International Journal of Rheumatic Diseases 2014; 17: 214–216
CORRESPONDENCE
Neurosarcoidosis mimicking multiple sclerosis successfully treated with methotrexate and adalimumab Dear Editor, A 54-year-old Hispanic woman presented to a rheumatology clinic with lower back pain and bilateral lower extremity weakness of 6 months duration. The patient’s pain was exacerbated with ambulation and standing for long periods of time. The patient also had headaches and mild confusion. She denied fever, chills, bowel or bladder incontinence, weight loss or eye inflammation. Her past medical and surgical history included migraine headaches, unspecified seizures, cervical spine fusion surgery and breast augmentation. There was a maternal family history of sarcoidosis. Physical examination revealed the patient to be afebrile with stable vital signs. Chest examination was normal. Neurological exam was significant for hyporeflexia and 4/5 strength in the bilateral lower extremities. Magnetic resonance imaging (MRI) of the spine revealed marrow edema and infiltrates in T2, T11, L5 and S1 (Fig. 1), suggesting possible osteomyelitis. The patient was subsequently hospitalized for intravenous antibiotics.
The erythrocyte sedimentation rate was 40 mm/h (normal 0–30 mm/h) and C-reactive protein level was 13.2 mg/dL (normal 0–4.9 mg/dL). Serologic tests were all negative. A lumbar puncture was performed. Cerebrospinal fluid (CSF) was clear with a normal cell count and differentials and was negative for infection or malignancy. The patient subsequently underwent a T11 vertebral body biopsy. Biopsy showed non-caseating granulomas. Culture and acid fast bacilli (AFB) smear were negative. Pulmonary function tests revealed low lung volumes and decreased diffusion capacity suggestive of mild restrictive disease. Computed tomography (CT) scan of the chest showed bilateral ground glass appearance. Bronchoscopy was performed and bronchial alveolar lavage (BAL) revealed pulmonary macrophages with a few mixed inflammatory cells. Lung biopsy was performed and showed no evidence of granulomas. Brain MRI revealed active demyelination (Fig. 2). Angiotensin converting enzyme (ACE) level had been examined in the CSF and was elevated.
Figure 1 Magnetic resonance imaging with gadolinium of the spine revealed marrow edema and infiltrates in L5 and S1.
Figure 2 Brain magnetic resonance imaging revealed active demyelination.
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
The patient was ultimately diagnosed with sarcoidosis with pulmonary and neurological involvement. She was started on prednisone 20 mg orally twice daily and intravenous cyclophosphamide. Her strength improved dramatically after the initiation of steroids. She received three doses of cyclophosphamide (750 mg/m2). There was some improvement of her confusion but she continued to have headaches and weakness. She declined to continue cyclophosphamide because of alopecia. Thus, adalimumab (40 mg subcutaneous very 2 weeks) and methotrexate were started. The patient’s headache completely resolved after just three doses of adalimumab. Her strength and function continued to improve and her steroids were able to be weaned down. The patient continued to do well with marked improvement in spinal mobility and range of motion and adalimumab was able to be discontinued after 12 months total treatment. Sarcoidosis is a multisystem inflammatory disorder of unknown etiology characterized by the formation of non-caseating granulomas. T cells and macrophages are activated at sites of granulomatous inflammation with the release of various chemokines and cytokines, including tumor necrosis factor (TNF)-a.1 The incidence of nervous system involvement in sarcoidosis is about 5%.2 Neurosarcoidosis without signs of systemic disease is rare and may be difficult to diagnose. Only 1% of patients with sarcoidosis have neurosarcoidosis alone.2 Neurosarcoidosis presents in a variety of ways. It may present as spinal cord lesions (extradural, intradural or intramedullary), resulting in abnormal sensation or weakness in one or more limbs. Sarcoidosis of the spinal cord is rare and is usually preceded by a history of systemic sarcoidosis. It may mimic malignancy or an inflammatory demyelinating disease. Thus, spinal cord tumors, lymphoma, infections, multiple sclerosis and other autoimmune disorders must be ruled out.3 The gold standard for diagnosing neurosarcoidosis is a biopsy documenting sterile non-caseating granulomas in the nervous system. In the absence of a positive tissue biopsy, the diagnosis is usually difficult. The most useful diagnostic tests, when no tissue biopsy is available, are a gadolinium enhanced MRI or CSF analysis. Magnetic resonance imaging findings are variable. About 40% of patients with neurosarcoidosis have either leptomeningeal enhancement or multiple white matter lesions that may resemble lesions seen in multiple sclerosis (MS) like in our patient.3 Cerebrospinal fluid Angiotensin converting enzyme levels are even more controversial. The diagnostic accuracy has not
International Journal of Rheumatic Diseases 2014; 17: 214–216
been established in the literature.4 However, despite the insensitivity (24–55%), some clinicians consider the specificity of CSF ACE (94–95%) is high enough to warrant the diagnosis in patients in which neurosarcoidosis is being considered.4 Corticosteroids are considered first-line treatment for neurosarcoidosis. Steroids may slow or reverse the course of the disease, but some patients do not respond. Other immunosuppressive agents (e.g. azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, cyclophosphamide) have emerged as effective agents in corticosteroid-recalcitrant cases but there are no randomized trials defining the optimal treatment for neurosarcoidosis.5 Anti-TNF-a agents are becoming increasingly used in the treatment of neurosarcoidosis. Infliximab is a chimeric monoclonal antibody that neutralizes the biological activity of TNF- a by binding to its soluble and transmembrane forms and inhibiting receptor binding.6 Evidence for its use came from elevated TNF- a levels in lymph nodes and bronchoalveolar lavage of patients with sarcoidosis.7 There are a number of case reports in the literature on the use of infliximab for refractory neurosarcoidosis, sometimes with other immunosuppressive agents. Toth et al. reported such a case of steroid-refractory neurosarcoidosis.8 Within months of starting intravenous infliximab, the patient regained her ability to walk and the MRI identified significant improvement. Our patient experienced a rapid remission with adalimumab and methotrexate therapy. Although there are case reports on the successful use of adalimumab in cutaneous sarcoidosis,9 there is only one case report in the literature describing successful treatment of neurosarcoidosis with adalimumab.10 Adalimumab has practical advantages for out-of-hospital use in ambulatory patients, as it may be self-administered by subcutaneous injection, unlike infliximab which requires intravenous infusion. This case illustrates the difficulty in diagnosing and managing neurosarcoidosis. Most patients require immunosuppressive treatment due to the high rates of recurrence or incomplete response. This patient achieved remission with adalimumab therapy, suggesting a promising therapeutic agent to treat neurosarcoidosis. Clinical trials of TNF- a antagonists for the treatment of neurosarcoidosis are required to further evaluate this approach.
CONFLICTS OF INTEREST Dr. Metyas has received consulting fees from Abbott Pharmaceuticals.
215
Correspondence
Samy METYAS,1Magdy TAWADROUS,2 Karen C. YETER1 and Daniel G. ARKFELD1 1
Department of Medicine–Rheumatology, Keck School of Medicine, University of Southern California, Los Angeles, and 2Rheumatology Research Associate, private practice, Covina, California, USA Correspondence: Dr Daniel Arkfeld, email: [email protected]
REFERENCES 1 Aladesanmi OA (2004) Sarcoidosis: An update for the primary care physician. MedGenMed 6, 7. 2 Burns TM (2003) Neurosarcoidosis. Arch Neurol 60, 1166–8. 3 Joseph FG, Scolding NJ (2007) Sarcoidosis of the nervous system. Pract Neurol 7, 234–44. 4 Khoury J, Wellik KE, Demaerschalk BM et al. (2009) Cerebrospinal fluid angiotensin–converting enzyme for diagnosis of central nervous system sarcoidosis. Neurologist 15, 108–11.
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5 Terushkin V, Stern BJ, Judson MA et al. (2010) Neurosarcoidosis: presentations and management. Neurologist 16, 2–15. 6 Santos E, Shaunak S, Renowden S et al. (2010) Treatment of refractory neurosarcoidosis with Infliximab. J Neurol Neurosurg Psychiatry 81, 241–6. 7 Hunninghake GW, Costabel U, Ando M et al. (1999) ATS/ ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 16, 149–73. 8 Toth C, Morrish W, Coutts S et al. (2007) Dramatic MRI improvement with refractory neurosarcoidosis treated with infliximab. Acta Neurol Scand 116, 259–62. 9 Wanat K, Rosenback M (2012) Case series demonstrating improvement in chronic cutaneous sarcoidosis following treatment with TNF inhibitors. Arch Dermatol 148, 1097–100. 10 Marnane M, Lynch T, Scott J et al. (2009) Steroid-unresponsive neurosarcoidosis successfully treated with adalimumab. J Neurol 256, 139–40.
International Journal of Rheumatic Diseases 2014; 17: 214–216
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CORRESPONDENCE
Neurosarcoidosis mimicking multiple sclerosis successfully treated with methotrexate and adalimumab Dear Editor, A 54-year-old Hispanic woman presented to a rheumatology clinic with lower back pain and bilateral lower extremity weakness of 6 months duration. The patient’s pain was exacerbated with ambulation and standing for long periods of time. The patient also had headaches and mild confusion. She denied fever, chills, bowel or bladder incontinence, weight loss or eye inflammation. Her past medical and surgical history included migraine headaches, unspecified seizures, cervical spine fusion surgery and breast augmentation. There was a maternal family history of sarcoidosis. Physical examination revealed the patient to be afebrile with stable vital signs. Chest examination was normal. Neurological exam was significant for hyporeflexia and 4/5 strength in the bilateral lower extremities. Magnetic resonance imaging (MRI) of the spine revealed marrow edema and infiltrates in T2, T11, L5 and S1 (Fig. 1), suggesting possible osteomyelitis. The patient was subsequently hospitalized for intravenous antibiotics.
The erythrocyte sedimentation rate was 40 mm/h (normal 0–30 mm/h) and C-reactive protein level was 13.2 mg/dL (normal 0–4.9 mg/dL). Serologic tests were all negative. A lumbar puncture was performed. Cerebrospinal fluid (CSF) was clear with a normal cell count and differentials and was negative for infection or malignancy. The patient subsequently underwent a T11 vertebral body biopsy. Biopsy showed non-caseating granulomas. Culture and acid fast bacilli (AFB) smear were negative. Pulmonary function tests revealed low lung volumes and decreased diffusion capacity suggestive of mild restrictive disease. Computed tomography (CT) scan of the chest showed bilateral ground glass appearance. Bronchoscopy was performed and bronchial alveolar lavage (BAL) revealed pulmonary macrophages with a few mixed inflammatory cells. Lung biopsy was performed and showed no evidence of granulomas. Brain MRI revealed active demyelination (Fig. 2). Angiotensin converting enzyme (ACE) level had been examined in the CSF and was elevated.
Figure 1 Magnetic resonance imaging with gadolinium of the spine revealed marrow edema and infiltrates in L5 and S1.
Figure 2 Brain magnetic resonance imaging revealed active demyelination.
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
The patient was ultimately diagnosed with sarcoidosis with pulmonary and neurological involvement. She was started on prednisone 20 mg orally twice daily and intravenous cyclophosphamide. Her strength improved dramatically after the initiation of steroids. She received three doses of cyclophosphamide (750 mg/m2). There was some improvement of her confusion but she continued to have headaches and weakness. She declined to continue cyclophosphamide because of alopecia. Thus, adalimumab (40 mg subcutaneous very 2 weeks) and methotrexate were started. The patient’s headache completely resolved after just three doses of adalimumab. Her strength and function continued to improve and her steroids were able to be weaned down. The patient continued to do well with marked improvement in spinal mobility and range of motion and adalimumab was able to be discontinued after 12 months total treatment. Sarcoidosis is a multisystem inflammatory disorder of unknown etiology characterized by the formation of non-caseating granulomas. T cells and macrophages are activated at sites of granulomatous inflammation with the release of various chemokines and cytokines, including tumor necrosis factor (TNF)-a.1 The incidence of nervous system involvement in sarcoidosis is about 5%.2 Neurosarcoidosis without signs of systemic disease is rare and may be difficult to diagnose. Only 1% of patients with sarcoidosis have neurosarcoidosis alone.2 Neurosarcoidosis presents in a variety of ways. It may present as spinal cord lesions (extradural, intradural or intramedullary), resulting in abnormal sensation or weakness in one or more limbs. Sarcoidosis of the spinal cord is rare and is usually preceded by a history of systemic sarcoidosis. It may mimic malignancy or an inflammatory demyelinating disease. Thus, spinal cord tumors, lymphoma, infections, multiple sclerosis and other autoimmune disorders must be ruled out.3 The gold standard for diagnosing neurosarcoidosis is a biopsy documenting sterile non-caseating granulomas in the nervous system. In the absence of a positive tissue biopsy, the diagnosis is usually difficult. The most useful diagnostic tests, when no tissue biopsy is available, are a gadolinium enhanced MRI or CSF analysis. Magnetic resonance imaging findings are variable. About 40% of patients with neurosarcoidosis have either leptomeningeal enhancement or multiple white matter lesions that may resemble lesions seen in multiple sclerosis (MS) like in our patient.3 Cerebrospinal fluid Angiotensin converting enzyme levels are even more controversial. The diagnostic accuracy has not
International Journal of Rheumatic Diseases 2014; 17: 214–216
been established in the literature.4 However, despite the insensitivity (24–55%), some clinicians consider the specificity of CSF ACE (94–95%) is high enough to warrant the diagnosis in patients in which neurosarcoidosis is being considered.4 Corticosteroids are considered first-line treatment for neurosarcoidosis. Steroids may slow or reverse the course of the disease, but some patients do not respond. Other immunosuppressive agents (e.g. azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, cyclophosphamide) have emerged as effective agents in corticosteroid-recalcitrant cases but there are no randomized trials defining the optimal treatment for neurosarcoidosis.5 Anti-TNF-a agents are becoming increasingly used in the treatment of neurosarcoidosis. Infliximab is a chimeric monoclonal antibody that neutralizes the biological activity of TNF- a by binding to its soluble and transmembrane forms and inhibiting receptor binding.6 Evidence for its use came from elevated TNF- a levels in lymph nodes and bronchoalveolar lavage of patients with sarcoidosis.7 There are a number of case reports in the literature on the use of infliximab for refractory neurosarcoidosis, sometimes with other immunosuppressive agents. Toth et al. reported such a case of steroid-refractory neurosarcoidosis.8 Within months of starting intravenous infliximab, the patient regained her ability to walk and the MRI identified significant improvement. Our patient experienced a rapid remission with adalimumab and methotrexate therapy. Although there are case reports on the successful use of adalimumab in cutaneous sarcoidosis,9 there is only one case report in the literature describing successful treatment of neurosarcoidosis with adalimumab.10 Adalimumab has practical advantages for out-of-hospital use in ambulatory patients, as it may be self-administered by subcutaneous injection, unlike infliximab which requires intravenous infusion. This case illustrates the difficulty in diagnosing and managing neurosarcoidosis. Most patients require immunosuppressive treatment due to the high rates of recurrence or incomplete response. This patient achieved remission with adalimumab therapy, suggesting a promising therapeutic agent to treat neurosarcoidosis. Clinical trials of TNF- a antagonists for the treatment of neurosarcoidosis are required to further evaluate this approach.
CONFLICTS OF INTEREST Dr. Metyas has received consulting fees from Abbott Pharmaceuticals.
215
Correspondence
Samy METYAS,1Magdy TAWADROUS,2 Karen C. YETER1 and Daniel G. ARKFELD1 1
Department of Medicine–Rheumatology, Keck School of Medicine, University of Southern California, Los Angeles, and 2Rheumatology Research Associate, private practice, Covina, California, USA Correspondence: Dr Daniel Arkfeld, email: [email protected]
REFERENCES 1 Aladesanmi OA (2004) Sarcoidosis: An update for the primary care physician. MedGenMed 6, 7. 2 Burns TM (2003) Neurosarcoidosis. Arch Neurol 60, 1166–8. 3 Joseph FG, Scolding NJ (2007) Sarcoidosis of the nervous system. Pract Neurol 7, 234–44. 4 Khoury J, Wellik KE, Demaerschalk BM et al. (2009) Cerebrospinal fluid angiotensin–converting enzyme for diagnosis of central nervous system sarcoidosis. Neurologist 15, 108–11.
216
5 Terushkin V, Stern BJ, Judson MA et al. (2010) Neurosarcoidosis: presentations and management. Neurologist 16, 2–15. 6 Santos E, Shaunak S, Renowden S et al. (2010) Treatment of refractory neurosarcoidosis with Infliximab. J Neurol Neurosurg Psychiatry 81, 241–6. 7 Hunninghake GW, Costabel U, Ando M et al. (1999) ATS/ ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 16, 149–73. 8 Toth C, Morrish W, Coutts S et al. (2007) Dramatic MRI improvement with refractory neurosarcoidosis treated with infliximab. Acta Neurol Scand 116, 259–62. 9 Wanat K, Rosenback M (2012) Case series demonstrating improvement in chronic cutaneous sarcoidosis following treatment with TNF inhibitors. Arch Dermatol 148, 1097–100. 10 Marnane M, Lynch T, Scott J et al. (2009) Steroid-unresponsive neurosarcoidosis successfully treated with adalimumab. J Neurol 256, 139–40.
International Journal of Rheumatic Diseases 2014; 17: 214–216
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
