http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2013; Early Online: 1–4 © 2013 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844306
CASE REPORT
TNF-alpha inhibitors in Systemic Lupus Erythematosus. A case report and a systematic literature review
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Marta Mosca1, Chiara Tani1, Maria Elena Filice3, Linda Carli1, Andrea Delle Sedie2, Sabrina Vagnani1, Alessandra Della Rossa2, Chiara Baldini1, and Stefano Bombardieri1 1Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa Italy, 2Rheumatology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy, and 3Pathology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
Abstract
Keywords
Joint involvement is a common manifestation of systemic lupus erythematosus (SLE) and is described as a non-erosive mild synovitis. However some SLE patients may present a more severe joint involvement requiring aggressive therapy. We describe the case of a SLE patient with a severe arthritis unresponsive to methotrexate, successfully treated with anti-TNF-alpha drug as induction therapy and we report the results of a systematic literature review on the use of TNF-alpha inhibitors in SLE.
Anti-TNF therapy, Joint involvement, Systemic lupus erythematosus, treatment targets
Introduction Joint involvement is a common manifestation of many rheumatic diseases [1–5]. In systemic lupus erythematosus (SLE), arthritis is observed in up to 80% of patients and is generally described as mild and non-erosive; however, SLE patients may develop a more severe type of joint involvement either as deforming non-erosive arthritis known as Jaccoud’s arthropathy or as erosive arthritis. Finally, the overlap of SLE and rheumatoid arthritis (RA) has been described, the so called rhupus syndrome, which may require a more aggressive treatment [6–10]. We describe the case of a patient with SLE and severe joint involvement, successfully treated with TNF-alpha inhibitors and report the results of a systematic literature review (SLR) on the use of TNF-alpha inhibitors in SLE. Clinical case A 25-year-old female patient came to our observation in 2009; she had been diagnosed with SLE 7 years before based on the presence of serositis, acute cutaneous lupus and positive antinuclear antibodies (ANA). At physical examination, she presented a diffuse subacute cutaneous rash and hands and wrists arthritis. The laboratory assessment showed the presence of low complement, mild proteinuria (600 mg/24 h), positive ANA, anti-dsDNA and anti-Ro/SSA antibodies, while anti-phospholipid and anti-Sm antibodies were negative as well as rheumatoid factor and antiCCP antibodies. A joint ultrasound showed the presence of active wrists synovitis and proliferative tenosynovitis. A kidney biopsy showed a Class II glomerulonephritis, confirmed with immunofluorescence (IgA, IgM, C3, C1q granular deposits, parietal Correspondence to: Marta Mosca, MD, PhD, Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, UO Reumatologia, Ospedale Santa Chiara, Via Roma 67, 56126 Pisa, Italy. Tel: ⫹ 39 050 558601. Fax: ⫹ 39 050 558630. E-mail: marta.mosca@ med.unipi.it
History Received 4 April 2013 Accepted 25 May 2013 Published online 31 October 2013
and mesangial, diffuse segmental. IgG granular parietal and mesangial deposits, diffuse segmental). The patient was treated with pulse methylprednisolone (MP) 250 mg for 3 consecutive days, hydroxychloroquine 200 mg/day, and azathioprine 100 mg/day, obtaining a partial response which was not maintained with MP tapering. Therefore methotrexate (MTX) 15 mg/week was started with a complete remission of cutaneous manifestations, joint involvement and proteinuria. However, with MP tapering below 12 mg/day, a flare of joint involvement was observed. An attempt was made to change MTX with leflunomide but this drug had to be discontinued due to a severe cutaneous adverse reaction. Since joint involvement was mainly localized at the left wrist, in 2010 the patient underwent surgical synovectomy. Surgery was followed by treatment with MTX 15 mg but only transient improvement was obtained, with reappearance of synovitis after 4 months. Over the following months the patient continued treatment with MTX, hydroxychloroquine and a MP dose ranging between 8 and 12 mg/daily. A repeated ultrasound confirmed the presence of active wrists synovitis and proliferative tenosynovitis with no evidence of erosions. At this time a joint MRI was also performed and no evidence of joint erosions was observed as well. RF and anti-CCP antibodies were persistently negative. Based on these observations arthritis was attributed to SLE and, in 2011, a second surgical synovectomy was performed. The histological analysis of the synovial tissue, revealed the presence of chronic inflammatory tissue, composed by lymphocytes, mononucleated cells and histiocytes, with abundant multinucleated giant cells, organized in submillimetric granulomas (granulomatous and gigantocellular synovitis) (Figures 1 and 2). Mycobacterial infection was excluded with Ziehl–Nielsen staining and PCR analysis for mycobacterial DNA. Considering the severity of the synovitis, the poor response to traditional DMARDs, and the chronic requirement of medium doses of MP, in July 2012 treatment with anti-CD20 was proposed to the patient who refused, and subsequently anti TNF-alpha treatment
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Figure 1. Magnification 10x; E-E; granuloma with multinucleated giant cells, surrounded by mononucleated cells (lymphocytes and plasma cells).
Figure 3. Ultrasound evaluation before and after anti-TNF therapy. (A) Wrist arthritis with joint effusion, synovial hyperplasia and Power Doppler signal (score 2). (B) Complete resolution of synovitis and absence of power Doppler signal.
SLR on the use of TNF-alpha blockers in SLE
Figure 2. Magnification 4x; E-E: multiple granulomas with multinucleated giant cells.
with etanercept was started. After 2 weeks of treatment, the patient presented with erythema and pruritus in the site of injection; for this reason in September 2012 she was switched to certolizumab pegol which was well tolerated. With this treatment we obtained a complete resolution of synovitis, anti-dsDNA and anti-cardiolipin antibodies remained negative and no disease flares were observed. In view of the complete clinical and ultrasonographic response, certolizumab pegol was stopped in December 2012 after 3 months of therapy (Figure 3). At our last observation, in March 2013, the patient had a complete clinical remission of joint involvement and had been able to taper MP to 4 mg/day. US evaluation of the wrist showed complete regression of the synovitis with no power Doppler signal. No disease flares were observed.
We systematically reviewed the available literature evidence on the therapeutic use of TNF-alpha blockers in SLE. In August 2012 MedLine (via PubMed) was searched according to the search strategies reported in Table 1. Searches were limited to articles published in the last 20 years (1992–2012), humans, adult patients, written in English, Italian or French. A total of 80 records were retrieved; after screening by title and abstract, a list of 20 potentially useful papers were evaluated as full text. At the end of the selection process, a total of 12 articles were included in the SLR, 4 clinical trials and 8 case reports (Tables 2 and 3) [11–23]. Only the study by Uppal et al. [16] was an open label randomized controlled trial, while the remaining were open label uncontrolled trials or observational studies. The majority of patients have been treated with Infliximab, employed at different dosages and treatment schedules for a mean of five doses (min 3–max 16 doses); only case reports are available on the use of etanercept. Infliximab therapy was effective in reducing global disease activity and GC doses [11–13], improving renal parameters [10, 13] and controlling arthritis [11, 10]. A single case of beneficial effect on interstitial lung disease has been reported [10], and four independent cases of refractory hemophagocytic lymphohistiocytosis successfully treated with Infliximab (2 cases) or Etanercept (2 cases) have been described [14–17]. Etanercept was used in one
Table 1. Search strategy for SLR. Clinical question Can TNF-alpha inhibitors be used in SLE?
PICO P ⫽ adult SLE patients I ⫽ anti-TNF alpha therapy C ⫽ none O ⫽ efficacy and safety
Search strategy (“lupus erythematosus, systemic” [MeSH Terms] OR “lupus” [All Fields] AND “erythematosus” [All Fields]) AND (“tumor necrosis factors” [MeSH Terms] OR “tumor necrosis factors” [All Fields] OR OR “tnf alpha” [All Fields] OR “tumor necrosis factoralpha” [MeSH Terms] OR “tumor necrosis factor-alpha” [All Fields] OR “infliximab” [All Fields] OR “TNFR-Fc fusion protein” [All Fields] OR “etanercept” [All Fields] OR “adalimumab” [All Fields] OR “certolizumab pegol” [All Fields] OR “certolizumab” [All Fields]) AND (“safety” [MeSH Terms] OR “safety” [All Fields] OR efficacy [All Fields])
TNF-alpha inhibitors in Systemic Lupus Erythematosus 3
DOI 10.3109/14397595.2013.844306
Table 2. Evidence table: clinical studies.
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Author, year of publication Aringer M, 2004
Study design Open label
Uppal SS, 2009
Open label randomized controlled trial
Aringer M, 2009
Open label⫹ observational
Matsumura R, 2009
Observational
No. of patients, organ involvement 6 low-moderate disease activity (4 renal, 3 joint) 27 9 assigned to the Infliximab arm (4 arthritis, 3 renal, 2 NP, 4 skin)
Treatment schedule Infliximab 4 i.v. doses 300 mg
Follow-up duration 62 weeks
Infliximab 3 mg/kg five doses
24 weeks
13 9 renal, 5 arthritis, 1 interstitial lung disease
Infliximab Mean no. of infusions 5.5 (min 4–max 16)
Mean 4.4 years (2.9–6.1)
9 Lupus nephritis resistant to standard treatment
Infliximab 200 mg/kg for three doses
24 weeks
patient to treat diffuse proliferative glomerulonephritis in association with plasmapheresis and IVIg [18]. As far as safety data are concerned, Uppal et al reported no differences in adverse events, infections, number of admissions and pulse GC requirements between treatment and control arms, four drop-outs for non-severe infusion reaction have been registered in the treatment group [12]. No increases in disease activity nor serious adverse events were reported by Aringer et al in 2004, while the same authors described one fatal pneumonia, one deep vein thrombosis, one cerebral lymphoma and one renal carcinoma, six minor infections and two rashes at the follow-up extension study [10]. One case of fatal progressive multifocal leukoencephalopathy has been described in a SLE patient with erosive arthritis under treatment etanercept [19]. In all the studies, an increase in autoantibodies titers has been observed, without clinically significant increase in disease activity. The longest observational period was 4.4 years, reported by Aringer et al. [10,11]. In conclusion, the available data on TNF-alpha blockers in SLE are still scarce; randomized controlled trials and long-term observational studies appear needed to confirm their efficacy and long-term safety
Discussion In our opinion, this case is interesting for a number of reasons. First, the severity of synovitis in this patient was uncommon and
Results Efficacy: global disease activity decrease, arthritis flare after discontinuation. Safety: no SAE, no increase in disease activity Efficacy: significant reduction in SLEDAI score and GC doses. Safety: four drop-outs because of non-severe drug reaction. No differences in adverse events, infections, number of admission and pulse GC requirements Efficacy: arthritis 100% remission but relapse after stopping therapy. Nephritis: sustained 50% improving in proteinuria in 77%. Safety: six minor infections, two rash, one fatal pneumonia, one deep vein thrombosis, one cerebral lymphoma, one renal carcinoma Efficacy: proteinuria improvement and SLEDAI decrease in 75%. Recurrence at 6 months: 16%. Safety: one pyelonephritis, one infusion reaction, one brainstem infarction
there were no data supporting a possible overlap with RA. In particular, rheumatoid factor and anti-CCP antibodies were negative, no erosions were observed at joint ultrasound and MRI and the patient had a typical SLE (kidney biopsy showing LN, subacute cutaneous lupus with a suggestive skin biopsy, autoantibody profile and hypocomplementemia). However the histological analysis of the synovial tissue showed the presence of granulomatous synovitis, which may be observed in RA [1] but, to the best of our knowledge, has never been reported in lupus arthropathy [24]. This suggests the need for extensive evaluations and synovial biopsies in patients who present with joint involvement refractory to traditional therapy. Secondly, this patient was treated with anti-TNF drugs which led to a complete remission of her joint involvement. Anti-TNF therapy was used as induction therapy as the patient was treated for 3 months and subsequently maintained with MTX with a complete joint response and no flares of disease activity. The use of anti-TNF drugs in SLE is controversial, increases in autoantibody titers have been reported and flares of joint involvement have been observed shortly after the end of anti-TNF drugs [13–15]. In our patient we did not observe an increase in autoantibody titers or an arthritis flares after anti-TNF withdrawal. Different explanations could be hypothesized for these observations such as the type of anti-TNF used, a relatively short follow-up as well as the short duration of the treatment. This last hypothesis
Table 3. Evidence table: case reports. Author, year of publication Kikuchi H, 2012 Takahashi N, 2008 Henzan T, 2006 Naretto C, 2009 Ideguchi H, 2007 Micheloud D, 2006 Hayat SJ, 2007 Graff-Radford J, 2012
No. of patients 1 1 1 1 1 1 1 1
Organ involvement indication Refractory hemophagocitosis Refractory hemophagocitosis Refractory hemophagocytic lymphohistiocytosis Sneddon–Wilkinson’s disease associated with SLE Refractory hemophagocytic lymphohistiocytosis Diffuse proliferative lupus nephritis (plus plasmapheresis and IVIG) Active non-renal SLE erosive arthritis
Drug Etanercept Etanercept Infliximab Infliximab Infliximab Etanercept Infliximab Etanercept
Outcome Symptoms resolution Symptoms resolution Symptom resolution Symptom resolution Symptom resolution Remission Symptoms resolution Progressive multifocal leukoencephalopathy
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could support the safety of the use of short term anti-TNF therapy as an induction therapy in selected SLE patients. Finally, this case also raises questions on the targets of therapy of SLE in routine clinical practice. In fact, initially, a low level of residual disease activity was considered acceptable when compared with the clinical picture observed at the beginning of the flare. However, the patient was treated with a medium dose of corticosteroids for a prolonged period with potential damage accrual. With the availability of new drugs, the definition of targets to treatment in SLE appears needed to guide the treating physicians [8–10]. In conclusion, although traditionally considered as mild, joint involvement in SLE may be severe and may cause significant burden on patients in terms of quality of life and treatment. Additional characterization of the disease with imaging techniques and, when needed, with biopsies as well as the identification of novel biomarkers, may guide to a more personalized therapeutic approach [25, 26]. In selected patients with SLE and severe joint involvement, short-term induction therapy with anti-TNF-alpha drugs could be a safe therapeutic option.
Mod Rheumatol, 2013; Early Online: 1–4
11.
12. 13. 14.
15. 16. 17.
Conflict of interest None.
18.
References 1. Cappelli S, Bellando Randone S, Martinović D, Tamas MM, Pasalić K, Allanore Y, et al. “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012;41(4): 589–98. 2. Mosca M, Tani C, Carli L, Bombardieri S. Undifferentiated CTD: a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol. 2012;26:73–7. 3. Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev. 2006;6:1–4. 4. Mosca M, Tani C, Talarico R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): simplified systemic autoimmune diseases. Autoimmun Rev. 2011;10:256–8. 5. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999; 17:615–20. 6. Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y. Systemic lupus erythematosus one disease or many? Autoimmun Rev. 2012;11:593–5. 7. Mosca M, Tani C, Carli L, Bombardieri S. Glucocorticoids in systemic lupus erythematosus. Clin Exp Rheumatol 2011;29:S126–9. 8. Tani C, D’Aniello D, Sedie AD, Carli L, Cagnoni M, Possemato N, et al. Rhupus syndrome: assessment of its prevalence and its clinical and instrumental characteristics in a prospective cohort of 103 SLE patients. Autoimmun Rev. 2013;12(4):537–41. 9. Mosca M, Boumpas DT, Bruce IN, Cervera R, Czirjak L, Dörner T, et al. Treat-to-target in systemic lupus erythematosus: where are we today? Clin Exp Rheumatol. 2012;30:S112–5. 10. Turchetti G, Yazdany J, Palla I, Yelin E, Mosca M. Systemic lupus erythematosus and the economic perspective: a systematic literature
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review and points to consider. Clin Exp Rheumatol. 2012;30 (4 Suppl 73):S116–22. Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor α: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum. 2000;43:2383–90. Aringer M, Smolen JS. Efficacy and safety of TNF blocker therapy in systemic lupus erythematosus. Expert Opin Drug Saf. 2008;7:411–9. Soforo E, Baumgartner M, Francis L, Allam F, Phillips PE, Perl A. Induction of systemic lupus erythematosus with tumor necrosis factor blockers. J Rheumatol. 2010;37:204–5. Aringer M, Houssiau F, Gordon C, Graninger WB, Voll RE, Rath E, et al. Adverse events and efficacy of TNF-alpha blockade with infliximab in patients with systemic lupus erythematosus: long-term follow-up of 13 patients. Rheumatology. 2009;48:1451–4. Aringer M, Graninger WB, Steiner G, Smolen JS. Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum. 2004;50:3161–9. Uppal SS, Hayat SJ, Raghupathy R. Efficacy and safety of infliximab in active SLE: a pilot study. Lupus. 2009;18:690–7. Matsumura R, Umemiya K, Sugiyama T, Sueishi M, Umibe T, Ichikawa K, Yoshimura M; Study Group on Nephrology at the National Hospital Organization of Japan. Anti-tumor necrosis factor therapy in patients with difficult-to-treat lupus nephritis: a prospective series of nine patients. Clin Exp Rheumatol. 2009;27:416–21. Kikuchi H, Yamamoto T, Asako K, Takayama M, Shirasaki R, Ono Y. Etanercept for the treatment of intractable hemophagocytic syndrome with systemic lupus erythematosus. Mod Rheumatol. 2012;22:308–11. Takahashi N, Naniwa T, Banno S. Successful use of etanercept in the treatment of acute lupus hemophagocytic syndrome. Mod Rheumatol. 2008;18:72–5. Henzan T, Nagafuji K, Tsukamoto H, Miyamoto T, Gondo H, Imashuku S, Harada M. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am J Hematol. 2006;81: 59–61. Ideguchi H, Ohno S, Takase K, Hattori H, Kirino Y, Takeno M, Ishigatsubo Y. Successful treatment of refractory lupus-associated haemophagocytic lymphohistiocytosis with infliximab. Rheumatology. 2007;46:1621–22. Micheloud D, Nuño L, Rodríguez-Mahou M, Sánchez-Ramón S, Ortega MC, Aguarón A, et al. Efficacy and safety of Etanercept, highdose intravenous gammaglobulin and plasmapheresis combined therapy for lupus diffuse proliferative nephritis complicating pregnancy. Lupus. 2006; 15: 881–5. Graff-Radford J, Robinson MT, Warsame RM, Matteson EL, Eggers SD, Keegan BM. Progressive multifocal leukoencephalopathy in a patient treated with etanercept. Neurologist. 2012;18:85–7. Weyand CM. Immunopathologic aspects of rheumatoid arthritis: who is the conductor and who plays the immunologic instrument? J Rheumatol. 2007;79:9–14. Martini D, Baldini C, Latorre M, Giorgerini V, Sernissi F, Della Rossa A, Mosca M. Future prospects for salivary proteomics in rheumatology: the example of eosinophil granulomatosis with polyangiitis. Clin Exp Rheumatol. 2012;30:810–11. Gallo A, Baldini C, Teos L, Mosca M, Bombardieri S, Alevizos I. Emerging trends in Sjögren’s syndrome: basic and translational research. Clin Exp Rheumatol. 2012;30:779–84.
CASE REPORT
TNF-alpha inhibitors in Systemic Lupus Erythematosus. A case report and a systematic literature review
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Marta Mosca1, Chiara Tani1, Maria Elena Filice3, Linda Carli1, Andrea Delle Sedie2, Sabrina Vagnani1, Alessandra Della Rossa2, Chiara Baldini1, and Stefano Bombardieri1 1Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa Italy, 2Rheumatology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy, and 3Pathology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
Abstract
Keywords
Joint involvement is a common manifestation of systemic lupus erythematosus (SLE) and is described as a non-erosive mild synovitis. However some SLE patients may present a more severe joint involvement requiring aggressive therapy. We describe the case of a SLE patient with a severe arthritis unresponsive to methotrexate, successfully treated with anti-TNF-alpha drug as induction therapy and we report the results of a systematic literature review on the use of TNF-alpha inhibitors in SLE.
Anti-TNF therapy, Joint involvement, Systemic lupus erythematosus, treatment targets
Introduction Joint involvement is a common manifestation of many rheumatic diseases [1–5]. In systemic lupus erythematosus (SLE), arthritis is observed in up to 80% of patients and is generally described as mild and non-erosive; however, SLE patients may develop a more severe type of joint involvement either as deforming non-erosive arthritis known as Jaccoud’s arthropathy or as erosive arthritis. Finally, the overlap of SLE and rheumatoid arthritis (RA) has been described, the so called rhupus syndrome, which may require a more aggressive treatment [6–10]. We describe the case of a patient with SLE and severe joint involvement, successfully treated with TNF-alpha inhibitors and report the results of a systematic literature review (SLR) on the use of TNF-alpha inhibitors in SLE. Clinical case A 25-year-old female patient came to our observation in 2009; she had been diagnosed with SLE 7 years before based on the presence of serositis, acute cutaneous lupus and positive antinuclear antibodies (ANA). At physical examination, she presented a diffuse subacute cutaneous rash and hands and wrists arthritis. The laboratory assessment showed the presence of low complement, mild proteinuria (600 mg/24 h), positive ANA, anti-dsDNA and anti-Ro/SSA antibodies, while anti-phospholipid and anti-Sm antibodies were negative as well as rheumatoid factor and antiCCP antibodies. A joint ultrasound showed the presence of active wrists synovitis and proliferative tenosynovitis. A kidney biopsy showed a Class II glomerulonephritis, confirmed with immunofluorescence (IgA, IgM, C3, C1q granular deposits, parietal Correspondence to: Marta Mosca, MD, PhD, Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, UO Reumatologia, Ospedale Santa Chiara, Via Roma 67, 56126 Pisa, Italy. Tel: ⫹ 39 050 558601. Fax: ⫹ 39 050 558630. E-mail: marta.mosca@ med.unipi.it
History Received 4 April 2013 Accepted 25 May 2013 Published online 31 October 2013
and mesangial, diffuse segmental. IgG granular parietal and mesangial deposits, diffuse segmental). The patient was treated with pulse methylprednisolone (MP) 250 mg for 3 consecutive days, hydroxychloroquine 200 mg/day, and azathioprine 100 mg/day, obtaining a partial response which was not maintained with MP tapering. Therefore methotrexate (MTX) 15 mg/week was started with a complete remission of cutaneous manifestations, joint involvement and proteinuria. However, with MP tapering below 12 mg/day, a flare of joint involvement was observed. An attempt was made to change MTX with leflunomide but this drug had to be discontinued due to a severe cutaneous adverse reaction. Since joint involvement was mainly localized at the left wrist, in 2010 the patient underwent surgical synovectomy. Surgery was followed by treatment with MTX 15 mg but only transient improvement was obtained, with reappearance of synovitis after 4 months. Over the following months the patient continued treatment with MTX, hydroxychloroquine and a MP dose ranging between 8 and 12 mg/daily. A repeated ultrasound confirmed the presence of active wrists synovitis and proliferative tenosynovitis with no evidence of erosions. At this time a joint MRI was also performed and no evidence of joint erosions was observed as well. RF and anti-CCP antibodies were persistently negative. Based on these observations arthritis was attributed to SLE and, in 2011, a second surgical synovectomy was performed. The histological analysis of the synovial tissue, revealed the presence of chronic inflammatory tissue, composed by lymphocytes, mononucleated cells and histiocytes, with abundant multinucleated giant cells, organized in submillimetric granulomas (granulomatous and gigantocellular synovitis) (Figures 1 and 2). Mycobacterial infection was excluded with Ziehl–Nielsen staining and PCR analysis for mycobacterial DNA. Considering the severity of the synovitis, the poor response to traditional DMARDs, and the chronic requirement of medium doses of MP, in July 2012 treatment with anti-CD20 was proposed to the patient who refused, and subsequently anti TNF-alpha treatment
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Figure 1. Magnification 10x; E-E; granuloma with multinucleated giant cells, surrounded by mononucleated cells (lymphocytes and plasma cells).
Figure 3. Ultrasound evaluation before and after anti-TNF therapy. (A) Wrist arthritis with joint effusion, synovial hyperplasia and Power Doppler signal (score 2). (B) Complete resolution of synovitis and absence of power Doppler signal.
SLR on the use of TNF-alpha blockers in SLE
Figure 2. Magnification 4x; E-E: multiple granulomas with multinucleated giant cells.
with etanercept was started. After 2 weeks of treatment, the patient presented with erythema and pruritus in the site of injection; for this reason in September 2012 she was switched to certolizumab pegol which was well tolerated. With this treatment we obtained a complete resolution of synovitis, anti-dsDNA and anti-cardiolipin antibodies remained negative and no disease flares were observed. In view of the complete clinical and ultrasonographic response, certolizumab pegol was stopped in December 2012 after 3 months of therapy (Figure 3). At our last observation, in March 2013, the patient had a complete clinical remission of joint involvement and had been able to taper MP to 4 mg/day. US evaluation of the wrist showed complete regression of the synovitis with no power Doppler signal. No disease flares were observed.
We systematically reviewed the available literature evidence on the therapeutic use of TNF-alpha blockers in SLE. In August 2012 MedLine (via PubMed) was searched according to the search strategies reported in Table 1. Searches were limited to articles published in the last 20 years (1992–2012), humans, adult patients, written in English, Italian or French. A total of 80 records were retrieved; after screening by title and abstract, a list of 20 potentially useful papers were evaluated as full text. At the end of the selection process, a total of 12 articles were included in the SLR, 4 clinical trials and 8 case reports (Tables 2 and 3) [11–23]. Only the study by Uppal et al. [16] was an open label randomized controlled trial, while the remaining were open label uncontrolled trials or observational studies. The majority of patients have been treated with Infliximab, employed at different dosages and treatment schedules for a mean of five doses (min 3–max 16 doses); only case reports are available on the use of etanercept. Infliximab therapy was effective in reducing global disease activity and GC doses [11–13], improving renal parameters [10, 13] and controlling arthritis [11, 10]. A single case of beneficial effect on interstitial lung disease has been reported [10], and four independent cases of refractory hemophagocytic lymphohistiocytosis successfully treated with Infliximab (2 cases) or Etanercept (2 cases) have been described [14–17]. Etanercept was used in one
Table 1. Search strategy for SLR. Clinical question Can TNF-alpha inhibitors be used in SLE?
PICO P ⫽ adult SLE patients I ⫽ anti-TNF alpha therapy C ⫽ none O ⫽ efficacy and safety
Search strategy (“lupus erythematosus, systemic” [MeSH Terms] OR “lupus” [All Fields] AND “erythematosus” [All Fields]) AND (“tumor necrosis factors” [MeSH Terms] OR “tumor necrosis factors” [All Fields] OR OR “tnf alpha” [All Fields] OR “tumor necrosis factoralpha” [MeSH Terms] OR “tumor necrosis factor-alpha” [All Fields] OR “infliximab” [All Fields] OR “TNFR-Fc fusion protein” [All Fields] OR “etanercept” [All Fields] OR “adalimumab” [All Fields] OR “certolizumab pegol” [All Fields] OR “certolizumab” [All Fields]) AND (“safety” [MeSH Terms] OR “safety” [All Fields] OR efficacy [All Fields])
TNF-alpha inhibitors in Systemic Lupus Erythematosus 3
DOI 10.3109/14397595.2013.844306
Table 2. Evidence table: clinical studies.
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Author, year of publication Aringer M, 2004
Study design Open label
Uppal SS, 2009
Open label randomized controlled trial
Aringer M, 2009
Open label⫹ observational
Matsumura R, 2009
Observational
No. of patients, organ involvement 6 low-moderate disease activity (4 renal, 3 joint) 27 9 assigned to the Infliximab arm (4 arthritis, 3 renal, 2 NP, 4 skin)
Treatment schedule Infliximab 4 i.v. doses 300 mg
Follow-up duration 62 weeks
Infliximab 3 mg/kg five doses
24 weeks
13 9 renal, 5 arthritis, 1 interstitial lung disease
Infliximab Mean no. of infusions 5.5 (min 4–max 16)
Mean 4.4 years (2.9–6.1)
9 Lupus nephritis resistant to standard treatment
Infliximab 200 mg/kg for three doses
24 weeks
patient to treat diffuse proliferative glomerulonephritis in association with plasmapheresis and IVIg [18]. As far as safety data are concerned, Uppal et al reported no differences in adverse events, infections, number of admissions and pulse GC requirements between treatment and control arms, four drop-outs for non-severe infusion reaction have been registered in the treatment group [12]. No increases in disease activity nor serious adverse events were reported by Aringer et al in 2004, while the same authors described one fatal pneumonia, one deep vein thrombosis, one cerebral lymphoma and one renal carcinoma, six minor infections and two rashes at the follow-up extension study [10]. One case of fatal progressive multifocal leukoencephalopathy has been described in a SLE patient with erosive arthritis under treatment etanercept [19]. In all the studies, an increase in autoantibodies titers has been observed, without clinically significant increase in disease activity. The longest observational period was 4.4 years, reported by Aringer et al. [10,11]. In conclusion, the available data on TNF-alpha blockers in SLE are still scarce; randomized controlled trials and long-term observational studies appear needed to confirm their efficacy and long-term safety
Discussion In our opinion, this case is interesting for a number of reasons. First, the severity of synovitis in this patient was uncommon and
Results Efficacy: global disease activity decrease, arthritis flare after discontinuation. Safety: no SAE, no increase in disease activity Efficacy: significant reduction in SLEDAI score and GC doses. Safety: four drop-outs because of non-severe drug reaction. No differences in adverse events, infections, number of admission and pulse GC requirements Efficacy: arthritis 100% remission but relapse after stopping therapy. Nephritis: sustained 50% improving in proteinuria in 77%. Safety: six minor infections, two rash, one fatal pneumonia, one deep vein thrombosis, one cerebral lymphoma, one renal carcinoma Efficacy: proteinuria improvement and SLEDAI decrease in 75%. Recurrence at 6 months: 16%. Safety: one pyelonephritis, one infusion reaction, one brainstem infarction
there were no data supporting a possible overlap with RA. In particular, rheumatoid factor and anti-CCP antibodies were negative, no erosions were observed at joint ultrasound and MRI and the patient had a typical SLE (kidney biopsy showing LN, subacute cutaneous lupus with a suggestive skin biopsy, autoantibody profile and hypocomplementemia). However the histological analysis of the synovial tissue showed the presence of granulomatous synovitis, which may be observed in RA [1] but, to the best of our knowledge, has never been reported in lupus arthropathy [24]. This suggests the need for extensive evaluations and synovial biopsies in patients who present with joint involvement refractory to traditional therapy. Secondly, this patient was treated with anti-TNF drugs which led to a complete remission of her joint involvement. Anti-TNF therapy was used as induction therapy as the patient was treated for 3 months and subsequently maintained with MTX with a complete joint response and no flares of disease activity. The use of anti-TNF drugs in SLE is controversial, increases in autoantibody titers have been reported and flares of joint involvement have been observed shortly after the end of anti-TNF drugs [13–15]. In our patient we did not observe an increase in autoantibody titers or an arthritis flares after anti-TNF withdrawal. Different explanations could be hypothesized for these observations such as the type of anti-TNF used, a relatively short follow-up as well as the short duration of the treatment. This last hypothesis
Table 3. Evidence table: case reports. Author, year of publication Kikuchi H, 2012 Takahashi N, 2008 Henzan T, 2006 Naretto C, 2009 Ideguchi H, 2007 Micheloud D, 2006 Hayat SJ, 2007 Graff-Radford J, 2012
No. of patients 1 1 1 1 1 1 1 1
Organ involvement indication Refractory hemophagocitosis Refractory hemophagocitosis Refractory hemophagocytic lymphohistiocytosis Sneddon–Wilkinson’s disease associated with SLE Refractory hemophagocytic lymphohistiocytosis Diffuse proliferative lupus nephritis (plus plasmapheresis and IVIG) Active non-renal SLE erosive arthritis
Drug Etanercept Etanercept Infliximab Infliximab Infliximab Etanercept Infliximab Etanercept
Outcome Symptoms resolution Symptoms resolution Symptom resolution Symptom resolution Symptom resolution Remission Symptoms resolution Progressive multifocal leukoencephalopathy
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could support the safety of the use of short term anti-TNF therapy as an induction therapy in selected SLE patients. Finally, this case also raises questions on the targets of therapy of SLE in routine clinical practice. In fact, initially, a low level of residual disease activity was considered acceptable when compared with the clinical picture observed at the beginning of the flare. However, the patient was treated with a medium dose of corticosteroids for a prolonged period with potential damage accrual. With the availability of new drugs, the definition of targets to treatment in SLE appears needed to guide the treating physicians [8–10]. In conclusion, although traditionally considered as mild, joint involvement in SLE may be severe and may cause significant burden on patients in terms of quality of life and treatment. Additional characterization of the disease with imaging techniques and, when needed, with biopsies as well as the identification of novel biomarkers, may guide to a more personalized therapeutic approach [25, 26]. In selected patients with SLE and severe joint involvement, short-term induction therapy with anti-TNF-alpha drugs could be a safe therapeutic option.
Mod Rheumatol, 2013; Early Online: 1–4
11.
12. 13. 14.
15. 16. 17.
Conflict of interest None.
18.
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