Journal of Neuroimmunology 278 (2015) 108–111
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Dermatomyositis as a presentation of neuromyelitis optica spectrum disorder David Delman a, Xianming Peng a, Daniel C. Zedek b, Valerie Jewells c, Nizar Chahin a, Silva Markovic-Plese a,d,⁎ a
Department of Neurology, 170 Manning Drive, Physician Office Building, Chapel Hill, NC 27599, USA Department of Dermatology, 414 Mary Ellen Jones Building, Chapel Hill, NC 27599, USA Department of Radiology, 101 Manning Drive, Chapel Hill, NC 37514, USA d Department of Microbiology and Immunology, Mary Ellen Jones Building, Chapel Hill, NC 27599, USA b c
a r t i c l e
i n f o
Article history: Received 18 April 2014 Received in revised form 19 July 2014 Accepted 23 July 2014 Available online xxxx Keywords: Neuromyelitis optica Dermatomyositis MDA5 antibody
a b s t r a c t Importance: This is the first report of neuromyelitis optica spectrum disorder (NMOSD) associated with dermatomyositis (DM). Report: A 40 year-old Caucasian female presented with 6 months of worsening fatigue, rash, acute weakness worse in her lower extremities, and urinary retention. She was found to have both NMOSD and antimelanoma differentiation-associated gene (MDA)5 positive DM with interstitial lung disease (ILD). She was treated aggressively and she regained her ability to ambulate. Conclusion: We recommend considering NMOSD in the differential diagnosis of patients with DM and other autoimmune disorders that also present with clinical signs of myelopathy. © 2014 Elsevier B.V. All rights reserved.
1. Introduction NMO is an inflammatory central nervous system disorder that presents with visual loss from optic neuritis (ON) and motor and sensory deficits due to longitudinally extensive transverse myelitis (LETM). It is associated with the presence of antibodies to the aquaporin (AQP)4 water channel (NMO-IgG), whose role in the pathogenesis of the disease is currently being investigated (Lennon et al., 2004). The diagnostic criteria for NMO include the presence of both ON and transverse myelitis, as well as two out of three of the minor criteria: contiguous spinal cord MRI lesion extending over more than three vertebral segments, a brain MRI scan not meeting diagnostic criteria for multiple sclerosis (MS), and NMO-IgG seropositive status (Wingerchuk et al., 2006). NMOSD includes limited forms of NMO that meet some but not all of the diagnostic criteria of NMO, and ON or LETM associated with autoimmune diseases, most frequently systemic lupus erythematosus (SLE), Sjogren's syndrome, or thyroiditis (Pittock and Lennon, 2008). DM is an autoimmune inflammatory myopathy (AIM) characterized by a distinctive skin rash and proximal muscle weakness. Autoantibodies are detected in the sera of most patients with myositis (Hengstman et al., 2002). Anti-MDA5 Ab is one of the most common DM-specific antibodies, detected in a subset of DM patients with acute, ⁎ Corresponding author at: Department of Neurology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Tel.: +1 919 966 3701; fax: +1 919 843 4576. E-mail address: [email protected] (S. Markovic-Plese).
http://dx.doi.org/10.1016/j.jneuroim.2014.07.016 0165-5728/© 2014 Elsevier B.V. All rights reserved.
rapidly progressive ILD (Kang et al., 2010). Several studies have reported that an anti-MDA5 Ab titer correlates with disease activity and predicts disease outcome in patients with DM and rapidly progressive ILD (Sato et al., 2013), where it is considered as an independent mortality risk factor for ILD in patients with DM (Chen et al., 2012). Although 10–40% of patients with NMO have other coexisting autoimmune disorders (Wingerchuk et al., 2007), an association of NMO with AIM has not been reported. This is the first report of a case with AQP4-Ab positive LETM with coexisting DM and ILD.
2. Report of the case A 40 year-old Caucasian female presented with a 6 month history of worsening fatigue, joint pain, rash and acute onset of back pain, severe lower extremity weakness, and urinary retention. The patient's general exam was remarkable for periorbital rash (heliotrope rash) (Fig. 1A), violaceous erythematous patches on the extensor surfaces of the upper extremities (Gottron's patches) (Fig. 1B, C), maculopapular rash on the upper chest (shawl sign), and fraying of multiple cuticles (Samitz's sign). Her initial neurologic examination revealed mild weakness in the proximal upper extremities and severe symmetric lower extremity weakness. She had normal reflexes in her upper extremities, but was areflexic in lower extremities with positive Babinski's sign bilaterally. Sensory examination revealed Th10–11 level with decreased light touch, proprioception, vibration and hyperesthesia below that levels.
D. Delman et al. / Journal of Neuroimmunology 278 (2015) 108–111
109
Fig. 1. Clinical presentation with skin rash suggestive of DM. (A) Periorbital, heliotrope rash. (B) Gottron patches on the extensor surfaces of fingers. (C) Erythematous Gottron patch on right elbow.
A spinal cord MRI revealed LETM with increased FLAIR/T2 signal abnormalities extending from C4 to Th10 level (Fig. 2A), with patchy contrast enhancement (Fig. 2B). Visual evoked potentials were normal. NMO IgG testing was positive for anti-AQP4 Abs by ELISA and confirmed by cell-binding assay, consistent with NMOSD. The patient was also found by EMG to have severe myopathy affecting the proximal lower extremity muscles. A right deltoid muscle biopsy showed atrophy and structural changes of the muscle fibers at the periphery of some fascicles, but no inflammation. It is of note that the patient was treated with two 5-day courses of high dose intravenous methylprednisolone prior to the biopsy. Laboratory studies following IV steroids, including CK, ANA, ENA, and anti-dsDNA, were normal. A skin biopsy of the patient's left hand showed a vacuolar interface dermatitis (Fig. 3A) that was consistent with DM based on the density and localization of plasmacytoid dendritic cells (pDCs) (McNiff and Kaplan, 2008) (Fig. 3B). The myositis panel was positive only for anti-MDA-5 Ab by western blotting. Based on the chest CT scan, the patient was also diagnosed with ILD, which is frequently associated with anti-MDA5 Ab. Both NMO and DM with anti-MDA5 Ab are associated with significant morbidity and mortality. The likelihood of recurrence of NMO disease activity is greater than 90% within 3 years, and 50% of those who remain untreated will require ambulatory assistance or are blind in at least one eye by 5 years (Wingerchuk et al., 2007). While the role of AQP4 antibodies in the complement activation
Fig. 2. Spinal cord MRI reveals LETM. (A) Cervical spine MRI (sagittal T2) with C4 to Th10 level increased signal abnormality consistent with transverse myelitis. (B) Inhomogeneous patchy Gd-contrast enhancement indicating acute inflammatory changes.
and immunoglobulin deposition in perivascular NMO lesions has been proposed (Wingerchuk et al., 2007), several studies have examined the predictive value of AQP seropositive status on the disease course. Seronegative NMO patients were found to have more frequently disease onset with simultaneous myelitis and ON and monophasic disease course (Jarius et al., 2012). Seropositive patients are more frequently women, more often have co-existing autoimmune disorders, and have more extensive spinal cord lesions (Jarius et al., 2012). While Jarius et al. have reported that seropositive patients have more frequent motor relapses and Jiao et al. (2013) found more frequent episodes of ON in seropositive patients, both studies found no difference in relapse rate, disability outcome, or prevalence of malignancy between the two subsets of NMO patients (Jiao et al., 2013). Recent studies have also examined the association between seropositive status in NMO patients and malignancy, since autoimmune response has been associated with the aberrant autoantigen expression in the tumor tissue. Pittock and Lennon (2008) have reported that 5% of NMOSD patients have a history malignancy, all of which are seropositive for AQP-4 Ab. Tissue microarray analyses have revealed AQP-4 activity in all tested cancer types encountered, indicating that AQP-4 may be a relevant tumor antigen. The same study reported that 0.2% of patients screened for paraneoplastic autoantibodies were AQP-4 positive and 93% of them were diagnosed with NMOSD. Thus, it has been proposed that NMO-Ig may be considered as a paraneoplastic marker (Ontaneda and Fox, 2014). DM has been associated with increased risk of malignancy for decades (Levine, 2006). Recent studies have identified DM-associated antibodies, in particular anti-transcription intermediary factor-1γ (anti-TIF-1γ) and nuclear matrix protein (NXP)2 antibodies, that are present in most (83%) of DM patients with cancer (Fiorentino et al., 2013). Interestingly, negative anti-myositis antibody panel, as it is the case in our patient has a negative predictive value for malignancy in DM patients, and anti-MDA5 Ab, which is detected in 10–20% patients with DM is not associated with malignancy (Selva-O'Callaghan et al., 2010). However, DM patients with anti-MDA5 Ab have significantly increased mortality compared to DM without this antibody, with deaths typically associated with rapidly progressive ILD (Chen et al., 2012). Aggressive treatment has been associated with improved outcomes. Rituximab is a monoclonal antibody against CD20, a pan-B cell antigen that in small open-label studies has decreased the relapse rate in patients with NMO (Cree et al., 2005). A recent study that used repeated rituximab treatments, upon reconstitution of CD27+ memory B cells have found that 60% of patients remained relapsefree over 5 years, and disability measures stabilized or improved in 93% of patients (Kim et al., 2013). Rapid ILD in patients who have DM with anti-MDA5 Ab is usually not responsive to glucocorticoids alone (Mimori et al., 2012). A small study of patients with refractory
110
D. Delman et al. / Journal of Neuroimmunology 278 (2015) 108–111
Fig. 3. Skin biopsy is consistent with DM. (A) The skin biopsy demonstrates vacuolar interface dermatitis with occasional necrotic keratinocytes along the dermo-epidermal junction. (B) Immunohistochemistry staining for CD123+ plasmacytoid dendritic cells (pDCs) reveals infiltrating pDCs in the epidermis.
ILD and myositis (either dermatomyositis or polymyositis) who were treated with IV cyclophosphamide (CYC) showed significant improvement in pulmonary function (Yamasaki et al., 2007). Our patient initially received two courses of high-dose IV steroids, plasma exchange, and two infusions of IV rituximab. Additionally, she was treated with two rounds of CYC, which was then continued monthly with daily prednisone. Due to excessive fatigue, she was switched from CYC to azathioprine (AZT) with prednisone. AZT has been used as a second-line immunosuppressive medication for ILD and myositis, often as a maintenance therapy. Upon discharge after one month, the patient ambulated with a walker. On follow-up visits over the ensuing 6 months, her rash has resolved and she has regained full strength. She is exercising again, and is now running 10 miles twice weekly. The patient complains of continued dyspnea, and has to take frequent breaks when running.
that also present with clinical signs of myelopathy. Early treatment of such patients with B-cell depleting therapies, including rituximab, CYC and AZA is recommended to avoid the potentially devastating progression of the disease. We also recommend avoiding the therapeutic use of IFNβ, a first line of treatment for relapsing remitting (RR)MS, which does not have therapeutic efficacy in NMO and may enhance inflammatory skin changes in DM.
3. Discussion
References
We report here for the first time a patient presenting with DM and NMOSD. The patient was diagnosed with two rare, disabling disorders, which raises the question of whether and how these disorders may be related. Both NMO and DM are B cell-mediated autoimmune diseases. Antibodies to AQP4 are now considered part of the diagnostic criteria for NMO. AQP4 is the most common water channel in the CNS and is found in astrocyte foot processes. Anti-AQP4 Abs in NMO are IgG1. MDA5 Ab is a cytoplasmic RNA helicase that belongs to the retinoic acid-inducible gene-I (RIG-I) family, and plays an important role in viral recognition. MDA5 activation upon binding viral dsRNA induces an innate immune response, and in particular Type I interferon (IFNα/β) (Crampton et al., 2012). Increased type I IFN levels induce IgG class switching and are considered to play a significant role in DM, as evidenced by accumulation of pDCs, the main cellular source of type I IFN, in the epidermis of the DM lesions (McNiff and Kaplan, 2008). In addition, and likely in response to the IFN β production, MDA5 expression is increased in the skin lesions in DM (Zahn et al., 2011). It is possible that MDA5 may act there as an autoantigen, inducing the anti-MDA5 Ab production, which may together with type I IFN contribute to the skin inflammatory changes and keratinocyte death. Due to the B cell-mediated pathogenesis of these disorders, we propose that patients with DM and NMO may benefit from B cell-targeting medications. While the efficacy of rituximab in NMO has been previously noted, it may also be beneficial in treatment of DM and ILD. Our patient with DM, ILD and NMOSD was treated aggressively with good results to date. We recommend considering NMOSD in the differential diagnosis of patients with DM and other autoimmune disorders
Chen, F.,Wang, D.,Shu, X.,Nakashima, R.,Wang, G., 2012. Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol. Int. 32, 3909–3915. Crampton, S.P., Deane, J.A., Feigenbaum, L.,Bolland, S., 2012. Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. J. Immunol. 188, 1451–1459. Cree, B.A.,Lamb, S.,Morgan, K.,Chen, A.,Waubant, E.,Genain, C., 2005. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64, 1270–1272. Fiorentino, D.F., Chung, L.S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A.L., Rosen, A., Casciola-Rosen, L., 2013. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1gamma. Arthritis Rheum. 65, 2954–2962. Hengstman, G.J., Brouwer, R., Egberts, W.T., Seelig, H.P., Jongen, P.J., van Venrooij, W.J., Van Engelen, B.G., 2002. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies. J. Neurol. 249, 69–75. Jarius, S., Ruprecht, K., Wildemann, B., Kuempfel, T., Ringelstein, M., Geis, C., Kleiter, I., Kleinschnitz, C., Berthele, A., Brettschneider, J., Hellwig, K., Hemmer, B., Linker, R.A., Lauda, F., Mayer, C.A., Tumani, H., Melms, A., Trebst, C., Stangel, M., Marziniak, M., Hoffmann, F., Schippling, S., Faiss, J.H., Neuhaus, O., Ettrich, B., Zentner, C., Guthke, K., Hofstadt-van Oy, U., Reuss, R., Pellkofer, H., Ziemann, U., Kern, P., Wandinger, K.P., Bergh, F.T., Boettcher, T., Langel, S., Liebetrau, M., Rommer, P.S., Niehaus, S., Munch, C., Winkelmann, A., Zettl, U.U., Metz, I., Veauthier, C., Sieb, J.P., Wilke, C., Hartung, H.P., Aktas, O.,Paul, F., 2012. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J. Neuroinflammation 9, 14. Jiao, Y., Fryer, J.P., Lennon, V.A., Jenkins, S.M., Quek, A.M., Smith, C.Y., McKeon, A., Costanzi, C., Iorio, R., Weinshenker, B.G., Wingerchuk, D.M., Shuster, E.A., Lucchinetti, C.F., Pittock, S.J., 2013. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology 81, 1197–1204. Kang, E.H., Nakashima, R., Mimori, T., Kim, J., Lee, Y.J., Lee, E.B., Wook, Y., 2010. Myositis autoantibodies in Korean patients with inflammatory myositis: anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis. BMC Musculoskelet. Disord. 11, 223. Kim, S.H.,Huh, S.Y.,Lee, S.J.,Joung, A.,Kim, H.J., 2013. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 70, 1110–1117.
Conflict of interest The authors do not have conflict of interest. S. Markovic-Plese received consultant fees from IMD Serono and Genzyme Inc. and research funding from IMD Serono, Genzyme Inc., Novartis and Biogen Idec.
D. Delman et al. / Journal of Neuroimmunology 278 (2015) 108–111 Lennon, V.A., Wingerchuk, D.M., Kryzer, T.J., Pittock, S.J., Luchinetti, C.F., Fujihara, K., Nakashima, I.,Weinshenker, B.G., 2004. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 364, 2106–2112. Levine, S.M., 2006. Cancer and myositis: new insights into an old association. Curr. Opin. Rheumatol. 18, 620–624. McNiff, J.M.,Kaplan, D.H., 2008. Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus. J. Cut. Path. 35, 452–456. Mimori, T., Nakashima, R., Hosono, Y., 2012. Interstitial lung disease in myositis: clinical subsets, biomarkers, and treatment. Curr Rheum Rep. 14, 264–274. Ontaneda, D., Fox, R.J., 2014. Is neuromyelitis optica with advanced age of onset a paraneoplastic disorder? Int. J. Neurosci. 124, 509–511. Pittock, S.J., Lennon, V.A., 2008. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch. Neurol. 65, 629–632. Sato, S., Kuwana, M., Fujita, T., Suzuki, Y., 2013. Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with
111
dermatomyositis and rapidly progressive interstitial lung disease. Mod. Rheumatol. 23, 496–502. Selva-O'Callaghan, A., Trallero-Araguas, E., Grau-Junyent, J.M., Labrador-Horrillo, M., 2010. Malignancy and myositis: novel autoantibodies and new insights. Curr. Opin. Rheumatol. 22, 627–632. Wingerchuk, D.M., Lennon, V.A., Lucchinetti, C.F., Pittock, S.J., Weinshenker, B.G., 2007. The spectrum of neuromyelitis optica. Lancet Neurol. 6, 805–815. Yamasaki, Y., Yamada, H., Yamasaki, M., Ohkubo, M., Azuma, K., Matsuoka, S., Kurihara, Y., Osada, H., Satoh, M., Ozaki, S., 2007. Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis. Rheumatology 46, 124–130. Zahn, S., Barchet, W.,Rehkamper, C., Hornung, T.,Bieber, T.,Tuting, T., Wenzel, J., 2011. Enhanced skin expression of melanoma differentiation-associated gene 5 (MDA5) in dermatomyositis and related autoimmune diseases. J Am Acad Derm. 64, 988–989.
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Dermatomyositis as a presentation of neuromyelitis optica spectrum disorder David Delman a, Xianming Peng a, Daniel C. Zedek b, Valerie Jewells c, Nizar Chahin a, Silva Markovic-Plese a,d,⁎ a
Department of Neurology, 170 Manning Drive, Physician Office Building, Chapel Hill, NC 27599, USA Department of Dermatology, 414 Mary Ellen Jones Building, Chapel Hill, NC 27599, USA Department of Radiology, 101 Manning Drive, Chapel Hill, NC 37514, USA d Department of Microbiology and Immunology, Mary Ellen Jones Building, Chapel Hill, NC 27599, USA b c
a r t i c l e
i n f o
Article history: Received 18 April 2014 Received in revised form 19 July 2014 Accepted 23 July 2014 Available online xxxx Keywords: Neuromyelitis optica Dermatomyositis MDA5 antibody
a b s t r a c t Importance: This is the first report of neuromyelitis optica spectrum disorder (NMOSD) associated with dermatomyositis (DM). Report: A 40 year-old Caucasian female presented with 6 months of worsening fatigue, rash, acute weakness worse in her lower extremities, and urinary retention. She was found to have both NMOSD and antimelanoma differentiation-associated gene (MDA)5 positive DM with interstitial lung disease (ILD). She was treated aggressively and she regained her ability to ambulate. Conclusion: We recommend considering NMOSD in the differential diagnosis of patients with DM and other autoimmune disorders that also present with clinical signs of myelopathy. © 2014 Elsevier B.V. All rights reserved.
1. Introduction NMO is an inflammatory central nervous system disorder that presents with visual loss from optic neuritis (ON) and motor and sensory deficits due to longitudinally extensive transverse myelitis (LETM). It is associated with the presence of antibodies to the aquaporin (AQP)4 water channel (NMO-IgG), whose role in the pathogenesis of the disease is currently being investigated (Lennon et al., 2004). The diagnostic criteria for NMO include the presence of both ON and transverse myelitis, as well as two out of three of the minor criteria: contiguous spinal cord MRI lesion extending over more than three vertebral segments, a brain MRI scan not meeting diagnostic criteria for multiple sclerosis (MS), and NMO-IgG seropositive status (Wingerchuk et al., 2006). NMOSD includes limited forms of NMO that meet some but not all of the diagnostic criteria of NMO, and ON or LETM associated with autoimmune diseases, most frequently systemic lupus erythematosus (SLE), Sjogren's syndrome, or thyroiditis (Pittock and Lennon, 2008). DM is an autoimmune inflammatory myopathy (AIM) characterized by a distinctive skin rash and proximal muscle weakness. Autoantibodies are detected in the sera of most patients with myositis (Hengstman et al., 2002). Anti-MDA5 Ab is one of the most common DM-specific antibodies, detected in a subset of DM patients with acute, ⁎ Corresponding author at: Department of Neurology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Tel.: +1 919 966 3701; fax: +1 919 843 4576. E-mail address: [email protected] (S. Markovic-Plese).
http://dx.doi.org/10.1016/j.jneuroim.2014.07.016 0165-5728/© 2014 Elsevier B.V. All rights reserved.
rapidly progressive ILD (Kang et al., 2010). Several studies have reported that an anti-MDA5 Ab titer correlates with disease activity and predicts disease outcome in patients with DM and rapidly progressive ILD (Sato et al., 2013), where it is considered as an independent mortality risk factor for ILD in patients with DM (Chen et al., 2012). Although 10–40% of patients with NMO have other coexisting autoimmune disorders (Wingerchuk et al., 2007), an association of NMO with AIM has not been reported. This is the first report of a case with AQP4-Ab positive LETM with coexisting DM and ILD.
2. Report of the case A 40 year-old Caucasian female presented with a 6 month history of worsening fatigue, joint pain, rash and acute onset of back pain, severe lower extremity weakness, and urinary retention. The patient's general exam was remarkable for periorbital rash (heliotrope rash) (Fig. 1A), violaceous erythematous patches on the extensor surfaces of the upper extremities (Gottron's patches) (Fig. 1B, C), maculopapular rash on the upper chest (shawl sign), and fraying of multiple cuticles (Samitz's sign). Her initial neurologic examination revealed mild weakness in the proximal upper extremities and severe symmetric lower extremity weakness. She had normal reflexes in her upper extremities, but was areflexic in lower extremities with positive Babinski's sign bilaterally. Sensory examination revealed Th10–11 level with decreased light touch, proprioception, vibration and hyperesthesia below that levels.
D. Delman et al. / Journal of Neuroimmunology 278 (2015) 108–111
109
Fig. 1. Clinical presentation with skin rash suggestive of DM. (A) Periorbital, heliotrope rash. (B) Gottron patches on the extensor surfaces of fingers. (C) Erythematous Gottron patch on right elbow.
A spinal cord MRI revealed LETM with increased FLAIR/T2 signal abnormalities extending from C4 to Th10 level (Fig. 2A), with patchy contrast enhancement (Fig. 2B). Visual evoked potentials were normal. NMO IgG testing was positive for anti-AQP4 Abs by ELISA and confirmed by cell-binding assay, consistent with NMOSD. The patient was also found by EMG to have severe myopathy affecting the proximal lower extremity muscles. A right deltoid muscle biopsy showed atrophy and structural changes of the muscle fibers at the periphery of some fascicles, but no inflammation. It is of note that the patient was treated with two 5-day courses of high dose intravenous methylprednisolone prior to the biopsy. Laboratory studies following IV steroids, including CK, ANA, ENA, and anti-dsDNA, were normal. A skin biopsy of the patient's left hand showed a vacuolar interface dermatitis (Fig. 3A) that was consistent with DM based on the density and localization of plasmacytoid dendritic cells (pDCs) (McNiff and Kaplan, 2008) (Fig. 3B). The myositis panel was positive only for anti-MDA-5 Ab by western blotting. Based on the chest CT scan, the patient was also diagnosed with ILD, which is frequently associated with anti-MDA5 Ab. Both NMO and DM with anti-MDA5 Ab are associated with significant morbidity and mortality. The likelihood of recurrence of NMO disease activity is greater than 90% within 3 years, and 50% of those who remain untreated will require ambulatory assistance or are blind in at least one eye by 5 years (Wingerchuk et al., 2007). While the role of AQP4 antibodies in the complement activation
Fig. 2. Spinal cord MRI reveals LETM. (A) Cervical spine MRI (sagittal T2) with C4 to Th10 level increased signal abnormality consistent with transverse myelitis. (B) Inhomogeneous patchy Gd-contrast enhancement indicating acute inflammatory changes.
and immunoglobulin deposition in perivascular NMO lesions has been proposed (Wingerchuk et al., 2007), several studies have examined the predictive value of AQP seropositive status on the disease course. Seronegative NMO patients were found to have more frequently disease onset with simultaneous myelitis and ON and monophasic disease course (Jarius et al., 2012). Seropositive patients are more frequently women, more often have co-existing autoimmune disorders, and have more extensive spinal cord lesions (Jarius et al., 2012). While Jarius et al. have reported that seropositive patients have more frequent motor relapses and Jiao et al. (2013) found more frequent episodes of ON in seropositive patients, both studies found no difference in relapse rate, disability outcome, or prevalence of malignancy between the two subsets of NMO patients (Jiao et al., 2013). Recent studies have also examined the association between seropositive status in NMO patients and malignancy, since autoimmune response has been associated with the aberrant autoantigen expression in the tumor tissue. Pittock and Lennon (2008) have reported that 5% of NMOSD patients have a history malignancy, all of which are seropositive for AQP-4 Ab. Tissue microarray analyses have revealed AQP-4 activity in all tested cancer types encountered, indicating that AQP-4 may be a relevant tumor antigen. The same study reported that 0.2% of patients screened for paraneoplastic autoantibodies were AQP-4 positive and 93% of them were diagnosed with NMOSD. Thus, it has been proposed that NMO-Ig may be considered as a paraneoplastic marker (Ontaneda and Fox, 2014). DM has been associated with increased risk of malignancy for decades (Levine, 2006). Recent studies have identified DM-associated antibodies, in particular anti-transcription intermediary factor-1γ (anti-TIF-1γ) and nuclear matrix protein (NXP)2 antibodies, that are present in most (83%) of DM patients with cancer (Fiorentino et al., 2013). Interestingly, negative anti-myositis antibody panel, as it is the case in our patient has a negative predictive value for malignancy in DM patients, and anti-MDA5 Ab, which is detected in 10–20% patients with DM is not associated with malignancy (Selva-O'Callaghan et al., 2010). However, DM patients with anti-MDA5 Ab have significantly increased mortality compared to DM without this antibody, with deaths typically associated with rapidly progressive ILD (Chen et al., 2012). Aggressive treatment has been associated with improved outcomes. Rituximab is a monoclonal antibody against CD20, a pan-B cell antigen that in small open-label studies has decreased the relapse rate in patients with NMO (Cree et al., 2005). A recent study that used repeated rituximab treatments, upon reconstitution of CD27+ memory B cells have found that 60% of patients remained relapsefree over 5 years, and disability measures stabilized or improved in 93% of patients (Kim et al., 2013). Rapid ILD in patients who have DM with anti-MDA5 Ab is usually not responsive to glucocorticoids alone (Mimori et al., 2012). A small study of patients with refractory
110
D. Delman et al. / Journal of Neuroimmunology 278 (2015) 108–111
Fig. 3. Skin biopsy is consistent with DM. (A) The skin biopsy demonstrates vacuolar interface dermatitis with occasional necrotic keratinocytes along the dermo-epidermal junction. (B) Immunohistochemistry staining for CD123+ plasmacytoid dendritic cells (pDCs) reveals infiltrating pDCs in the epidermis.
ILD and myositis (either dermatomyositis or polymyositis) who were treated with IV cyclophosphamide (CYC) showed significant improvement in pulmonary function (Yamasaki et al., 2007). Our patient initially received two courses of high-dose IV steroids, plasma exchange, and two infusions of IV rituximab. Additionally, she was treated with two rounds of CYC, which was then continued monthly with daily prednisone. Due to excessive fatigue, she was switched from CYC to azathioprine (AZT) with prednisone. AZT has been used as a second-line immunosuppressive medication for ILD and myositis, often as a maintenance therapy. Upon discharge after one month, the patient ambulated with a walker. On follow-up visits over the ensuing 6 months, her rash has resolved and she has regained full strength. She is exercising again, and is now running 10 miles twice weekly. The patient complains of continued dyspnea, and has to take frequent breaks when running.
that also present with clinical signs of myelopathy. Early treatment of such patients with B-cell depleting therapies, including rituximab, CYC and AZA is recommended to avoid the potentially devastating progression of the disease. We also recommend avoiding the therapeutic use of IFNβ, a first line of treatment for relapsing remitting (RR)MS, which does not have therapeutic efficacy in NMO and may enhance inflammatory skin changes in DM.
3. Discussion
References
We report here for the first time a patient presenting with DM and NMOSD. The patient was diagnosed with two rare, disabling disorders, which raises the question of whether and how these disorders may be related. Both NMO and DM are B cell-mediated autoimmune diseases. Antibodies to AQP4 are now considered part of the diagnostic criteria for NMO. AQP4 is the most common water channel in the CNS and is found in astrocyte foot processes. Anti-AQP4 Abs in NMO are IgG1. MDA5 Ab is a cytoplasmic RNA helicase that belongs to the retinoic acid-inducible gene-I (RIG-I) family, and plays an important role in viral recognition. MDA5 activation upon binding viral dsRNA induces an innate immune response, and in particular Type I interferon (IFNα/β) (Crampton et al., 2012). Increased type I IFN levels induce IgG class switching and are considered to play a significant role in DM, as evidenced by accumulation of pDCs, the main cellular source of type I IFN, in the epidermis of the DM lesions (McNiff and Kaplan, 2008). In addition, and likely in response to the IFN β production, MDA5 expression is increased in the skin lesions in DM (Zahn et al., 2011). It is possible that MDA5 may act there as an autoantigen, inducing the anti-MDA5 Ab production, which may together with type I IFN contribute to the skin inflammatory changes and keratinocyte death. Due to the B cell-mediated pathogenesis of these disorders, we propose that patients with DM and NMO may benefit from B cell-targeting medications. While the efficacy of rituximab in NMO has been previously noted, it may also be beneficial in treatment of DM and ILD. Our patient with DM, ILD and NMOSD was treated aggressively with good results to date. We recommend considering NMOSD in the differential diagnosis of patients with DM and other autoimmune disorders
Chen, F.,Wang, D.,Shu, X.,Nakashima, R.,Wang, G., 2012. Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol. Int. 32, 3909–3915. Crampton, S.P., Deane, J.A., Feigenbaum, L.,Bolland, S., 2012. Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. J. Immunol. 188, 1451–1459. Cree, B.A.,Lamb, S.,Morgan, K.,Chen, A.,Waubant, E.,Genain, C., 2005. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64, 1270–1272. Fiorentino, D.F., Chung, L.S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A.L., Rosen, A., Casciola-Rosen, L., 2013. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1gamma. Arthritis Rheum. 65, 2954–2962. Hengstman, G.J., Brouwer, R., Egberts, W.T., Seelig, H.P., Jongen, P.J., van Venrooij, W.J., Van Engelen, B.G., 2002. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies. J. Neurol. 249, 69–75. Jarius, S., Ruprecht, K., Wildemann, B., Kuempfel, T., Ringelstein, M., Geis, C., Kleiter, I., Kleinschnitz, C., Berthele, A., Brettschneider, J., Hellwig, K., Hemmer, B., Linker, R.A., Lauda, F., Mayer, C.A., Tumani, H., Melms, A., Trebst, C., Stangel, M., Marziniak, M., Hoffmann, F., Schippling, S., Faiss, J.H., Neuhaus, O., Ettrich, B., Zentner, C., Guthke, K., Hofstadt-van Oy, U., Reuss, R., Pellkofer, H., Ziemann, U., Kern, P., Wandinger, K.P., Bergh, F.T., Boettcher, T., Langel, S., Liebetrau, M., Rommer, P.S., Niehaus, S., Munch, C., Winkelmann, A., Zettl, U.U., Metz, I., Veauthier, C., Sieb, J.P., Wilke, C., Hartung, H.P., Aktas, O.,Paul, F., 2012. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J. Neuroinflammation 9, 14. Jiao, Y., Fryer, J.P., Lennon, V.A., Jenkins, S.M., Quek, A.M., Smith, C.Y., McKeon, A., Costanzi, C., Iorio, R., Weinshenker, B.G., Wingerchuk, D.M., Shuster, E.A., Lucchinetti, C.F., Pittock, S.J., 2013. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology 81, 1197–1204. Kang, E.H., Nakashima, R., Mimori, T., Kim, J., Lee, Y.J., Lee, E.B., Wook, Y., 2010. Myositis autoantibodies in Korean patients with inflammatory myositis: anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis. BMC Musculoskelet. Disord. 11, 223. Kim, S.H.,Huh, S.Y.,Lee, S.J.,Joung, A.,Kim, H.J., 2013. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 70, 1110–1117.
Conflict of interest The authors do not have conflict of interest. S. Markovic-Plese received consultant fees from IMD Serono and Genzyme Inc. and research funding from IMD Serono, Genzyme Inc., Novartis and Biogen Idec.
D. Delman et al. / Journal of Neuroimmunology 278 (2015) 108–111 Lennon, V.A., Wingerchuk, D.M., Kryzer, T.J., Pittock, S.J., Luchinetti, C.F., Fujihara, K., Nakashima, I.,Weinshenker, B.G., 2004. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 364, 2106–2112. Levine, S.M., 2006. Cancer and myositis: new insights into an old association. Curr. Opin. Rheumatol. 18, 620–624. McNiff, J.M.,Kaplan, D.H., 2008. Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus. J. Cut. Path. 35, 452–456. Mimori, T., Nakashima, R., Hosono, Y., 2012. Interstitial lung disease in myositis: clinical subsets, biomarkers, and treatment. Curr Rheum Rep. 14, 264–274. Ontaneda, D., Fox, R.J., 2014. Is neuromyelitis optica with advanced age of onset a paraneoplastic disorder? Int. J. Neurosci. 124, 509–511. Pittock, S.J., Lennon, V.A., 2008. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch. Neurol. 65, 629–632. Sato, S., Kuwana, M., Fujita, T., Suzuki, Y., 2013. Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with
111
dermatomyositis and rapidly progressive interstitial lung disease. Mod. Rheumatol. 23, 496–502. Selva-O'Callaghan, A., Trallero-Araguas, E., Grau-Junyent, J.M., Labrador-Horrillo, M., 2010. Malignancy and myositis: novel autoantibodies and new insights. Curr. Opin. Rheumatol. 22, 627–632. Wingerchuk, D.M., Lennon, V.A., Lucchinetti, C.F., Pittock, S.J., Weinshenker, B.G., 2007. The spectrum of neuromyelitis optica. Lancet Neurol. 6, 805–815. Yamasaki, Y., Yamada, H., Yamasaki, M., Ohkubo, M., Azuma, K., Matsuoka, S., Kurihara, Y., Osada, H., Satoh, M., Ozaki, S., 2007. Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis. Rheumatology 46, 124–130. Zahn, S., Barchet, W.,Rehkamper, C., Hornung, T.,Bieber, T.,Tuting, T., Wenzel, J., 2011. Enhanced skin expression of melanoma differentiation-associated gene 5 (MDA5) in dermatomyositis and related autoimmune diseases. J Am Acad Derm. 64, 988–989.
