granulomatous pneumonitis associated with adalimumab: A case report Tarek Abdallah, MD *, Mokhtar Abdallah, MD, Chadi Saifan, MD, Dany El Sayegh, MD, Michel Chalhoub, MD, Louis Sasso, MD Staten Island University Hospital, Department of Medicine, Pulmonary and Critical Care Division, 475 Seaview Ave., Staten Island, NY 10305, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 July 2013 Received in revised form 6 October 2013 Accepted 7 October 2013 Available online 16 November 2013
Adalimumab is a fully human monoclonal anti-TNF-alpha antibody. Reported adverse effects have raised a number of safety concerns associated with their prolonged use. A case of granulomatous pneumonitis and hemidiaphragm paresis associated with adalimumab therapy for rheumatoid arthritis is described. In May 2012, a 57 year old male presented with dry cough, dyspnea and orthopnea after 4 months of treatment with adalimumab for rheumatoid arthritis. The patient received adalimumab from November 2011 to February 2012. A right hemidiaphragm elevation was shown on chest radiograph. A right hemidiaphragm paresis was shown on chest fluoroscopy. Bilateral lower lobe interstitial disease was shown on the chest HRCT scan. Open lung biopsy of the right lower lobe showed subacute granulomatous pneumonitis. In July 2013, the patient’s respiratory symptoms and the previous restrictive pattern on PFTs resolved. In a same patient, a rare association of hemidiaphragm paresis and granulomatous pneumonitis with adalimumab treatment is herein reported. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Pulmonary Interstitial lung disease Pharmacology (pulmonary)
Introduction Adalimumab is a fully human monoclonal anti tumor necrosis factor alpha antibody used in the treatment of rheumatoid arthritis. Reported adverse effects have raised a number of safety concerns. Adalimumab induced granulomatous pneumonitis has been reported.1 Phrenic neuropathy and diaphragm paralysis have been associated with adalimumab treatment.2 We report a 57 year old male with inactive Crohn’s disease for 6 years who presented in May 2012 with a worsening dry cough, dyspnea and orthopnea for 2 months. In November 2011, he was diagnosed with rheumatoid arthritis and was started on adalimumab. He discontinued adalimumab in February 2012 after the onset of his respiratory symptoms and no other therapy was started for rheumatoid arthritis. Chest radiograph showed an elevation of the right hemidiaphragm, a finding that was absent in 2008. Chest fluoroscopy showed right hemidiaphragm paresis. There was a worsening restrictive pattern on PFTs that fully resolved a year after discontinuing adalimumab. The open lung biopsy revealed subacute nonnecrotizing granulomatous pneumonitis. It is challenging to firmly prove the causal role of adalimumab, however the patient clinical course, the findings on PFTs, the findings on lung biopsy and the radiologic abnormalities, led us to believe that our patient symptoms were * Corresponding author. Tel.: þ1 347 703 6169. E-mail address: [email protected] (T. Abdallah). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2013.10.010
related to a unique combination of two rare adverse effects associated with adalimumab treatment; hemidiaphragm paresis and granulomatous pneumonitis. Case presentation In May 2012, a 57 year old male, non-smoker, presented to the pulmonary clinic with worsening dyspnea, orthopnea, dry cough and intermittent wheezing that started in February 2012. After an extensive rheumatological work up in November 2011, he received a diagnosis of rheumatoid arthritis which was treated with adalimumab subcutaneous injection 40 mg once a week. The patient attributed his respiratory symptoms to adalimumab and he discontinued the medication after receiving approximately adalimumab therapy for 4 months. His rheumatoid arthritis remained in remission. He was diagnosed in 2001 with Crohn’s disease that has been inactive since he underwent a partial ileocolic resection in 2006. He had systemic hypertension since 2009 that was controlled with quinapril. His past medical history and past surgical history were otherwise nonrelevant. He did not have a family history of lung disease or rheumatological disorder. He did not have a significant history of environmental or occupational exposure. His vital signs on physical exam were normal. His oxygen saturation on room air was normal. The auscultation and percussive findings were normal. His CBC and CMP were normal. A chest radiograph showed an elevated right hemidiaphragm. This finding was absent
T. Abdallah et al. / Heart & Lung 43 (2014) 84e86
85
Table 1 Serial Pulmonary function tests. Pulmonary function analysis
FVC (L) FEV1 (L) FEV1/FVC (%) TLC (L) DLCO, mL/mm Hg/min
Ref
3.66 2.71 74 5.03 22.1
Pre Meas
Pre% Ref
Pre Meas
Pre% Ref
Pre Meas
Pre% Ref
May 2012a
May 2012a
Sept 2012b
Sept 2012b
July 2013c
July 2013c
2.5 2.06 83 4.34 13.9
68 76
2.06 1.73 84 3.52 11.8
56 64
3.01 2.36 78 5.14 14.1
86 88
86 68
70 54
103 68
A mild response to bronchodilator was present only in July 2013. a Patient received adalimumab from November 2011 till February 2012, in May 2012 he presented to the pulmonary clinic. b In September 2012, after 2 months of therapy with prednisone, a worsening restriction was shown. c In July 2013, PFT’s were normal.
on the chest radiograph performed in 2008. PFTs showed mild restrictive pattern (Table 1). Pulmonary involvement in Crohn’s disease was suspected. The patient was treated with inhaled albuterol and inhaled budesonide. Two weeks later he returned to the clinic and did not report any improvement. Inhaled tiotropium was added, and a short course of prednisone was prescribed. In July 2012, he presented to the emergency department, complaining of severe dyspnea, orthopnea and wheezing. His oxygen saturation was 94% on room air. He had mild expiratory wheezing at lung bases. His blood work was normal. His chest radiograph showed a persistent right hemidiaphragm elevation, and no other abnormal findings. A conventional CT scan of the chest did not reveal interstitial lung disease. He did not have a thromboembolic lung disease. The patient was treated for possible exacerbation of a pulmonary involvement in Crohn’s disease. He received intravenous methylprednisolone for 3 days; he had a poor response, and he was discharged on inhaled albuterol, inhaled salmeterol/fluticasone, inhaled tiotropium and nebulized budesonide. He was also discharged on a maintenance dose of prednisone 60 mg daily. In August 2012, the patient remained symptomatic. The same treatment was continued. In September 2012, he presented to the pulmonary clinic with worsening dyspnea, orthopnea, and dry cough. His oxygen saturation was 95% on room air. His physical exam was normal. Chest radiograph showed a persistent right hemidiaphragm elevation. The repeat PFTs showed a significant worsening of his restrictive pattern (Table 1). An HRCT scan of the chest revealed bilateral lower lobe non-specific interstitial disease
Fig. 2. Right lower lobe biopsy showed subacute granulomatous pneumonitis.
(Fig. 1). In light of the worsening restrictive pattern on PFTs, the radiological findings and the lack of clinical improvement while receiving prednisone, the patient was referred for open lung biopsy. A slow taper of prednisone was continued. In October 2012, prior to open lung biopsy, the cardiothoracic surgeon investigated the overlooked right hemidiaphragm elevation. The chest fluoroscopy showed a right hemidiapghragm paresis. The open lung biopsy revealed subacute nonnecrotizing granulomatous pneumonitis with variable airspace organization compatible with pulmonary involvement in Crohn’s disease or idiosyncratic drug reaction (Fig. 2). The patient was discharged on the same inhaled regimen. It was complicated to distinguish in October 2012 if the biopsy findings were a pulmonary manifestation of his Crohn’s disease or related to adalimumab. During his follow up visits in January and February 2013, the patient did not report a significant improvement. The same treatment was continued. In July 2013, the patient presented for a follow up appointment at the pulmonary clinic, his respiratory symptoms resolved after a gradual amelioration that started in March 2013. His physical exam was normal. The right hemidiaphragm elevation was still present on the chest radiograph. However the PFTs were normal (Table 1). We did not repeat the chest fluoroscopy and the HRCT scan. The patient was continued on inhaled albuterol, tiotropium and salmeterol/fluticasone. Discussion
Fig. 1. Bilateral lower lobe interstitial disease on HRCT scan of the chest.
A potential association between TNF alpha inhibitors and demyelinating diseases has been suspected. In the FDA database review of demyelinating diseases, in 2001, nineteen cases were associated with the use anti TNF alpha inhibitors.3 Affected patients experienced confusion, ataxia, and paresthesia. Neurologic findings included facial nerve palsy, optic neuritis, hemiparesis, transverse myelitis, and GuillaineBarré syndrome.4 The biological neutralization of TNF-alpha has been suspected to induce demyelination.5 One case of phrenic neuropathy and diaphragm paralysis following adalimumab therapy for psoriasis was reported.2 The patient chest radiograph in 2008 did not show a right hemidiaphragm elevation. The only new relevant event since 2008 was the diagnosis of rheumatoid arthritis in November 2011 and the inception of adalimumab therapy. We were unable to find in the literature a causal relationship between rheumatoid arthritis or Crohn’s disease, and phrenic neuropathy or diaphragm myopathy. Although we did not
86
T. Abdallah et al. / Heart & Lung 43 (2014) 84e86
perform phrenic nerve electrodiagnostic or histopathologic studies, we believe that the new right hemidiaghragm elevation and paresis could be the result of a demyelinating right phrenic neuropathy. Granulomatous pneumonitis was associated with adalimumab and other TNF alpha inhibitors.1,6,7 A recent case of acute lung injury associated with adalimumab has also been reported.8 On the other hand, pulmonary involvement in patients with inflammatory bowel disease can occur.9 Hence, it is a challenge to confirm that the findings on lung biopsy are related to adalimumab. We will discuss facts that argue in favor of adalimumab causal role. Pulmonary involvement in Crohn’s disease is rare and patients usually have a concomitant active intestinal disease.10 Adalimumab is one of the first line treatments of intestinal Crohn’s disease.11 In responders who have pulmonary involvement, it is suggested as a treatment for the pulmonary manifestations of Crohn’s disease. If pulmonary involvement was present, we believe that it would be paradoxical and unusual for adalimumab to cause a flare up of the preexisting silent pulmonary disease. It is essential also to point out that our patient with history of intestinal Crohn’s disease since 2001, did not report any prior respiratory symptoms for 11 years except after treatment with adalimumab for 4 months. The temporal relationship between the inception of adalimumab treatment and the onset of symptoms was clear. In literature, the range of onset of respiratory symptoms after initiation of anti-TNF therapy for rheumatoid arthritis was 3 weeks to 51 months, with most occurring within 3 months.12,13 Our patient onset of respiratory symptoms fell in this range. Furthermore, parenchymal lung disease due to inflammatory bowel disease commonly improve with glucocorticoid therapy.14 Paradoxically, our patient treated with prednisone between July and September 2012 presented with worsening respiratory symptoms and clear deterioration of the PFTs that imposed the lung biopsy as a last diagnostic option after we performed the HRCT scan of the chest. This fact supports the causal role of adalimumab. In March 2013, a year after discontinuing adalimumab, the patient noticed a significant clinical improvement and in July 2013 his symptoms completely resolved and the PFTs were normal. The complete resolution of the restrictive pattern is another fact in favor of adalimumab causal role. The right hemidiaphragm elevation persisted on chest radiograph. A repeat chest fluoroscopy and a repeat HRCT scan of the chest can be helpful to document possible improvement of the right hemidiaphragm paresis and the parenchymal lung disease respectively. The patient is currently asymptomatic and those tests were not performed. We believe that within a year, the parenchymal injury resolved and the hemidiaphragm paresis might still be present but is not alone enough to cause the patient respiratory symptoms. It is necessary to rule out another medication engagement and a potential drug interaction. We were unable to find in literature an association between quinapril and granulomatous pneumonitis or diaphragm myopathy. In addition, the patient was on quinapril for 3 years prior to onset of his respiratory symptoms. We were also unable to find a report about interaction between quinapril and adalimumab that can support the suspicion of a drug interaction. It is also important to exclude an infectious etiology of the granulomatous lung disease. However, we did not suspect an infectious
etiology. On presentation, our patient did not report a productive cough, fever, chills or weight loss. In July 2012, based on the normal findings on the chest CT scan, we did not perform a bronchoscopy. In October 2012, tuberculous mycobacteria or fungal infection seemed unlikely because the lung biopsy did not show necrotizing granulomas. Our patient also improved without antimicrobial treatment. We did not perform special stains for mycobacteria, fungi or parasites but we do think infectious etiology must be carefully excluded according to the clinical presentation and patient risk factors. In light of the clear temporal relationship between the onset of respiratory symptoms and the inception of adalimumab treatment, the new right hemidiaphragm elevation and paresis which probably resulted from a demyelinating phrenic neuropathy, the deterioration despite prednisone therapy, the resolution of symptoms and the reversal of restrictive abnormalities on PFTs a year after discontinuing adalimumab, and after a thorough literature review, we attributed the patient findings to adalimumab.
Conclusion In summary, respiratory symptoms in patients receiving adalimumab must be an alarming sign. A pulmonary diagnostic work up must be initiated while weighing risk versus benefit of adalimumab therapy. Further investigation is needed to understand the mechanism of adalimumab adverse effects. We report in a same patient two rare adverse effects associated with adalimumab treatment: hemidiaphragm paresis and granulomatous pneumonitis.
References 1. Reid JD, Bressler B, English J. A case of adalimumab-induced pneumonitis in a 45-year-old man with Crohn’s disease. Can Respir J. 2011;18(5):262e264. 2. Alexopoulou A, Koskinas J, Soultati A, et al. Acute bilateral phrenic neuropathy following treatment with adalimumab. Clin Rheumatol. 2009;28(11):1337e 1340. 3. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during antitumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862e2869. 4. Manganelli S, Rossi M, Tuccori M, Galeazzi M. Guillain-Barre syndrome following adalimumab treatment. Clin Exp Rheumatol. 2012;30(4):592. 5. Magnano MD, Robinson WH, Genovese MC. Demyelination and inhibition of tumor necrosis factor (TNF). Clin Exp Rheumatol. 2004;22(5 suppl 35): S134eS140. 6. Khasnis AA, Calabrese LH. Tumor necrosis factor inhibitors and lung disease: a paradox of efficacy and risk. Semin Arthritis Rheum. 2010;40(2):147e163. 7. Thavarajah K, Wu P, Rhew EJ, Yelandi AK, Kamp DW. Pulmonary complications of tumor necrosis factor-targeted therapy. Respir Med. 2009;103(5):661e669. 8. Kohli R, Namek K. Adalimumab (Humira) induced acute lung injury. Am J Case Rep. 2013;14:173e175. 9. Bachmann O, Langer F, Rademacher J. Pulmonary manifestations of inflammatory bowel disease. Internist (Berl). 2010;51(suppl 1):264e268. 10. Ott C, Scholmerich J. Extraintestinal manifestations and complications in IBD. Nat Rev Gastroenterol Hepatol. 2013;10(10):585e595. 11. Girardin M, Manz M, Manser C, et al. First-line therapies in inflammatory bowel disease. Digestion. 2012;86(suppl 1):6e10. 12. Yousem SA, Dacic S. Pulmonary lymphohistiocytic reactions temporally related to etanercept therapy. Mod Pathol. 2005;18(5):651e655. 13. Hagiwara K, Sato T, Takagi-Kobayashi S, Hasegawa S, Shigihara N, Akiyama O. Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis. J Rheumatol. 2007;34(5):1151e1154. 14. Camus P, Piard F, Ashcroft T, Gal AA, Colby TV. The lung in inflammatory bowel disease. Medicine (Baltimore). 1993;72(3):151e183.
