American Journal of Therapeutics 23, e639–e645 (2016)
Successful Treatment of Life-Threatening Interstitial Lung Disease Secondary to Antisynthetase Syndrome Using Rituximab: A Case Report and Review of the Literature Osama Dasa, MD, Mohammed Ruzieh, MD, and Omar Oraibi, MD*
We are presenting a case of antisynthetase syndrome (ASS) that manifested with severe interstitial pneumonitis in the presence of anti-Jo-1 and Ro (SSA) antibodies. Our patient developed respiratory failure with high oxygen requirements despite treatment by high-dose steroids. The patient was then treated with rituximab. This treatment led to significant improvement in the patient condition, with resolution of the ground glass opacities on high-resolution computerized tomography and near normalization of pulmonary function tests. In this communication, we performed a literature review and summarized previous reports pertinent to using of rituximab to treat interstitial lung disease (ILD) secondary to ASS by searching the PubMed database from 1980 to 2014. We were able to find 14 reports that included total of 45 patients with ILD secondary to ASS. A significant improvement in ILD was reported in the majority of reported patients who received rituximab, while there was only 1 mortality-related to Pneumocystis jirovecii pneumonia. Rituximab treatment was tolerated well in the majority of cases. It is our conclusion that rituximab can be considered a therapeutic option in ILD secondary to ASS based on our experience with this case and the currently available evidence in the literature. Nevertheless, there is a need for additional controlled studies to assess the efficacy and safety of rituximab in ILD secondary to ASS compared with other immunosuppressive regimens. Keywords: antisynthetase syndrome, myositis, interstitial lung disease, cryptogenic organizing pneumonia, rituximab
INTRODUCTION Pulmonary manifestations of rheumatic diseases include, but not limited to, interstitial lung disease (ILD), involvement of the pleura, and pulmonary vascular disease among others. The antisynthetase syndrome (ASS) is a systemic autoimmune syndrome that represents a subset of idiopathic inflammatory myopathy. ASS is characterized by the presence of
Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mailstop 1150, Toledo, OH 43614. E-mail: omar.oraibi@ utoledo.edu
circulating antibodies against aminoacyl-t-RNA synthetases,1 in association with ILD, inflammatory myopathy, arthritis, fever, mechanic’s hands, and Raynaud phenomenon. The lung is the most frequently involved and often the only manifestation of ASS even in the absence of other manifestations, which may delay diagnosis, hindering management of this rapidly progressive disease.2,3 Prognosis of ASS is largely determined by severity of lung disease.4 To date, there are limited data about efficacy of immunosuppressive therapy in ILD secondary to ASS or what is the preferred therapeutic regimen in these patients, which may explain lack of standardized approach to therapy for these patients. In this report, we present a case of ILD secondary to ASS that failed treatment with high-dose steroids and was subsequently treated with rituximab with remarkable sustained improvement in ILD. We performed a literature
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search and summarized the evidence in the literature about efficacy of using rituximab as potential treatment for ILD secondary to ASS.
CASE REPORT A 49-year-old white woman with no significant past medical illnesses presented with cough and shortness of breath that started gradually over 2 days, which then rapidly progressed to respiratory failure requiring mechanical ventilation. She did not experience muscle weakness or rash preceding this illness. She was treated with antibiotics for presumed pneumonia with no improvement in respiratory status. An extensive infection-related workup for bacterial, fungal, and viral infections as well as acid-fast bacilli stains was all negative. An open lung biopsy was performed, which demonstrated patchy involvement of the lungs by inflammatory granulation tissue in distal bronchioles and alveoli, suggestive of cryptogenic organizing pneumonia. The patient was started on high-dose systemic steroids (methylprednisolone 1000 mg per day for 3 days), which was then transitioned to oral prednisone 1 mg/kg, with some improvement in respiratory status allowing for extubation after 2 weeks. However, 2 weeks later, she had a relapse with worsening of shortness of breath and respiratory failure again, which continued to worsen with high oxygen requirements despite resuming methylprednisolone at 1000 mg daily for 3 days, followed by minipulse doses of methylprednisolone of 250 mg daily for 1 week. Physical examination revealed an intubated young woman with oxygen saturation of 88% despite using 100% oxygen. Skin appeared with no rash or lesions. Otherwise, physical examination was unremarkable. Laboratory tests were pertinent for slightly elevated creatine phosphokinase level at 1 occasion (out of 7 tests) at 251 (n , 180 IU/L). Immunology tests were positive for JO-1 and SSA (Ro) antibodies.
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Chest computerized tomography (CT) scan demonstrated diffuse patchy ground glass opacities associated with confluent airspace opacities bilaterally (Figure 1A). Muscle biopsy demonstrated regions of mild perivascular and endomysial inflammation with abundance of T-cell lymphocytes. Minor salivary gland biopsy was performed, which demonstrated normal histology with no significant inflammatory lesions. Due to lack of response to systemic corticosteroids and the critical situation of the patient, we treated our patient with rituximab 1000 mg, 2 doses, 2 weeks apart and continued prednisone 1 mg/kg. We noticed significant improvement in respiratory status allowing for extubation after 12 days of the first rituximab dose. Over the next 3 months, we noticed resolution of lung opacities, improvement in pulmonary function tests, and continuous improvement in oxygen requirements, and we were able to taper prednisone gradually to 20 mg/d. We treated this patient with another cycle of rituximab at 6 months and continued prednisone at 5 mg/d. One year later, lung CT scan demonstrated resolution of ground glass opacities (Figure 1B) and continuous improvement of pulmonary function tests (Figure 2). The patient currently does not require oxygen supplementation; 6-minute walk test was 430 m (normal . 400 m).
DISCUSSION The ASS is a systemic autoimmune disease that represents a unique subset of idiopathic inflammatory myositis. ASS is characterized by the presence of antibodies against aminoacyl-transfer RNA synthetases. To date, antibodies against 8 of the antisynthetases have been identified: anti-Jo-1 (the most common antisynthetase antibody, named after John P, a patient with polymyositis and ILD detected in 19805), PL-7, PL-12, EJ, OJ, KS, Zo, and anti-Ha.6 It is estimated that 15%–25% of patients with idiopathic inflammatory myositis are
FIGURE 1. Chest CT scan imaging demonstrating diffuse patchy ground glass opacities associated with confluent airspace densities, before initiating rituximab (A). CT imaging 1 year after rituximab treatment (B). American Journal of Therapeutics (2016) 23(2)
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FIGURE 2. Pulmonary function test parameters over the course of treatment with rituximab*. * indicates time in reference to initiating treatment with rituximab.
Jo-1-positive across different populations, the prevalence of the other antisythetase antibodies is difficult to determine due to low frequency. ILD is a heterogeneous group of disorders that may occur in association with variety of causes including connective tissue diseases. The reported prevalence of ILD in idiopathic inflammatory myositis in general varies between 23% and 65%,7,8 whereas prevalence of ILD secondary to ASS is estimated at 86% and 93% in anti–Jo-1-positive ASS patients.9,10 Not only that ILD is the most common manifestation of ASS but also ILD can be the only primary manifestation of ASS.11 Moreover, the presence and severity of the ILD is an important prognostic factor to determine outcome of ASS. Coexistence of SSA (Ro) antibodies and Jo-1 antibodies in the sera usually correlate with more severe and extensive lung disease compared with patients who have only positive anti-Jo-1 antibody,12 and it appears that the presence of SSA may predict more fibrotic disease in ASS.8 There are no specific guidelines to dictate how to treat ILD related to ASS due to lack of clinical trials to compare the efficacy of various immunosuppressive regimens. However, favorable outcome with immunosuppressive therapy that includes steroids alone or in combination with cyclophosphamide, azathioprine, cyclosporine, and tacrolimus has been reported, sporadically.13,14 Rituximab is an anti-CD20 chimeric monoclonal antibody targeting B cells at different stages of B-cell development but not plasma cells.15 Rituximab has www.americantherapeutics.com
been used with success in a wide variety of autoimmune diseases. In recent studies, it was demonstrated that rituximab may be effective in treatment of refractory polymyositis and dermatomyositis,16 and that the presence of antisynthetase antibodies strongly predicts good clinical response to treatment with rituximab.17 Although, it seems that the antisynthetase antibodies may have a pathogenic role in ILD related to ASS, as demonstrated by the ability of Jo-1 antibody to upregulate the major histocompatibility complex I, and to induce expression of intercellular adhesion molecule 1 (ICAM-1) in human lung endothelial cells,18 but the response to this treatment could not be completely explained by B-cell depletion, as treatment with rituximab would not affect emerging B cells or plasma cells, which maintains the capacity to secrete antibodies. It seems plausible that rituximab may impair the process of B-cell antigen presentation, interfere with B- and T-cell costimulation,18 and may restore regulatory T-cell function.19 We performed a review of the literature by using PubMed to evaluate the available evidence of using rituximab to treat ILD secondary to ASS. The search included literature from 1980 to 2014, which we summarized in (Table 1). We used a combination of terms that include synthetase, antisynthetase, myositis, ILD, Jo1, and rituximab. We evaluated reports that described myositis-related ILD and filtered out cases that do not describe antisynthetase-related ILD. Overall, we found 14 reports that describe total of 45 patients with ILD secondary to ASS; 4 of these reports American Journal of Therapeutics (2016) 23(2)
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Table 1. Summary of the literature that describes the use of rituximab in treatment of interstitial lung disease related to ASS. Authors 20
Lambotte et al Levine et al21 Brulhart et al22 Sultan et al23 Frikha et al24 Sem et al25 Vandenbroucke et al26 Limaye et al27 Ball et al28 Andres et al29 Zappa et al30 Marie et al31 Nalotto et al32 Unger et al33 Dasa et al†
No. patients
Study type
Age*
Sex
1 3 1 2 1 11 1 1 1 1 1 7 3 11 1
Case report Open-label study Case report Case reports Case report Retrospective case series Case report Case report Case report Case report Case report Retrospective case series Retrospective case series Retrospective case series Case report
47 51.3 (48–53) 57 56, 63 19 51.7 (23–66) 48 31 30 46 58 55.7 (47–59) 55 (52–61) 51.7 (36–73) 49
F (3) F F (2) F F (4) M (7) F M F M M M (3) M (4) F (3) F (1) M (10) F F
Antisynthetase antibodies
SSA (Ro)
+Jo-1
NA
AZA, Cs, IVIg, MTX
(2) +Jo-1
NA
AZA, Cs, CSA, CYC, ETC, MTX
+Jo-1
+
(2) +Jo-1
NA
+Jo-1
NA
(10) +Jo-1
(8) +
Prior therapy
Cs, MTX
AZA, Cs, CYC, ETC, IVIg, LEF, MTX, P
Cs, MMF
AZA, Cs, CSA, CYC, IVIg TAC
Rituximab regimen 375 mg/m2 4 biweekly infusions 1 received 100 mg/m2; 2 received 375 mg/m2. All of them received weekly infusions for 4 weeks 1 g, 2 wk apart; 2 cycles (repeated at 8 mo)
Outcome PFTs remained stable
PFTs improved by week 12 in all 3 patients. Rituximab facilitated a reduction in concomitant medications Improvement of ILD after first cycle. Relapse of myositis after 8 months of the initial rituximab dose, which required another dose of rituximab 1 g, 2 wk apart; 1 cycle PFTs were stable throughout the study in both patients with some resolution of ground glass appearance in 1 patient. Myositis improved in both patients 1 g, 2 wk apart; 2 cycles Improved then relapse at 14 (repeated at 17 months) months. Second cycle of rituximab was given at 17 months, which leads to improvement of ground glass opacities, but fibrotic lesions persisted on CT scan 1 g, 2 wk apart; 1 cycle in 7 7 patients out of 11 improved or patients; 2 cycles in 1 patient; stabilized after 6 months. Ground 700 mg, 2 wk apart in 1 glass attenuation on HRCT patient; 375 mg/m2 weekly showed improvement in 5 out of 11 patients. Most patients infusions for 4 wk in 2 experienced improvement in patients PFTs (Continued on next page)
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Table 1. (Continued) Summary of the literature that describes the use of rituximab in treatment of interstitial lung disease related to ASS. Antisynthetase antibodies
SSA (Ro)
(1) +PL-12
+Jo-1
+
+Jo-1
+
+Jo-1
NA
+Jo-1
NA
+Jo-1
+
(7) +Jo-1
NA
(2) +Jo-1 (1) +PL-12
(3) +
(9) +Jo-1 (1) +Ku (1) +PL-7
NA
+Jo-1
+
Prior therapy
Rituximab regimen
Outcome
One patient died due to Pneumocystis jirovecii infection 3 mo after last infusion of rituximab Cs, CYC 1 g, 2 wk apart; 1 cycle Less ground glass on CT scan but fibrosis stabilized. Improvement in PFTs AZA, Cs, CSA, IVIg 500 mg/m2 weekly for 4 wk; 3 Initial clinical improvement, followed by a relapse at months cycles (repeated at 10 and 10 and 16, which was associated 16 mo) with clinical improvement of ILD ADA, AZA, Cs, CSA, 500 mg weekly for 6 wk. Then, Improvement in myositis, improved ETC, IVIg MMF, MMF 500 mg weekly lung disease for 4 wk 6 months later AZA, Cs, CYC, MMG, Rituximab single cycle PFT stabilized, authors did not MTX comment on CT scan changes AZA, Cs, CSA 1 g, 2 wk apart; 2 cycles Clinical improvement in patient (repeated at 6 mo) with dyspnea. Improvement of PFT parameters, resolution of ground glass opacities on HRCT. Fibrotic lung lesions stabilized Outcome at 1 yr: 5 patients AZA, Cs, CYC, IVIg, 1 g, 2 wk apart, 1 cycle and improved, 2 complete resolution MMF additional 1 g once at of ILD 6 mo Significant improvement in ILD in AZA, Cs, HCQ, IVIg, 1 g, 2 wk apart; 1 cycle (1 all patients after 1 cycle of LEF, MMF, MTX patient received second treatment. Rituximab was well cycle at 16 mo due to tolerated in 2 cases. Skin reaction arthritis relapse) developed during infusions in 1 patient ILD improved in 6 patients and 1 g, 2 wk apart (2 patients ADA, Anakinra, AZA, stabilized in 2 patients. No PFT received 1 cycle, 5 had 4 Cs, CSA, CYC, ETC, data on 3 patients cycles. Others had IFX, IVIg, LEF, MMF, a mixture of dosing MTX, SSZ regimens and schedules) Cs 1 g, 2 wk apart; 2 cycles Remarkable improvement of PFTs and resolution of ground glass opacities
ADA: adalimumab; AZA: azathioprine; Cs: corticosteroids; CSA: cyclosporin; CYC: cyclophosphamide; ETC: etanercept; HCQ: hydroxychloroquine; HRCT: high-resolution CT scan; IFX: infliximab; IVIg: intravenous immunoglobulin; LEF: leflunomide; MMF: mycophenolate mofetil; MTX: methotrexate; P: penicillamine; PFT: pulmonary function tests; SSZ: sulfasalazine; TAC: tacrolimus. *Age reported in years or average and range in reports that included more than 2 patients. †The current case.
represent retrospective case series of 32 patients in total. We did not find any controlled study to evaluate rituximab in ASS among these reports. The majority of these patients (40 out of the 45) are Jo-1-positive, 2 patients had positive serology for PL-12, and 1 patient was positive for Ku and another for PL-7 antibody. Seventy-three percent www.americantherapeutics.com
of these patients were female with average age of 51.1 years. Of the 14 reports that included 45 patients in total, 9 studies described 32 patients that received the 2 rituximab dose regimen, each dose of 1 gram, 2 weeks apart. Of particular interest, rituximab was effective in the majority of patients, as demonstrated by improvement in pulmonary function tests and chest imaging. American Journal of Therapeutics (2016) 23(2)
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There was only 1 mortality described due to Pneumocystis jirovecii pneumonia infection in 1 patient 3 months after receiving rituximab for acute-onset severe ILD, who was using steroids only.25 Our patient presented with severe life-threatening ILD, positive serology for SSA (Ro) and Jo-1, with no clinical features of myositis by history or laboratory testing; however, muscle biopsy demonstrated minimal inflammation in the perivascular and endomysial spaces, which may suggest ASS-related myositis. Clinical myositis is less common in ASS with a reported frequency of 40%–50% only, and usually, muscle involvement tends to be subclinical and milder in ASS compared with dermatomyositis or polymyositis.34 Lung CT scan and lung biopsy findings are consistent with cryptogenic organizing pneumonia (COP), which is one of the histopathological patterns associated with (but not specific to) ASS-associated ILD. Cryptogenic organizing pneumonia is more likely to be associated with acute presentation of ILD compared with other histopathological subtypes of ILD in ASSassociated ILD.35 Our patient responded initially to high-dose pulse steroids, but she relapsed despite using prednisone 1 mg$kg21$d21, and the patient did not respond to pulse doses of methylprednisolone (1 g/d 3 3 days, followed by 250 mg/d for 1 week). Based on severity of her ILD and resistance to treatment with high-dose corticosteroids and coexistence of SSA and Jo-1, we elected to treat this patient with rituximab 1000 mg intravenous, 2 doses, 2 weeks apart. This treatment was associated with favorable outcome and significant reduction in steroid dose. This case shades light on several interesting features of inflammatory myositis-associated ILD. First, inflammatory myositis should be considered in the differential diagnosis of ILD, in this case, it could have been missed if Jo-1 antibody was not checked, or perhaps, if we relied on single CK level. Second, rituximab could be a promising therapy in myositis-associated ILD. Finally, in ASS, inflammation in the muscles could be subtle with normal clinical and/or laboratory evidence of myositis. In conclusion, treatment of ILD in ASS is not standardized due to lack of evidence from randomized controlled studies to evaluate the efficacy of different treatment regimens, which will require multicenter collaboration due to the relative rarity of the disease. One can see from the summary of the literature that the available data supports the notion that rituximab is effective, and probably safe, in ILD related to ASS. But, we need to keep in mind the issue of publication bias, as negative reports are less likely to be published. We recommend (1) to search carefully for the presence of connective tissue disease in cases of idiopathic ILD, (2) serological profiling by including antisynthetase and American Journal of Therapeutics (2016) 23(2)
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SSA antibodies in the workup of idiopathic ILD, (3) primary prophylaxis for Pneumocystis jirovecii pneumonia should be considered in patients who are treated with rituximab, especially in the presence of ILD, other cytotoxic agents, or high-dose steroids,36 and (4) finally, we underscore the potential for using rituximab as a treatment option in ILD related to ASS especially in severe or treatment-resistant cases.
REFERENCES 1. Marguerie C, Bunn CC, Beynon HL, et al. Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyltRNA synthetase enzymes. Q J Med. 1990;77:1019–1038. 2. Sundaragiri PR, Vallabhajosyula S, Kanaan JP. Interstitial lung disease in antisynthetase syndrome without clinical myositis. BMJ Case Rep. 2014. doi:10.1136/bcr2014-204296. 3. Plastiras SC, Soliotis FC, Vlachoyiannopoulos P, et al. Interstitial lung disease in a patient with antisynthetase syndrome and no myositis. Clin Rheumatol. 2007;26: 108–111. 4. Schnabel A, Reuter M, Biederer J, et al. Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin Arthritis Rheum. 2003;32:273–284. 5. Nishikai M, Reichlin M. Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis. Characterization of the Jo-1 antibody system. Arthritis Rheum. 1980;23:881–888. 6. Targoff IN. Autoantibodies and their significance in myositis. Curr Rheumatol Rep. 2008;10:333–340. 7. Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyositis and interstitial lung disease: a new therapeutic approach with T-cell-specific immunosuppressants. Autoimmunity. 2005;38:383–392. 8. Vancsa A, Csípo I, Nemeth J, et al. Characteristics of interstitial lung disease in SS-A positive/Jo-1 positive inflammatory myopathy patients. Rheumatol Int. 2009; 29:989–994. 9. Richards TJ, Eggebeen A, Gibson K, et al. Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum. 2009;60:2183–2192. 10. Mileti LM, Strek ME, Niewold TB, et al. Clinical characteristics of patients with anti-Jo-1 antibodies: a single center experience. J Clin Rheumatol. 2009;15:254–255. 11. Katzap E, Barilla-LaBarca ML, Marder G. Antisynthetase syndrome. Curr Rheumatol Rep. 2011;13:175–181. 12. La Corte R, Lo Mo Naco A, Locaputo A, et al. In patients with antisynthetase syndrome the occurrence of antiRo/SSA antibodies causes a more severe interstitial lung disease. Autoimmunity. 2006;39:249–253. 13. Connors GR, Christopher-Stine L, Oddis CV, et al. Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest. 2010;138:1464–1474. www.americantherapeutics.com
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Rituximab and ASS 14. Marie I, Mouthon L. Therapy of polymyositis and dermatomyositis. Autoimmun Rev. 2011;11:6–13. 15. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum. 2003;48:1484–1492. 16. Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65:314–324. 17. Aggarwal R, Bandos A, Reed AM, et al. Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol. 2014;66:740–749. 18. Tokunaga M, Fujii K, Saito K, et al. Down-regulation of CD40 and CD80 on B cells in patients with lifethreatening systemic lupus erythematosus after successful treatment with rituximab. Rheumatology (Oxford). 2005;44:176–182. 19. Vigna-Perez M, Hernández-Castro B, ParedesSaharopulos O, et al. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther. 2006;8:R83. 20. Lambotte O, Kotb R, Maigne G, et al. Efficacy of rituximab in refractory polymyositis. J Rheumatol. 2005;32: 1369–1370. 21. Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum. 2005;52: 601–607. 22. Brulhart L, Waldburger JM, Gabay C. Rituximab in the treatment of antisynthetase syndrome. Ann Rheum Dis. 2006;65:974–975. 23. Sultan SM, Ng KP, Edwards JC, et al. Clinical outcome following B cell depletion therapy in eight patients with refractory idiopathic inflammatory myopathy. Clin Exp Rheumatol. 2008;26:887–893. 24. Frikha F, Rigolet A, Behin A, et al. Efficacy of rituximab in refractory and relapsing myositis with anti-JO1 antibodies: a report of two cases. Rheumatology (Oxford). 2009;48:1166–1168.
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e645 25. Sem M, Molberg Ø, Lund MB, et al. Rituximab treatment of the anti-synthetase syndrome: a retrospective case series. Rheumatol (oxford). 2009;48:968–971. 26. Vandenbroucke E, Grutters JC, Altenburg J, et al. Rituximab in life threatening antisynthetase syndrome. Rheumatol Int. 2009;29:1499–1502. 27. Limaye V, Hissaria P, Liew CL, et al. Efficacy of rituximab in refractory antisynthetase syndrome. Intern Med J. 2012;42:e4–e7. 28. Ball EM, Savage EM, Pendleton A. Refractory antisynthetase syndrome treated with rituximab. Rheumatol (oxford). 2010;49:1013. 29. Andres M, Courtney P. No hepatitis B reactivation in a patient with refractory antisynthetase syndrome successfully treated with rituximab. Joint Bone Spine. 2011; 78:653–654. 30. Zappa MC, Trequattrini T, Mattioli F, et al. Rituximab treatment in a case of antisynthetase syndrome with severe interstitial lung disease and acute respiratory failure. Multidiscip Respir Med. 2011;6:183–188. 31. Marie I, Dominique S, Janvresse A, et al. Rituximab therapy for refractory interstitial lung disease related to antisynthetase syndrome. Respir Med. 2012;106:581–587. 32. Nalotto L, Iaccarino L, Zen M, et al. Rituximab in refractory idiopathic inflammatory myopathies and antisynthetase syndrome: personal experience and review of the literature. Immunol Res. 2013;56:362–370. 33. Unger L, Kampf S, Lüthke K, et al. Rituximab therapy in patients with refractory dermatomyositis or polymyositis: differential effects in a real-life population. Rheumatology (Oxford). 2014;53:1630–1638. 34. Marie I, Josse S, Decaux O, et al. Clinical manifestations and outcome of anti-PL7 positive patients with antisynthetase syndrome. Eur J Intern Med. 2013;24:474–479. 35. Tillie-Leblond I, Wislez M, Valeyre D, et al. Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset. Thorax. 2008;63:53–59. 36. Martin-Garrido I, Carmona EM, Specks U, et al. Pneumocystis pneumonia in patients treated with rituximab. Chest. 2013;144:258–265.
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Successful Treatment of Life-Threatening Interstitial Lung Disease Secondary to Antisynthetase Syndrome Using Rituximab: A Case Report and Review of the Literature Osama Dasa, MD, Mohammed Ruzieh, MD, and Omar Oraibi, MD*
We are presenting a case of antisynthetase syndrome (ASS) that manifested with severe interstitial pneumonitis in the presence of anti-Jo-1 and Ro (SSA) antibodies. Our patient developed respiratory failure with high oxygen requirements despite treatment by high-dose steroids. The patient was then treated with rituximab. This treatment led to significant improvement in the patient condition, with resolution of the ground glass opacities on high-resolution computerized tomography and near normalization of pulmonary function tests. In this communication, we performed a literature review and summarized previous reports pertinent to using of rituximab to treat interstitial lung disease (ILD) secondary to ASS by searching the PubMed database from 1980 to 2014. We were able to find 14 reports that included total of 45 patients with ILD secondary to ASS. A significant improvement in ILD was reported in the majority of reported patients who received rituximab, while there was only 1 mortality-related to Pneumocystis jirovecii pneumonia. Rituximab treatment was tolerated well in the majority of cases. It is our conclusion that rituximab can be considered a therapeutic option in ILD secondary to ASS based on our experience with this case and the currently available evidence in the literature. Nevertheless, there is a need for additional controlled studies to assess the efficacy and safety of rituximab in ILD secondary to ASS compared with other immunosuppressive regimens. Keywords: antisynthetase syndrome, myositis, interstitial lung disease, cryptogenic organizing pneumonia, rituximab
INTRODUCTION Pulmonary manifestations of rheumatic diseases include, but not limited to, interstitial lung disease (ILD), involvement of the pleura, and pulmonary vascular disease among others. The antisynthetase syndrome (ASS) is a systemic autoimmune syndrome that represents a subset of idiopathic inflammatory myopathy. ASS is characterized by the presence of
Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mailstop 1150, Toledo, OH 43614. E-mail: omar.oraibi@ utoledo.edu
circulating antibodies against aminoacyl-t-RNA synthetases,1 in association with ILD, inflammatory myopathy, arthritis, fever, mechanic’s hands, and Raynaud phenomenon. The lung is the most frequently involved and often the only manifestation of ASS even in the absence of other manifestations, which may delay diagnosis, hindering management of this rapidly progressive disease.2,3 Prognosis of ASS is largely determined by severity of lung disease.4 To date, there are limited data about efficacy of immunosuppressive therapy in ILD secondary to ASS or what is the preferred therapeutic regimen in these patients, which may explain lack of standardized approach to therapy for these patients. In this report, we present a case of ILD secondary to ASS that failed treatment with high-dose steroids and was subsequently treated with rituximab with remarkable sustained improvement in ILD. We performed a literature
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e640
search and summarized the evidence in the literature about efficacy of using rituximab as potential treatment for ILD secondary to ASS.
CASE REPORT A 49-year-old white woman with no significant past medical illnesses presented with cough and shortness of breath that started gradually over 2 days, which then rapidly progressed to respiratory failure requiring mechanical ventilation. She did not experience muscle weakness or rash preceding this illness. She was treated with antibiotics for presumed pneumonia with no improvement in respiratory status. An extensive infection-related workup for bacterial, fungal, and viral infections as well as acid-fast bacilli stains was all negative. An open lung biopsy was performed, which demonstrated patchy involvement of the lungs by inflammatory granulation tissue in distal bronchioles and alveoli, suggestive of cryptogenic organizing pneumonia. The patient was started on high-dose systemic steroids (methylprednisolone 1000 mg per day for 3 days), which was then transitioned to oral prednisone 1 mg/kg, with some improvement in respiratory status allowing for extubation after 2 weeks. However, 2 weeks later, she had a relapse with worsening of shortness of breath and respiratory failure again, which continued to worsen with high oxygen requirements despite resuming methylprednisolone at 1000 mg daily for 3 days, followed by minipulse doses of methylprednisolone of 250 mg daily for 1 week. Physical examination revealed an intubated young woman with oxygen saturation of 88% despite using 100% oxygen. Skin appeared with no rash or lesions. Otherwise, physical examination was unremarkable. Laboratory tests were pertinent for slightly elevated creatine phosphokinase level at 1 occasion (out of 7 tests) at 251 (n , 180 IU/L). Immunology tests were positive for JO-1 and SSA (Ro) antibodies.
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Chest computerized tomography (CT) scan demonstrated diffuse patchy ground glass opacities associated with confluent airspace opacities bilaterally (Figure 1A). Muscle biopsy demonstrated regions of mild perivascular and endomysial inflammation with abundance of T-cell lymphocytes. Minor salivary gland biopsy was performed, which demonstrated normal histology with no significant inflammatory lesions. Due to lack of response to systemic corticosteroids and the critical situation of the patient, we treated our patient with rituximab 1000 mg, 2 doses, 2 weeks apart and continued prednisone 1 mg/kg. We noticed significant improvement in respiratory status allowing for extubation after 12 days of the first rituximab dose. Over the next 3 months, we noticed resolution of lung opacities, improvement in pulmonary function tests, and continuous improvement in oxygen requirements, and we were able to taper prednisone gradually to 20 mg/d. We treated this patient with another cycle of rituximab at 6 months and continued prednisone at 5 mg/d. One year later, lung CT scan demonstrated resolution of ground glass opacities (Figure 1B) and continuous improvement of pulmonary function tests (Figure 2). The patient currently does not require oxygen supplementation; 6-minute walk test was 430 m (normal . 400 m).
DISCUSSION The ASS is a systemic autoimmune disease that represents a unique subset of idiopathic inflammatory myositis. ASS is characterized by the presence of antibodies against aminoacyl-transfer RNA synthetases. To date, antibodies against 8 of the antisynthetases have been identified: anti-Jo-1 (the most common antisynthetase antibody, named after John P, a patient with polymyositis and ILD detected in 19805), PL-7, PL-12, EJ, OJ, KS, Zo, and anti-Ha.6 It is estimated that 15%–25% of patients with idiopathic inflammatory myositis are
FIGURE 1. Chest CT scan imaging demonstrating diffuse patchy ground glass opacities associated with confluent airspace densities, before initiating rituximab (A). CT imaging 1 year after rituximab treatment (B). American Journal of Therapeutics (2016) 23(2)
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FIGURE 2. Pulmonary function test parameters over the course of treatment with rituximab*. * indicates time in reference to initiating treatment with rituximab.
Jo-1-positive across different populations, the prevalence of the other antisythetase antibodies is difficult to determine due to low frequency. ILD is a heterogeneous group of disorders that may occur in association with variety of causes including connective tissue diseases. The reported prevalence of ILD in idiopathic inflammatory myositis in general varies between 23% and 65%,7,8 whereas prevalence of ILD secondary to ASS is estimated at 86% and 93% in anti–Jo-1-positive ASS patients.9,10 Not only that ILD is the most common manifestation of ASS but also ILD can be the only primary manifestation of ASS.11 Moreover, the presence and severity of the ILD is an important prognostic factor to determine outcome of ASS. Coexistence of SSA (Ro) antibodies and Jo-1 antibodies in the sera usually correlate with more severe and extensive lung disease compared with patients who have only positive anti-Jo-1 antibody,12 and it appears that the presence of SSA may predict more fibrotic disease in ASS.8 There are no specific guidelines to dictate how to treat ILD related to ASS due to lack of clinical trials to compare the efficacy of various immunosuppressive regimens. However, favorable outcome with immunosuppressive therapy that includes steroids alone or in combination with cyclophosphamide, azathioprine, cyclosporine, and tacrolimus has been reported, sporadically.13,14 Rituximab is an anti-CD20 chimeric monoclonal antibody targeting B cells at different stages of B-cell development but not plasma cells.15 Rituximab has www.americantherapeutics.com
been used with success in a wide variety of autoimmune diseases. In recent studies, it was demonstrated that rituximab may be effective in treatment of refractory polymyositis and dermatomyositis,16 and that the presence of antisynthetase antibodies strongly predicts good clinical response to treatment with rituximab.17 Although, it seems that the antisynthetase antibodies may have a pathogenic role in ILD related to ASS, as demonstrated by the ability of Jo-1 antibody to upregulate the major histocompatibility complex I, and to induce expression of intercellular adhesion molecule 1 (ICAM-1) in human lung endothelial cells,18 but the response to this treatment could not be completely explained by B-cell depletion, as treatment with rituximab would not affect emerging B cells or plasma cells, which maintains the capacity to secrete antibodies. It seems plausible that rituximab may impair the process of B-cell antigen presentation, interfere with B- and T-cell costimulation,18 and may restore regulatory T-cell function.19 We performed a review of the literature by using PubMed to evaluate the available evidence of using rituximab to treat ILD secondary to ASS. The search included literature from 1980 to 2014, which we summarized in (Table 1). We used a combination of terms that include synthetase, antisynthetase, myositis, ILD, Jo1, and rituximab. We evaluated reports that described myositis-related ILD and filtered out cases that do not describe antisynthetase-related ILD. Overall, we found 14 reports that describe total of 45 patients with ILD secondary to ASS; 4 of these reports American Journal of Therapeutics (2016) 23(2)
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Table 1. Summary of the literature that describes the use of rituximab in treatment of interstitial lung disease related to ASS. Authors 20
Lambotte et al Levine et al21 Brulhart et al22 Sultan et al23 Frikha et al24 Sem et al25 Vandenbroucke et al26 Limaye et al27 Ball et al28 Andres et al29 Zappa et al30 Marie et al31 Nalotto et al32 Unger et al33 Dasa et al†
No. patients
Study type
Age*
Sex
1 3 1 2 1 11 1 1 1 1 1 7 3 11 1
Case report Open-label study Case report Case reports Case report Retrospective case series Case report Case report Case report Case report Case report Retrospective case series Retrospective case series Retrospective case series Case report
47 51.3 (48–53) 57 56, 63 19 51.7 (23–66) 48 31 30 46 58 55.7 (47–59) 55 (52–61) 51.7 (36–73) 49
F (3) F F (2) F F (4) M (7) F M F M M M (3) M (4) F (3) F (1) M (10) F F
Antisynthetase antibodies
SSA (Ro)
+Jo-1
NA
AZA, Cs, IVIg, MTX
(2) +Jo-1
NA
AZA, Cs, CSA, CYC, ETC, MTX
+Jo-1
+
(2) +Jo-1
NA
+Jo-1
NA
(10) +Jo-1
(8) +
Prior therapy
Cs, MTX
AZA, Cs, CYC, ETC, IVIg, LEF, MTX, P
Cs, MMF
AZA, Cs, CSA, CYC, IVIg TAC
Rituximab regimen 375 mg/m2 4 biweekly infusions 1 received 100 mg/m2; 2 received 375 mg/m2. All of them received weekly infusions for 4 weeks 1 g, 2 wk apart; 2 cycles (repeated at 8 mo)
Outcome PFTs remained stable
PFTs improved by week 12 in all 3 patients. Rituximab facilitated a reduction in concomitant medications Improvement of ILD after first cycle. Relapse of myositis after 8 months of the initial rituximab dose, which required another dose of rituximab 1 g, 2 wk apart; 1 cycle PFTs were stable throughout the study in both patients with some resolution of ground glass appearance in 1 patient. Myositis improved in both patients 1 g, 2 wk apart; 2 cycles Improved then relapse at 14 (repeated at 17 months) months. Second cycle of rituximab was given at 17 months, which leads to improvement of ground glass opacities, but fibrotic lesions persisted on CT scan 1 g, 2 wk apart; 1 cycle in 7 7 patients out of 11 improved or patients; 2 cycles in 1 patient; stabilized after 6 months. Ground 700 mg, 2 wk apart in 1 glass attenuation on HRCT patient; 375 mg/m2 weekly showed improvement in 5 out of 11 patients. Most patients infusions for 4 wk in 2 experienced improvement in patients PFTs (Continued on next page)
American Journal of Therapeutics (2016) 23(2)
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Table 1. (Continued) Summary of the literature that describes the use of rituximab in treatment of interstitial lung disease related to ASS. Antisynthetase antibodies
SSA (Ro)
(1) +PL-12
+Jo-1
+
+Jo-1
+
+Jo-1
NA
+Jo-1
NA
+Jo-1
+
(7) +Jo-1
NA
(2) +Jo-1 (1) +PL-12
(3) +
(9) +Jo-1 (1) +Ku (1) +PL-7
NA
+Jo-1
+
Prior therapy
Rituximab regimen
Outcome
One patient died due to Pneumocystis jirovecii infection 3 mo after last infusion of rituximab Cs, CYC 1 g, 2 wk apart; 1 cycle Less ground glass on CT scan but fibrosis stabilized. Improvement in PFTs AZA, Cs, CSA, IVIg 500 mg/m2 weekly for 4 wk; 3 Initial clinical improvement, followed by a relapse at months cycles (repeated at 10 and 10 and 16, which was associated 16 mo) with clinical improvement of ILD ADA, AZA, Cs, CSA, 500 mg weekly for 6 wk. Then, Improvement in myositis, improved ETC, IVIg MMF, MMF 500 mg weekly lung disease for 4 wk 6 months later AZA, Cs, CYC, MMG, Rituximab single cycle PFT stabilized, authors did not MTX comment on CT scan changes AZA, Cs, CSA 1 g, 2 wk apart; 2 cycles Clinical improvement in patient (repeated at 6 mo) with dyspnea. Improvement of PFT parameters, resolution of ground glass opacities on HRCT. Fibrotic lung lesions stabilized Outcome at 1 yr: 5 patients AZA, Cs, CYC, IVIg, 1 g, 2 wk apart, 1 cycle and improved, 2 complete resolution MMF additional 1 g once at of ILD 6 mo Significant improvement in ILD in AZA, Cs, HCQ, IVIg, 1 g, 2 wk apart; 1 cycle (1 all patients after 1 cycle of LEF, MMF, MTX patient received second treatment. Rituximab was well cycle at 16 mo due to tolerated in 2 cases. Skin reaction arthritis relapse) developed during infusions in 1 patient ILD improved in 6 patients and 1 g, 2 wk apart (2 patients ADA, Anakinra, AZA, stabilized in 2 patients. No PFT received 1 cycle, 5 had 4 Cs, CSA, CYC, ETC, data on 3 patients cycles. Others had IFX, IVIg, LEF, MMF, a mixture of dosing MTX, SSZ regimens and schedules) Cs 1 g, 2 wk apart; 2 cycles Remarkable improvement of PFTs and resolution of ground glass opacities
ADA: adalimumab; AZA: azathioprine; Cs: corticosteroids; CSA: cyclosporin; CYC: cyclophosphamide; ETC: etanercept; HCQ: hydroxychloroquine; HRCT: high-resolution CT scan; IFX: infliximab; IVIg: intravenous immunoglobulin; LEF: leflunomide; MMF: mycophenolate mofetil; MTX: methotrexate; P: penicillamine; PFT: pulmonary function tests; SSZ: sulfasalazine; TAC: tacrolimus. *Age reported in years or average and range in reports that included more than 2 patients. †The current case.
represent retrospective case series of 32 patients in total. We did not find any controlled study to evaluate rituximab in ASS among these reports. The majority of these patients (40 out of the 45) are Jo-1-positive, 2 patients had positive serology for PL-12, and 1 patient was positive for Ku and another for PL-7 antibody. Seventy-three percent www.americantherapeutics.com
of these patients were female with average age of 51.1 years. Of the 14 reports that included 45 patients in total, 9 studies described 32 patients that received the 2 rituximab dose regimen, each dose of 1 gram, 2 weeks apart. Of particular interest, rituximab was effective in the majority of patients, as demonstrated by improvement in pulmonary function tests and chest imaging. American Journal of Therapeutics (2016) 23(2)
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There was only 1 mortality described due to Pneumocystis jirovecii pneumonia infection in 1 patient 3 months after receiving rituximab for acute-onset severe ILD, who was using steroids only.25 Our patient presented with severe life-threatening ILD, positive serology for SSA (Ro) and Jo-1, with no clinical features of myositis by history or laboratory testing; however, muscle biopsy demonstrated minimal inflammation in the perivascular and endomysial spaces, which may suggest ASS-related myositis. Clinical myositis is less common in ASS with a reported frequency of 40%–50% only, and usually, muscle involvement tends to be subclinical and milder in ASS compared with dermatomyositis or polymyositis.34 Lung CT scan and lung biopsy findings are consistent with cryptogenic organizing pneumonia (COP), which is one of the histopathological patterns associated with (but not specific to) ASS-associated ILD. Cryptogenic organizing pneumonia is more likely to be associated with acute presentation of ILD compared with other histopathological subtypes of ILD in ASSassociated ILD.35 Our patient responded initially to high-dose pulse steroids, but she relapsed despite using prednisone 1 mg$kg21$d21, and the patient did not respond to pulse doses of methylprednisolone (1 g/d 3 3 days, followed by 250 mg/d for 1 week). Based on severity of her ILD and resistance to treatment with high-dose corticosteroids and coexistence of SSA and Jo-1, we elected to treat this patient with rituximab 1000 mg intravenous, 2 doses, 2 weeks apart. This treatment was associated with favorable outcome and significant reduction in steroid dose. This case shades light on several interesting features of inflammatory myositis-associated ILD. First, inflammatory myositis should be considered in the differential diagnosis of ILD, in this case, it could have been missed if Jo-1 antibody was not checked, or perhaps, if we relied on single CK level. Second, rituximab could be a promising therapy in myositis-associated ILD. Finally, in ASS, inflammation in the muscles could be subtle with normal clinical and/or laboratory evidence of myositis. In conclusion, treatment of ILD in ASS is not standardized due to lack of evidence from randomized controlled studies to evaluate the efficacy of different treatment regimens, which will require multicenter collaboration due to the relative rarity of the disease. One can see from the summary of the literature that the available data supports the notion that rituximab is effective, and probably safe, in ILD related to ASS. But, we need to keep in mind the issue of publication bias, as negative reports are less likely to be published. We recommend (1) to search carefully for the presence of connective tissue disease in cases of idiopathic ILD, (2) serological profiling by including antisynthetase and American Journal of Therapeutics (2016) 23(2)
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SSA antibodies in the workup of idiopathic ILD, (3) primary prophylaxis for Pneumocystis jirovecii pneumonia should be considered in patients who are treated with rituximab, especially in the presence of ILD, other cytotoxic agents, or high-dose steroids,36 and (4) finally, we underscore the potential for using rituximab as a treatment option in ILD related to ASS especially in severe or treatment-resistant cases.
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