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Alveolar hemorrhage after infliximab therapy
Joint Bone Spine 77 (2010) 189–193
Letters to the editor
Alveolar hemorrhage after infliximab therapy Keywords: Spondyloarthropathy TNF antagonists Infliximab Alveolar hemorrhage Ankylosing spondylitis
Infliximab (Remicade® ) is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF␣) that was initially developed for the treatment of rheumatoid arthritis and inflammatory bowel disease [1,2]. The indications of infliximab were subsequently extended to severe active ankylosing spondylitis with failure of conventional therapy [3]. The main pulmonary side effects of infliximab therapy are pyogenic infections and, above all, reactivation of latent tuberculosis [4]. Other reported pulmonary side effects seem exceedingly rare; they include rapidly progressive and occasionally fatal interstitial fibrosis, organizing pneumonia, and eosinophilic pneumonia [5,6]. A case of diffuse alveolar hemorrhage has been reported in a patient receiving infliximab for Crohn’s disease [7]. Here, we report another case in a patient with ankylosing spondylitis.
Case-report This 42-year-old man started experiencing inflammatory neck pain in 2006 and was diagnosed with ankylosing spondylitis based on magnetic resonance imaging findings of inflammation and a positive test for HLA B27. In 2007, he had persistent neck pain and new-onset inflammatory low back with a total BASDAI of 51.3/100, a BASDAI inflammation subscore of 56.6/100, and a BASFI of 44.1/100. Appropriate anti-inflammatory therapy was not effective and TNF␣ antagonist therapy was therefore considered. The chest radiograph done as part of the pretreatment evaluation was normal but the intradermal tuberculin test was positive. Prophylactic treatment with isoniazid and rifampin was started as recommended by the French Healthcare Product Safety Agency (AFSSAPS). Infliximab therapy was started 3 weeks later in combination with a nonsteroidal anti-inflammatory drug (piroxicam). The patient was admitted 3 weeks after the second infliximab infusion for evaluation of bright red hemoptysis. Computed tomography of the chest showed a multifocal alveolointerstitial infiltrate in the lower lobes. The infiltrate was more marked on the left side, where intrabronchial clots were visible (Fig. 1). There were no other parenchymatous or pleural abnormalities such as bronchiectasis, tuberculous cavities, mediastinal lymphadenopathy, or vascular emboli. Fiberoptic bronchoscopy visualized blood in both basal pyramids, in a larger amount on the left side. Examination of
the bronchial aspirates showed no microorganisms or malignant cells. Clotting tests were normal, as well as the platelet count and hemoglobin level. Symptomatic treatment with tranexamic acid and prophylactic antimicrobials was started, and the piroxicam was stopped. The hemoptysis resolved spontaneously. A repeat CT scan 8 days later showed fading of the abnormal pulmonary images. No further infliximab infusions were given, the patient being treated instead with nonsteroidal anti-inflammatory drugs. At last followup 6 months later there was no evidence of a relapse. Many conditions can cause alveolar hemorrhage, including infections (leptospirosis), toxic agents (trimellitic anhydrite, cocaine, and isocyanates), vasculitis (Wegener’s granulomatosis, Churg-Strauss vasculitis, and microscopic polyangiitis), and drugs [8]. We are not aware of previously published cases in patients with ankylosing spondylitis, a condition in which lung involvement is uncommon and manifests as apical fibrolinear shadows that may progress to apical fibrosis [9]. Treatment with anticoagulant or antiplatelet agents is a well-known cause of alveolar hemorrhage. Many other drugs have been implicated, including amiodarone, propylthiouracil, antimicrobials, anticonvulsants, and anticancer agents. Cases of alveolar hemorrhage have also been reported in patients taking immunosuppressants (sirolimus, cyclosporine, azathioprine, methotrexate, or rituximab) or recombinant TNF␣ [10]. In the previously reported case of alveolar hemorrhage during infliximab therapy, the bleeding started 48 hours after the second infusion given to treat Crohn’s disease [7]. Concomitant medications were 6-mercaptopurine and 5-aminosalicylic acid, two medications known to induce severe lung toxicity. Furthermore, the patient had a staphylococcal lung infection. Our patient was also on concomitant medications (piroxicam and tramadol). However, there are no data to suggest that either medication may have been involved. Among nonsteroidal anti-inflammatory drugs, only rofecoxib has been found to contribute to alveolar hemorrhage, and in our patient the reintroduction of piroxicam was not followed by further bleeding. No cases of alveolar hemorrhage have been reported in association with tramadol. Based on semiological and chronological criteria, the causal relation was plausible for infliximab and doubtful for the two concomitant medications. A direct toxic effect of infliximab on the lungs was suggested by the authors of the previously reported case [7]. The clinical presentation of alveolar hemorrhage is fairly characteristic and rapidly suggests the diagnosis. The patient coughs up blood and complains of dyspnea. Imaging studies show images of variable density ranging from a ground glass appearance to diffuse bilateral consolidation as in our patient. The definitive diagnosis depends on fiberoptic bronchoscopy, which shows diffuse distal bleeding with no identifiable lesion. Alveolar hemorrhage may present as occult bleeding responsible for iron deficiency anemia. The diagnosis is made by examination of the bronchoalveolar lavage fluid, whose cell population contains more than 30% of siderophages. The management of alveolar hemorrhage consists in
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
190
Letters to the editor / Joint Bone Spine 77 (2010) 189–193
b
63003 Clermont-Ferrand, France Service de rhumatologie, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France c Service d’anatomopathologie, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France ∗ Corresponding
author. E-mail address: [email protected] (G. Jeannin). 11 October 2009 Available online 19 February 2010 doi:10.1016/j.jbspin.2009.12.007
Reactive arthritis due to Clostridium difficile Keywords:
Fig. 1. First computed tomography scan of the chest: note the multifocal alveolointerstitial infiltrates in the lower lobes predominating on the left side.
treating the cause whenever possible and in administering glucocorticoid therapy. Given the possible existence of occult forms, the rate of alveolar hemorrhage may be underestimated in patients on TNF␣ antagonist therapy. Conflicts of interest
Clostridium difficile Arthritis Diarrhea Pseudomembranous colitis HLA B27
The main organisms associated with reactive arthritis after gastrointestinal tract infections are Salmonella, Shigella, Campylobacter and Yersinia. The Gram-positive bacillus Clostridium difficile is the main cause of nosocomial diarrhea in patients on antimicrobial therapy. We report a new case of reactive arthritis due to C. difficile.
The authors have not declared any conflict of interest. 1. Case report References [1] Maini R, St Clair EW, Breedveld F, et al. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial ATTRACT Study Group. Lancet 1999;354:1932–9. [2] Baert F, D’Haens G, Peeters M, et al. Tumor necrosis factor ␣ antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology 1999;116:22–8. [3] Pham T, Fautrel B, Dernis E, et al. Recommendations of the French Society for Rheumatology regarding TNFalpha antagonist therapy in patients with ankylosing spondylitis or psoriatic arthritis: 2007 update. Joint Bone Spine 2007;74:638–46. [4] Furst DE, Keystone EC, Kirkham B, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases. Ann Rheum Dis 2008;67(Suppl. 3):iii2–25. [5] Ostör A, Chilvers E, Somerville M, et al. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis. J Rheumatol 2006;33: 622–8. [6] Villeneuve E, St-Pierre A, Haraoui B. Interstitial pneumonitis associated with infliximab therapy. J Rheumatol 2006;33:1189–93. [7] Panagi S, Palka W, Korelitz B, et al. Diffuse alveolar hemorrhage after infliximab treatment of Crohn’s disease. Inflamm Bowel Dis 2004;10: 274–7. [8] Ioachimescu O, Stoller J. Diffuse alveolar hemorrhage: diagnosing it and finding the cause. Cleve Clin J Med 2008;75:258–80. [9] Wiedemann HP, Matthay RA. Pulmonary manifestation of the collagen vascular diseases. Clin Chest Med 1989;10:677–722. [10] Site pneumotox: www. pneumotox.com, accessed on.
Gaelle Jeannin a,∗ Sylvain Mathieu b Jean-Louis Kemeny c Denis Caillaud a Martin Soubrier b a Service de pneumologie, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, rue Montalembert,
A 64-year-old woman was admitted for a 48-hour history of febrile monoarthritis of the right knee. One month earlier, she had been successfully treated for a lower respiratory tract infection with an 8-day course of amoxicillin–clavulanic acid. She reported persistent diarrhea since the antimicrobial treatment. At admission, she had a fever of 39 ◦ C with chills. The C-reactive protein level was 96 mg/L and the leukocyte count was 10.1 G/L. Aspiration of the right knee was performed before starting antimicrobial therapy. The fluid contained 8000 leukocytes/mm3 , with no detectable organisms or crystals. The abrupt onset prompted intravenous antimicrobial therapy. Stool cultures were negative for Shigella, Salmonella, Campylobacter and Yersinia but the stool test for C. difficile toxin was positive. Oral metronidazole therapy was started and the intravenous antimicrobials were stopped after 48 hours. Both the diarrhea and the monoarthritis resolved fully without non steroidal anti-inflammatory therapy. The HLA B27 test was positive. Radiographs showed no evidence of sacroiliitis. At re-evaluation 6 months later, there was no evidence of a relapse. The diagnosis was reactive arthritis related to C. difficile. 2. Discussion Reactive arthritis is among the events that can complicate gastrointestinal infections due to Salmonella, Shigella, Yersinia or Campylobacter [1]. C. difficile infection rarely causes reactive arthritis. The first report of reactive arthritis after pseudomembranous colitis was published in 1976 [2]. Since then, 45 cases in
Letters to the editor
Alveolar hemorrhage after infliximab therapy Keywords: Spondyloarthropathy TNF antagonists Infliximab Alveolar hemorrhage Ankylosing spondylitis
Infliximab (Remicade® ) is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF␣) that was initially developed for the treatment of rheumatoid arthritis and inflammatory bowel disease [1,2]. The indications of infliximab were subsequently extended to severe active ankylosing spondylitis with failure of conventional therapy [3]. The main pulmonary side effects of infliximab therapy are pyogenic infections and, above all, reactivation of latent tuberculosis [4]. Other reported pulmonary side effects seem exceedingly rare; they include rapidly progressive and occasionally fatal interstitial fibrosis, organizing pneumonia, and eosinophilic pneumonia [5,6]. A case of diffuse alveolar hemorrhage has been reported in a patient receiving infliximab for Crohn’s disease [7]. Here, we report another case in a patient with ankylosing spondylitis.
Case-report This 42-year-old man started experiencing inflammatory neck pain in 2006 and was diagnosed with ankylosing spondylitis based on magnetic resonance imaging findings of inflammation and a positive test for HLA B27. In 2007, he had persistent neck pain and new-onset inflammatory low back with a total BASDAI of 51.3/100, a BASDAI inflammation subscore of 56.6/100, and a BASFI of 44.1/100. Appropriate anti-inflammatory therapy was not effective and TNF␣ antagonist therapy was therefore considered. The chest radiograph done as part of the pretreatment evaluation was normal but the intradermal tuberculin test was positive. Prophylactic treatment with isoniazid and rifampin was started as recommended by the French Healthcare Product Safety Agency (AFSSAPS). Infliximab therapy was started 3 weeks later in combination with a nonsteroidal anti-inflammatory drug (piroxicam). The patient was admitted 3 weeks after the second infliximab infusion for evaluation of bright red hemoptysis. Computed tomography of the chest showed a multifocal alveolointerstitial infiltrate in the lower lobes. The infiltrate was more marked on the left side, where intrabronchial clots were visible (Fig. 1). There were no other parenchymatous or pleural abnormalities such as bronchiectasis, tuberculous cavities, mediastinal lymphadenopathy, or vascular emboli. Fiberoptic bronchoscopy visualized blood in both basal pyramids, in a larger amount on the left side. Examination of
the bronchial aspirates showed no microorganisms or malignant cells. Clotting tests were normal, as well as the platelet count and hemoglobin level. Symptomatic treatment with tranexamic acid and prophylactic antimicrobials was started, and the piroxicam was stopped. The hemoptysis resolved spontaneously. A repeat CT scan 8 days later showed fading of the abnormal pulmonary images. No further infliximab infusions were given, the patient being treated instead with nonsteroidal anti-inflammatory drugs. At last followup 6 months later there was no evidence of a relapse. Many conditions can cause alveolar hemorrhage, including infections (leptospirosis), toxic agents (trimellitic anhydrite, cocaine, and isocyanates), vasculitis (Wegener’s granulomatosis, Churg-Strauss vasculitis, and microscopic polyangiitis), and drugs [8]. We are not aware of previously published cases in patients with ankylosing spondylitis, a condition in which lung involvement is uncommon and manifests as apical fibrolinear shadows that may progress to apical fibrosis [9]. Treatment with anticoagulant or antiplatelet agents is a well-known cause of alveolar hemorrhage. Many other drugs have been implicated, including amiodarone, propylthiouracil, antimicrobials, anticonvulsants, and anticancer agents. Cases of alveolar hemorrhage have also been reported in patients taking immunosuppressants (sirolimus, cyclosporine, azathioprine, methotrexate, or rituximab) or recombinant TNF␣ [10]. In the previously reported case of alveolar hemorrhage during infliximab therapy, the bleeding started 48 hours after the second infusion given to treat Crohn’s disease [7]. Concomitant medications were 6-mercaptopurine and 5-aminosalicylic acid, two medications known to induce severe lung toxicity. Furthermore, the patient had a staphylococcal lung infection. Our patient was also on concomitant medications (piroxicam and tramadol). However, there are no data to suggest that either medication may have been involved. Among nonsteroidal anti-inflammatory drugs, only rofecoxib has been found to contribute to alveolar hemorrhage, and in our patient the reintroduction of piroxicam was not followed by further bleeding. No cases of alveolar hemorrhage have been reported in association with tramadol. Based on semiological and chronological criteria, the causal relation was plausible for infliximab and doubtful for the two concomitant medications. A direct toxic effect of infliximab on the lungs was suggested by the authors of the previously reported case [7]. The clinical presentation of alveolar hemorrhage is fairly characteristic and rapidly suggests the diagnosis. The patient coughs up blood and complains of dyspnea. Imaging studies show images of variable density ranging from a ground glass appearance to diffuse bilateral consolidation as in our patient. The definitive diagnosis depends on fiberoptic bronchoscopy, which shows diffuse distal bleeding with no identifiable lesion. Alveolar hemorrhage may present as occult bleeding responsible for iron deficiency anemia. The diagnosis is made by examination of the bronchoalveolar lavage fluid, whose cell population contains more than 30% of siderophages. The management of alveolar hemorrhage consists in
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
190
Letters to the editor / Joint Bone Spine 77 (2010) 189–193
b
63003 Clermont-Ferrand, France Service de rhumatologie, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France c Service d’anatomopathologie, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France ∗ Corresponding
author. E-mail address: [email protected] (G. Jeannin). 11 October 2009 Available online 19 February 2010 doi:10.1016/j.jbspin.2009.12.007
Reactive arthritis due to Clostridium difficile Keywords:
Fig. 1. First computed tomography scan of the chest: note the multifocal alveolointerstitial infiltrates in the lower lobes predominating on the left side.
treating the cause whenever possible and in administering glucocorticoid therapy. Given the possible existence of occult forms, the rate of alveolar hemorrhage may be underestimated in patients on TNF␣ antagonist therapy. Conflicts of interest
Clostridium difficile Arthritis Diarrhea Pseudomembranous colitis HLA B27
The main organisms associated with reactive arthritis after gastrointestinal tract infections are Salmonella, Shigella, Campylobacter and Yersinia. The Gram-positive bacillus Clostridium difficile is the main cause of nosocomial diarrhea in patients on antimicrobial therapy. We report a new case of reactive arthritis due to C. difficile.
The authors have not declared any conflict of interest. 1. Case report References [1] Maini R, St Clair EW, Breedveld F, et al. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial ATTRACT Study Group. Lancet 1999;354:1932–9. [2] Baert F, D’Haens G, Peeters M, et al. Tumor necrosis factor ␣ antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology 1999;116:22–8. [3] Pham T, Fautrel B, Dernis E, et al. Recommendations of the French Society for Rheumatology regarding TNFalpha antagonist therapy in patients with ankylosing spondylitis or psoriatic arthritis: 2007 update. Joint Bone Spine 2007;74:638–46. [4] Furst DE, Keystone EC, Kirkham B, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases. Ann Rheum Dis 2008;67(Suppl. 3):iii2–25. [5] Ostör A, Chilvers E, Somerville M, et al. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis. J Rheumatol 2006;33: 622–8. [6] Villeneuve E, St-Pierre A, Haraoui B. Interstitial pneumonitis associated with infliximab therapy. J Rheumatol 2006;33:1189–93. [7] Panagi S, Palka W, Korelitz B, et al. Diffuse alveolar hemorrhage after infliximab treatment of Crohn’s disease. Inflamm Bowel Dis 2004;10: 274–7. [8] Ioachimescu O, Stoller J. Diffuse alveolar hemorrhage: diagnosing it and finding the cause. Cleve Clin J Med 2008;75:258–80. [9] Wiedemann HP, Matthay RA. Pulmonary manifestation of the collagen vascular diseases. Clin Chest Med 1989;10:677–722. [10] Site pneumotox: www. pneumotox.com, accessed on.
Gaelle Jeannin a,∗ Sylvain Mathieu b Jean-Louis Kemeny c Denis Caillaud a Martin Soubrier b a Service de pneumologie, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, rue Montalembert,
A 64-year-old woman was admitted for a 48-hour history of febrile monoarthritis of the right knee. One month earlier, she had been successfully treated for a lower respiratory tract infection with an 8-day course of amoxicillin–clavulanic acid. She reported persistent diarrhea since the antimicrobial treatment. At admission, she had a fever of 39 ◦ C with chills. The C-reactive protein level was 96 mg/L and the leukocyte count was 10.1 G/L. Aspiration of the right knee was performed before starting antimicrobial therapy. The fluid contained 8000 leukocytes/mm3 , with no detectable organisms or crystals. The abrupt onset prompted intravenous antimicrobial therapy. Stool cultures were negative for Shigella, Salmonella, Campylobacter and Yersinia but the stool test for C. difficile toxin was positive. Oral metronidazole therapy was started and the intravenous antimicrobials were stopped after 48 hours. Both the diarrhea and the monoarthritis resolved fully without non steroidal anti-inflammatory therapy. The HLA B27 test was positive. Radiographs showed no evidence of sacroiliitis. At re-evaluation 6 months later, there was no evidence of a relapse. The diagnosis was reactive arthritis related to C. difficile. 2. Discussion Reactive arthritis is among the events that can complicate gastrointestinal infections due to Salmonella, Shigella, Yersinia or Campylobacter [1]. C. difficile infection rarely causes reactive arthritis. The first report of reactive arthritis after pseudomembranous colitis was published in 1976 [2]. Since then, 45 cases in