Accelerated subcutaneous nodulosis in patients with rheumatoid arthritis treated with tocilizumab: a case series

Accelerated subcutaneous nodulosis in patients with rheumatoid arthritis treated with... Background: Tocilizumab is a monoclonal antibody directed against the interleukin-6 receptor, which is approved for the treatment of moderate-to-severe rheumatoid arthritis. Authors have found that it prevents lung and subcutaneous nodulosis in patients with rheumatoid arthritis but, to the best of our knowledge, there are no data concerning the acceleration of subcutaneous nodulosis during tocilizumab therapy. Case presentation: We report for the first time a small case series of five patients with rheumatoid arthritis: a 46-year-old white woman, a 70-year-old white woman, a 63-year-old white woman, a 69-year-old white man, and a 72-year-old white woman (mean age 64 ± 10.6 years); they experienced worsening subcutaneous nodulosis during treatment with intravenously administered tocilizumab. Four of the five patients were positive for rheumatoid factor and five for anti-citrullinated peptide antibodies. All of the patients had previously been treated with various conventional and biological drugs; at the time of our observation, three were taking methotrexate, two hydroxychloroquine, and four were taking prednisone. Tocilizumab 8 mg/kg was administered intravenously every 4 weeks for a mean of 43.4 ± 32.4 months, and led to good disease control in three cases. All of the patients had a history of subcutaneous nodulosis, which considerably worsened during tocilizumab treatment, with the development of new nodules on their fingers, elbows, or in the inframammary fold, tending to ulcerate. The management of this medical event included discontinuation of methotrexate, the administration of steroids, the addition of hydroxychloroquine or colchicine, the use of antibiotics, and surgery. However, neither pharmacological nor surgical treatment was completely effective, as the nodules tended to recur and increased in number and size. Conclusions: To the best of our knowledge, this is the first report describing accelerated subcutaneous nodulosis in a small case series of patients with rheumatoid arthritis treated with tocilizumab. Keywords: Rheumatic nodulosis, Tocilizumab, Rheumatoid arthritis Background methotrexate (MTX) and, to some extent, azathioprine, Subcutaneous nodulosis describes an extra-articular mani- leflunomide, and anti-tumor necrosis factor (TNF) agents, festation occurring in patients affected by rheumatoid whereas the use of colchicine and hydroxychloroquine arthritis (RA). The nodules may develop in the subcutane- (HCQ) may improve the course of the disease. ous layer of the hands and elbows, on Achilles tendons, The development of subcutaneous nodules in patients and may also involve the lungs and vocal chords. Nodulo- with RA has been explained on the basis of a rheumatic sis may be accelerated by concomitant treatment with vasculitis, which is characterized by the precipitation of immune complexes in the small vessels and the subsequent activation of the complement cascade. Vessel * Correspondence: talotta1@virgilio.it inflammation is attributed to the infiltration of poly- Department of Rheumatology, ASST Fatebenefratelli-Sacco, via GB Grassi n. morphonuclear and mononuclear leukocytes, and the 74, 20157 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 2 of 6 development of granulomas that are finally responsible for TCZ treatment. Due to persistent high disease activity and the formation of nodules. the increase in the number and size of the rheumatoid Subtypes of RA characterized by high titers of rheuma- nodules she was swapped to golimumab 50 mg every toid factor (RF), other autoantibodies, or, more generic- month in January 2017, without any further progres- ally, a high degree of systemic inflammation are the sion of subcutaneous nodulosis despite poor control most susceptible to extra-articular complications, in- of RA symptoms. cluding subcutaneous nodulosis. The use of biological drugs that interfere with the cytokines involved in sys- Patient 2 temic inflammation, such as interleukin (IL)-6, should The second case was a 70-year-old, white, menopausal, be valuable in preventing the extra-articular manifesta- non-smoker of tobacco, retired woman. Since 1995 she tions of RA. Tocilizumab (TCZ) is a monoclonal anti- had suffered from immunoglobulin M (IgM) RF- body (moAb) directed against the IL-6 receptor that is negative, ACPA-positive and erosive RA, and rheuma- approved for the treatment of moderate-to-severe RA, toid nodules. Since 1997 she received MTX 15 mg/week and some authors have found that it prevents lung and plus HCQ 400 mg/day, and in 2003, due to poor control subcutaneous nodulosis in patients with RA [1, 2] but, of the disease, she underwent a treatment with intraven- to the best of our knowledge, there are no data concern- ously administered infliximab 3 mg/kg every 8 weeks, ing the acceleration of subcutaneous nodulosis during which was discontinued in 2014 for a progressive lack of TCZ therapy. efficacy and the de novo detection of ANA and anti- dsDNA (appearing at the eighth infusion and undetect- Case presentation able at baseline). Subsequent biologic treatments with We describe a small case series of five white patients with golimumab and abatacept showed no clinical effects; RA (one man and four women; mean age 64 ± 10.6 years; therefore, intravenously administered TCZ 8 mg/kg mean disease duration 21.8 ± 10.9 years) who experienced every 4 weeks combined with MTX 15 mg/week was significant worsening of subcutaneous nodulosis during started in June 2016. Since the start of TCZ, she experi- treatment with intravenously administered TCZ. Pa- enced a progressive worsening of subcutaneous nodulo- tients were consecutively recruited from October 2016 sis in her hands, with nodules tending to cluster and to January 2017. ulcerate. Moreover, new ulcerating nodules appeared in her inframammary folds. An antibiotic treatment with Patient 1 amoxicillin/clavulanate acid 1000 mg/day for 6 consecu- The first case was a 46-year-old white woman who was tive days was prescribed in order to avoid infections. In nullipara, a non-smoker of tobacco, and unemployed. December 2016 colchicine 1 mg every other day was Since 1998 she had suffered from RF and anti-citrullinated added and MTX discontinued. However, subcutaneous peptide antibodies (ACPA)-positive and erosive RA associ- nodulosis did not ameliorate, although no more ulcera- ated with rheumatoid nodules; she had been treated with tions were reported. several conventional and biological drugs (MTX, sulfasala- At the time of enrollment (November 2016), RA dis- zine, leflunomide, HCQ, infliximab, etanercept, adalimu- ease activity was moderate (CRP-DAS28 4.79), and she mab, rituximab, certolizumab, abatacept) plus prednisone was also taking prednisone 5 mg/day. (at a stable dose of 7.5 mg/day throughout the years); all of the drugs were discontinued for inefficacy or adverse Patient 3 events. In June 2014 she started intravenously adminis- The third case was a 63-year-old white woman who was tered TCZ 8 mg/kg every 4 weeks plus MTX 10 mg/week menopausal, a tobacco smoker, and employed. She was (further increase in dose not tolerated) and HCQ 6 mg/kg RF and ACPA-positive, had rheumatoid nodules, and a day, with minimal beneficial effects: C-reactive protein erosive RA was diagnosed in 1979 at another rheumato- disease activity score on 28 joints (CRP-DAS28) was > 5.1 logic center. Since 2006 she attended our Department and at the time of enrollment in the study. In 2006 (under started receiving orally administered MTX 7.5 mg/week etanercept therapy), anti-nuclear antibodies (ANA) turned and etanercept 50 mg/week administered by subcutaneous positive to a 1.160 titer with a homogeneous pattern; anti- injection, both discontinued in 2009 for adverse events. double stranded DNA (dsDNA) and anti-cardiolipin were Subsequently, she was treated with intravenously adminis- always negative at follow-up. In 2010, anti-Ro SSA anti- tered rituximab (discontinued for inefficacy), intraven- bodies were detected despite no report of symptoms of an ously administered abatacept (discontinued for inefficacy), overlapping connective tissue disease. Rheumatoid and, since April 2010, intravenously administered TCZ nodules at the fingers of both her hands, which never 8 mg/kg every 4 weeks in monotherapy (no compliance to showed a beneficial effect from all of the previous therap- conventional anti-rheumatic drugs), achieving and main- ies, dramatically increased in size and number during taining a good clinical response (CRP-DAS28 1.40 at the Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 3 of 6 enrollment time). Subcutaneous nodules of her right autoantibodies were persistently negative. In June 2010 elbow and fingers were pre-existent to the introduction of she was considered a candidate for intravenously adminis- TCZ. However, 2 months later, she reported a worsening tered TCZ 8 mg/kg every 4 weeks, which resulted in good of subcutaneous nodulosis at the fingers of her left hand control of RA (CRP-DAS28 1.74 at the enrollment time, and at her right elbow, which underwent a central ulcer- in November 2016), despite a mild leukopenia (absolute ation in February 2013. ANA and other auto-antibodies neutrophil count > 1000/mm ). From 2014 she also were negative at baseline and throughout the follow-up. A received HCQ 400 mg/day which was permanently brief course of methylprednisolone 4 mg/day for 4 weeks discontinued in 2016 due to visual disturbances. She was and a preventive antibiotic therapy with amoxicillin/clavu- affected by subcutaneous nodules at her elbows and lanate acid 1000 mg/day for 6 days were prescribed, with fingers prior to the start of TCZ; she experienced a some beneficial effects on ulcer healing. progressive increase in the size and number of the nodules during the treatment, and these manifestations Patient 4 partially worsened following the discontinuation of HCQ The fourth case was a 69-year-old white man who was (not assumed at the enrollment time). retired and who smoked tobacco; he had suffered from Table 1 shows the patients’ demographic characteristics. RF and ACPA-positive, non-erosive RA since 2009. In 2009 he started a treatment with intravenously adminis- Discussion tered infliximab 3 mg/kg every 8 weeks plus orally ad- We report five cases of accelerated subcutaneous nodulo- ministered MTX 7.5 mg/week and prednisone 2.5 mg/day sis under intravenously administered TCZ 8 mg/kg every with initial good disease control. In March 2010 his 4 weeks for a mean 43.4 ± 32.4 months of treatment. ANA titer was 1.160, with other autoantibody subsets All the patients had a history of subcutaneous nodulo- negative. In March 2014 he was swapped to intravenously sis, which considerably worsened during treatment with administered TCZ 8 mg/kg every 4 weeks due to progres- TCZ. They developed new subcutaneous nodules mainly sive inefficacy and development of rheumatoid nodulosis. on the fingers (Fig. 1a-f), but also on the elbow or in Concomitantly, a subcutaneous nodule of the first finger the inframammary fold. The nodules had a tendency to of his right hand was removed; the histologic diagnosis was compatible with a rheumatoid nodule. However, in Table 1 Demographic characteristics of the five patients with April 2014, soon after the introduction of TCZ, he com- rheumatoid arthritis plained from the onset of a new subcutaneous ulcerated Patients n =5 nodule at his left elbow. An antibiotic treatment with Gender (F/M), n 4/1 amoxicillin/clavulanate acid 1000 mg/day for 6 consecu- Age (years), mean ± SD 64.0 ± 10.6 tive days was started. In July 2014, giving the benefit of Disease duration (years), mean ± SD 21.8 ± 10.9 TCZ in clinical disease activity and the risk of precipita- Patients RF-positive, n (%) 4 (80%) ting nodulosis, MTX was definitively discontinued. How- ever, rheumatoid nodules at his fingers increased in Patients ACPA-positive, n (%) 5 (100%) number and, in November 2016, HCQ 200 mg/day was Patients ANA-positive, n (%) 4 (80%) added. At the enrollment time (November 2016), RA Patients anti-dsDNA-positive, n (%) 1 (20%) disease activity was in remission (CRP-DAS28 2.1). TCZ treatment duration (months), 43.4 ± 32.4 No development of new autoantibody positivity or change mean ± SD in ANA titration was recorded. Patients treated with prednisone 4 (80%) (2.5–7.5 mg/day), n (%) Patient 5 Patients treated with methotrexate 3 (60%) The last case was a 72-year-old white woman who was (7.5–15 mg/week), n (%) menopausal, a non-smoker of tobacco, and a housewife. Patients treated with hydroxychloroquine 2 (40%) In 1990 she was diagnosed as having erosive RF and (200–400 mg/day), n (%) ACPA-positive RA and rheumatoid nodules. Since then Demographic characteristics of the five patients included in the study. Four of the patients were positive for rheumatoid factor and five for anti-citrullinated peptide she received MTX 7.5 mg/week (further increase in dose antibodies; four patients had anti-nuclear antibodies and one had anti-double- not tolerated) plus prednisone 5 mg/day, with few stranded DNA antibodies. All of the patients had previously been treated with improvements in symptoms, and subsequently several bio- various conventional and biological drugs; at the time of observation, three were taking methotrexate at a mean dose ± SD of 11.6 ± 3.8 mg/week with folic acid logic drugs (infliximab, etanercept, rituximab, and adali- supplementation; two were taking hydroxychloroquine at a dose of 300 or mumab), which were all discontinued for adverse events 400 mg/day; and four were taking prednisone 2.5–7.5 mg/day. The patients had also been treated with intravenously administered TCZ 8 mg/kg every 4 weeks or inefficacy. During follow-up, her ANA titers fluctuated for a mean ± SD of 43.4 ± 32.4 months. ACPA anti-citrullinated peptide antibodies, from negative to positive values and vice versa (maximum ANA anti-nuclear antibodies, dsDNA anti-double stranded DNA, F females, M titer recorded 1.160), whereas anti-dsDNA and other males, RF rheumatoid factor, SD standard deviation, TCZ tocilizumab Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 4 of 6 ab c de f Fig. 1 Subcutaneous nodules on the dorsal surface of the hands of five patients with rheumatoid arthritis treated with tocilizumab. The nodules tended to cluster and ulcerate (c–e), and were surrounded by an erythematous halo (f) that was associated with local pain and disability ulcerate and released a serous but not purulent fluid, and a peripheral layer of epithelioid macrophages, lym- and perilesional inflammation and local pain greatly af- phocytes, and histiocytes. There is some evidence that fected their quality of life. the nodules may arise as a T helper (Th)1-mediated re- As there are still no standardized guidelines, this med- sponse, and highly express cytokines such TNF-α, IL-10, ical event was managed in various ways, including the IL-15, IL-18, and IL-12 [5, 6] but, interestingly, IL-17 tapering or discontinuation of MTX (two cases), the ad- does not seem to be involved in their pathogenesis. ministration of steroids (one case), the addition of HCQ Granulomatous responses are related to the activation of or colchicine (one case), the use of antibiotics to prevent Th1 lymphocytes and macrophages favoured by the local infective complications (three cases), and surgery with a production of cytokines such as IL-2 and TNF-α, histological examination that revealed a granulomatous whereas IL-17 seems to be mainly involved in lymph pattern compatible with rheumatoid nodules (one case). node organization and in the formation of germinal cen- However, neither pharmacological nor surgical treatment ters [7]; IL-17 is therefore associated with Th2 and B was completely effective as the nodules tended to recur lymphocyte activation and antibody production that de- and increased in number and size. In one case, TCZ was pend on a distinct immune pathway. By preventing the permanently discontinued because of poor clinical effi- maturation of Th-17 lymphocytes and the subsequent cacy; the patient was switched to an anti-TNF agent release of IL-17, TCZ may shift the immunological (golimumab) and is still being followed up. balance toward a more pronounced Th1 response that Subcutaneous nodulosis is the most frequently en- indirectly promotes rheumatic nodulosis, although cur- countered extra-articular manifestation of RA, and oc- rently available data are contrasting [8–10]. curs in up to 35% of patients [3]. The nodules typically The use of MTX (and sometimes azathioprine, leflu- develop on the dorsal surface of the fingers, the elbows nomide, and anti-TNF agents) may accelerate the growth or Achilles tendons, although they may also involve the of pre-existing nodules [11–14]. Drug-induced subcuta- lungs or vocal chords, and are often associated with high neous nodules have the same clinical and histological RF or ACPA titers, and a more aggressive and erosive characteristics as RA-related nodules, but the mechan- course of RA. A genetic substrate, cigarette smoking, ism by means of which the drugs favor subcutaneous and male gender have been controversially associated nodulosis while controlling articular symptoms is still with the risk of developing nodulosis [4]. The nodules unclear. Genetic susceptibility has been described in are usually characterized histologically by a granuloma- patients carrying the polymorphic variants of methionine tous process, with a central area of fibrinoid necrosis synthase reductase (MTR) or haplotype HLA-DRB1*0401 Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 5 of 6 [15, 16], and some authors have demonstrated that treat- Availability of data and materials Please contact author for data requests. ment with MTX is associated with the reactivation of Ep- stein–Barr virus, which may be responsible for the Authors’ contributions development of lymphoproliferative disorders or subcuta- RT conceived of the study, drafted the manuscript, and collected clinical and iconographic data; MCG, MCD, and AB collected clinical data; FA and PS neous nodules [17]. The concomitant use of colchicine, participated in the design and coordination of the study and helped to draft sulfasalazine, or HCQ seems to improve the course of the the manuscript. All authors read and approved the final manuscript. complication, and is therefore recommended in cases in Ethics approval and consent to participate which the discontinuation of MTX is contraindicated [11]. Not applicable. Anti-TNF-α biologic therapy (for example, infliximab and etanercept) is commonly used in the management of RA, Consent for publication Written informed consent was obtained from the patients for publication of especially in patients who are MTX-resistant. There have this case report and any accompanying images. A copy of the written been reports of accelerated subcutaneous and lung nodu- consents is available for review by the Editor-in-Chief of this journal. losis in patients with RA, developing early after starting Competing interests infliximab or etanercept, perhaps as a result of new auto- The authors declare that they have no competing interests. immune phenomena triggered by the neutralization of TNF-α [12, 18]. Publisher’sNote To the best of our knowledge, there are no data con- Springer Nature remains neutral with regard to jurisdictional claims in cerning accelerated subcutaneous nodulosis during treat- published maps and institutional affiliations. ment with TCZ. Some reports have even highlighted the Author details usefulness of TCZ in treating lung nodulosis induced by 1 Department of Rheumatology, ASST Fatebenefratelli-Sacco, via GB Grassi n. previous treatment with anti-TNF agents [1], and there 74, 20157 Milan, Italy. Rheumatology Unit, University of Messina, via Consolare Valeria 1, 98100 Messina, Italy. is one case report indicating its beneficial effect on olec- ranon subcutaneous nodules in a patient with RA [2]. Received: 21 July 2017 Accepted: 12 April 2018 Given its biological properties, TCZ reduces the burden of systemic inflammation and prevents extra-articular References manifestations, endothelial dysfunction, and vasculitis, 1. Andres M, Vela P, Romera C. Marked improvement of lung rheumatoid but there are some published reports describing the oc- nodules after treatment with tocilizumab. Rheumatology (Oxford). 2012; 51(6):1132–4. currence of dermatological complications such as leuko- 2. Al Attia HM, Abushawish M. Treatment with tocilizumab leads to the cytoclastic vasculitis and toxidermia [19, 20]. disappearance of olecranon rheumatoid nodules. Int J Dermatol. 2012; We have observed a visible worsening of subcutaneous 51(2):197–8. 3. Tilstra JS, Rheumatoid Nodules LDW. Dermatol Clin. 2015;33(3):361–71. nodulosis in 8.3% of the 60 patients receiving TCZ treat- 4. Mattey DL, Dawes PT, Fisher J, Brownfield A, Thomson W, Hajeer AH, et al. ment at our center, which may be related to a change in Nodular disease in rheumatoid arthritis: association with cigarette smoking the immune response toward more pronounced Th1 acti- and HLA-DRB1/TNF gene interaction. J Rheumatol. 2002;29(11):2313–8. 5. Hessian PA, Highton J, Kean A, Sun CK, Chin M. Cytokine profile of the vation. In addition, in our cohort of patients treated with rheumatoid nodule suggests that it is a Th1 granuloma. Arthritis Rheum. TCZ, there have also been three cases (5%) with subcuta- 2003;48(2):334–8. neous nodulosis which, however, remained stable during 6. Stamp LK, Easson A, Lehnigk U, Highton J, Hessian PA, Different T. cell subsets in the nodule and synovial membrane: absence of interleukin-17A the treatment. Further studies are required to clarify the in rheumatoid nodules. Arthritis Rheum. 2008;58(6):1601–8. mechanisms of pathogenesis underlying this association, 7. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, et al. and the real incidence of this little known event. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 2011;35(6):986–96. 8. Pesce B, Soto L, Sabugo F, Wurmann P, Cuchacovich M, Lòpez MN, Sotelo PH, . Effect of interleukin-6 receptor blockade on the balance between Conclusions regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exp Immunol. 2013;171(3):237–42. In conclusion, we report for the first time five cases of 9. Thiolat A, Semerano L, Pers YM, Biton J, Lemeiter D, Portales P, et al. accelerating subcutaneous nodulosis in patients with RA Interleukin-6 receptor blockade enhances CD39+ regulatory T cell intravenously treated with TCZ. All five patients suffering development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol. 2014;66(2):273–83. from pre-existing rheumatic nodulosis experienced its 10. Guggino G, Giardina AR, Raimondo S, Giardina G, Sireci G, Dieli F, et al. severe progression with local inflammation and ulceration. Targeting IL-6 signalling in early rheumatoid arthritis is followed by Th1 and Our data suggest that a clearer understanding of RA may Th17 suppression and Th2 expansion. Clin Exp Rheumatol. 2014;32(1):77–81. 11. Patatanian E, Thompson DF. A review of methotrexate-induced accelerated allow the identification of subtypes not previously appreci- nodulosis. Pharmacotherapy. 2002;22:1157–62. ated, finally leading to personalized therapies. However, 12. Mackley CL, Ostrov BE, Ioffreda MD. Accelerated cutaneous nodulosis during given the apparently protective effect of TCZ on the infliximab therapy in a patient with rheumatoid arthritis. J Clin Rheumatol. 2004;10(6):336–8. extra-articular manifestations of RA, the association be- 13. Braun MG, Van Rhee R, Becker-Capeller D. Development and/or increase of tween its use and the development/worsening of subcuta- rheumatoid nodules in RA patients following leflunomide therapy. Z neous nodulosis deserves further investigations. Rheumatol. 2004;63(1):84–7. Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 6 of 6 14. Chao J, Parker BA, Zvaifler NJ. Accelerated cutaneous nodulosis associated with aromatase inhibitor therapy in a patient with rheumatoid arthritis. J Rheumatol. 2009;36(5):1087–8. 15. Berkun Y, Abou Atta I, Rubinow A, Orbach H, Levartovsky D, Aamar S, et al. 2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis. J Rheumatol. 2007;34(8):1664–9. 16. Ahmed SS, Arnett FC, Smith CA, Ahn C, Reveille JD. The HLA- DRB1*0401 allele and the development of methotrexate-induced accelerated rheumatoid nodulosis: a follow-up study of 79 Caucasian patients with rheumatoid arthritis. Medicine (Baltimore). 2001;80(4):271–8. 17. Shimoura N, Fukunaga A, Nagai H, Oka M, Nishigori C. Epstein-Barr virus- associated methotrexate-induced accelerated rheumatoid nodulosis. Acta Derm Venereol. 2015;95(1):100–1. 18. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum. 2002;47(4):445–9. 19. Sakaue S, Sumitomo S, Kubo K, Fujio K, Yamamoto K. Tocilizumab-induced leucocytoclastic vasculitis in a patient with rheumatoid arthritis. Rheumatology (Oxford). 2014;53(8):1529–30. 20. Fechtenbaum M, Banse C, Boyard-Lasselin P, Goëb V. Toxidermia under treatment with tocilizumab for rheumatoid arthritis. Joint Bone Spine. 2015;82(1):69–70. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Medical Case Reports Springer Journals

Accelerated subcutaneous nodulosis in patients with rheumatoid arthritis treated with tocilizumab: a case series

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Abstract

Background: Tocilizumab is a monoclonal antibody directed against the interleukin-6 receptor, which is approved for the treatment of moderate-to-severe rheumatoid arthritis. Authors have found that it prevents lung and subcutaneous nodulosis in patients with rheumatoid arthritis but, to the best of our knowledge, there are no data concerning the acceleration of subcutaneous nodulosis during tocilizumab therapy. Case presentation: We report for the first time a small case series of five patients with rheumatoid arthritis: a 46-year-old white woman, a 70-year-old white woman, a 63-year-old white woman, a 69-year-old white man, and a 72-year-old white woman (mean age 64 ± 10.6 years); they experienced worsening subcutaneous nodulosis during treatment with intravenously administered tocilizumab. Four of the five patients were positive for rheumatoid factor and five for anti-citrullinated peptide antibodies. All of the patients had previously been treated with various conventional and biological drugs; at the time of our observation, three were taking methotrexate, two hydroxychloroquine, and four were taking prednisone. Tocilizumab 8 mg/kg was administered intravenously every 4 weeks for a mean of 43.4 ± 32.4 months, and led to good disease control in three cases. All of the patients had a history of subcutaneous nodulosis, which considerably worsened during tocilizumab treatment, with the development of new nodules on their fingers, elbows, or in the inframammary fold, tending to ulcerate. The management of this medical event included discontinuation of methotrexate, the administration of steroids, the addition of hydroxychloroquine or colchicine, the use of antibiotics, and surgery. However, neither pharmacological nor surgical treatment was completely effective, as the nodules tended to recur and increased in number and size. Conclusions: To the best of our knowledge, this is the first report describing accelerated subcutaneous nodulosis in a small case series of patients with rheumatoid arthritis treated with tocilizumab. Keywords: Rheumatic nodulosis, Tocilizumab, Rheumatoid arthritis Background methotrexate (MTX) and, to some extent, azathioprine, Subcutaneous nodulosis describes an extra-articular mani- leflunomide, and anti-tumor necrosis factor (TNF) agents, festation occurring in patients affected by rheumatoid whereas the use of colchicine and hydroxychloroquine arthritis (RA). The nodules may develop in the subcutane- (HCQ) may improve the course of the disease. ous layer of the hands and elbows, on Achilles tendons, The development of subcutaneous nodules in patients and may also involve the lungs and vocal chords. Nodulo- with RA has been explained on the basis of a rheumatic sis may be accelerated by concomitant treatment with vasculitis, which is characterized by the precipitation of immune complexes in the small vessels and the subsequent activation of the complement cascade. Vessel * Correspondence: talotta1@virgilio.it inflammation is attributed to the infiltration of poly- Department of Rheumatology, ASST Fatebenefratelli-Sacco, via GB Grassi n. morphonuclear and mononuclear leukocytes, and the 74, 20157 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 2 of 6 development of granulomas that are finally responsible for TCZ treatment. Due to persistent high disease activity and the formation of nodules. the increase in the number and size of the rheumatoid Subtypes of RA characterized by high titers of rheuma- nodules she was swapped to golimumab 50 mg every toid factor (RF), other autoantibodies, or, more generic- month in January 2017, without any further progres- ally, a high degree of systemic inflammation are the sion of subcutaneous nodulosis despite poor control most susceptible to extra-articular complications, in- of RA symptoms. cluding subcutaneous nodulosis. The use of biological drugs that interfere with the cytokines involved in sys- Patient 2 temic inflammation, such as interleukin (IL)-6, should The second case was a 70-year-old, white, menopausal, be valuable in preventing the extra-articular manifesta- non-smoker of tobacco, retired woman. Since 1995 she tions of RA. Tocilizumab (TCZ) is a monoclonal anti- had suffered from immunoglobulin M (IgM) RF- body (moAb) directed against the IL-6 receptor that is negative, ACPA-positive and erosive RA, and rheuma- approved for the treatment of moderate-to-severe RA, toid nodules. Since 1997 she received MTX 15 mg/week and some authors have found that it prevents lung and plus HCQ 400 mg/day, and in 2003, due to poor control subcutaneous nodulosis in patients with RA [1, 2] but, of the disease, she underwent a treatment with intraven- to the best of our knowledge, there are no data concern- ously administered infliximab 3 mg/kg every 8 weeks, ing the acceleration of subcutaneous nodulosis during which was discontinued in 2014 for a progressive lack of TCZ therapy. efficacy and the de novo detection of ANA and anti- dsDNA (appearing at the eighth infusion and undetect- Case presentation able at baseline). Subsequent biologic treatments with We describe a small case series of five white patients with golimumab and abatacept showed no clinical effects; RA (one man and four women; mean age 64 ± 10.6 years; therefore, intravenously administered TCZ 8 mg/kg mean disease duration 21.8 ± 10.9 years) who experienced every 4 weeks combined with MTX 15 mg/week was significant worsening of subcutaneous nodulosis during started in June 2016. Since the start of TCZ, she experi- treatment with intravenously administered TCZ. Pa- enced a progressive worsening of subcutaneous nodulo- tients were consecutively recruited from October 2016 sis in her hands, with nodules tending to cluster and to January 2017. ulcerate. Moreover, new ulcerating nodules appeared in her inframammary folds. An antibiotic treatment with Patient 1 amoxicillin/clavulanate acid 1000 mg/day for 6 consecu- The first case was a 46-year-old white woman who was tive days was prescribed in order to avoid infections. In nullipara, a non-smoker of tobacco, and unemployed. December 2016 colchicine 1 mg every other day was Since 1998 she had suffered from RF and anti-citrullinated added and MTX discontinued. However, subcutaneous peptide antibodies (ACPA)-positive and erosive RA associ- nodulosis did not ameliorate, although no more ulcera- ated with rheumatoid nodules; she had been treated with tions were reported. several conventional and biological drugs (MTX, sulfasala- At the time of enrollment (November 2016), RA dis- zine, leflunomide, HCQ, infliximab, etanercept, adalimu- ease activity was moderate (CRP-DAS28 4.79), and she mab, rituximab, certolizumab, abatacept) plus prednisone was also taking prednisone 5 mg/day. (at a stable dose of 7.5 mg/day throughout the years); all of the drugs were discontinued for inefficacy or adverse Patient 3 events. In June 2014 she started intravenously adminis- The third case was a 63-year-old white woman who was tered TCZ 8 mg/kg every 4 weeks plus MTX 10 mg/week menopausal, a tobacco smoker, and employed. She was (further increase in dose not tolerated) and HCQ 6 mg/kg RF and ACPA-positive, had rheumatoid nodules, and a day, with minimal beneficial effects: C-reactive protein erosive RA was diagnosed in 1979 at another rheumato- disease activity score on 28 joints (CRP-DAS28) was > 5.1 logic center. Since 2006 she attended our Department and at the time of enrollment in the study. In 2006 (under started receiving orally administered MTX 7.5 mg/week etanercept therapy), anti-nuclear antibodies (ANA) turned and etanercept 50 mg/week administered by subcutaneous positive to a 1.160 titer with a homogeneous pattern; anti- injection, both discontinued in 2009 for adverse events. double stranded DNA (dsDNA) and anti-cardiolipin were Subsequently, she was treated with intravenously adminis- always negative at follow-up. In 2010, anti-Ro SSA anti- tered rituximab (discontinued for inefficacy), intraven- bodies were detected despite no report of symptoms of an ously administered abatacept (discontinued for inefficacy), overlapping connective tissue disease. Rheumatoid and, since April 2010, intravenously administered TCZ nodules at the fingers of both her hands, which never 8 mg/kg every 4 weeks in monotherapy (no compliance to showed a beneficial effect from all of the previous therap- conventional anti-rheumatic drugs), achieving and main- ies, dramatically increased in size and number during taining a good clinical response (CRP-DAS28 1.40 at the Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 3 of 6 enrollment time). Subcutaneous nodules of her right autoantibodies were persistently negative. In June 2010 elbow and fingers were pre-existent to the introduction of she was considered a candidate for intravenously adminis- TCZ. However, 2 months later, she reported a worsening tered TCZ 8 mg/kg every 4 weeks, which resulted in good of subcutaneous nodulosis at the fingers of her left hand control of RA (CRP-DAS28 1.74 at the enrollment time, and at her right elbow, which underwent a central ulcer- in November 2016), despite a mild leukopenia (absolute ation in February 2013. ANA and other auto-antibodies neutrophil count > 1000/mm ). From 2014 she also were negative at baseline and throughout the follow-up. A received HCQ 400 mg/day which was permanently brief course of methylprednisolone 4 mg/day for 4 weeks discontinued in 2016 due to visual disturbances. She was and a preventive antibiotic therapy with amoxicillin/clavu- affected by subcutaneous nodules at her elbows and lanate acid 1000 mg/day for 6 days were prescribed, with fingers prior to the start of TCZ; she experienced a some beneficial effects on ulcer healing. progressive increase in the size and number of the nodules during the treatment, and these manifestations Patient 4 partially worsened following the discontinuation of HCQ The fourth case was a 69-year-old white man who was (not assumed at the enrollment time). retired and who smoked tobacco; he had suffered from Table 1 shows the patients’ demographic characteristics. RF and ACPA-positive, non-erosive RA since 2009. In 2009 he started a treatment with intravenously adminis- Discussion tered infliximab 3 mg/kg every 8 weeks plus orally ad- We report five cases of accelerated subcutaneous nodulo- ministered MTX 7.5 mg/week and prednisone 2.5 mg/day sis under intravenously administered TCZ 8 mg/kg every with initial good disease control. In March 2010 his 4 weeks for a mean 43.4 ± 32.4 months of treatment. ANA titer was 1.160, with other autoantibody subsets All the patients had a history of subcutaneous nodulo- negative. In March 2014 he was swapped to intravenously sis, which considerably worsened during treatment with administered TCZ 8 mg/kg every 4 weeks due to progres- TCZ. They developed new subcutaneous nodules mainly sive inefficacy and development of rheumatoid nodulosis. on the fingers (Fig. 1a-f), but also on the elbow or in Concomitantly, a subcutaneous nodule of the first finger the inframammary fold. The nodules had a tendency to of his right hand was removed; the histologic diagnosis was compatible with a rheumatoid nodule. However, in Table 1 Demographic characteristics of the five patients with April 2014, soon after the introduction of TCZ, he com- rheumatoid arthritis plained from the onset of a new subcutaneous ulcerated Patients n =5 nodule at his left elbow. An antibiotic treatment with Gender (F/M), n 4/1 amoxicillin/clavulanate acid 1000 mg/day for 6 consecu- Age (years), mean ± SD 64.0 ± 10.6 tive days was started. In July 2014, giving the benefit of Disease duration (years), mean ± SD 21.8 ± 10.9 TCZ in clinical disease activity and the risk of precipita- Patients RF-positive, n (%) 4 (80%) ting nodulosis, MTX was definitively discontinued. How- ever, rheumatoid nodules at his fingers increased in Patients ACPA-positive, n (%) 5 (100%) number and, in November 2016, HCQ 200 mg/day was Patients ANA-positive, n (%) 4 (80%) added. At the enrollment time (November 2016), RA Patients anti-dsDNA-positive, n (%) 1 (20%) disease activity was in remission (CRP-DAS28 2.1). TCZ treatment duration (months), 43.4 ± 32.4 No development of new autoantibody positivity or change mean ± SD in ANA titration was recorded. Patients treated with prednisone 4 (80%) (2.5–7.5 mg/day), n (%) Patient 5 Patients treated with methotrexate 3 (60%) The last case was a 72-year-old white woman who was (7.5–15 mg/week), n (%) menopausal, a non-smoker of tobacco, and a housewife. Patients treated with hydroxychloroquine 2 (40%) In 1990 she was diagnosed as having erosive RF and (200–400 mg/day), n (%) ACPA-positive RA and rheumatoid nodules. Since then Demographic characteristics of the five patients included in the study. Four of the patients were positive for rheumatoid factor and five for anti-citrullinated peptide she received MTX 7.5 mg/week (further increase in dose antibodies; four patients had anti-nuclear antibodies and one had anti-double- not tolerated) plus prednisone 5 mg/day, with few stranded DNA antibodies. All of the patients had previously been treated with improvements in symptoms, and subsequently several bio- various conventional and biological drugs; at the time of observation, three were taking methotrexate at a mean dose ± SD of 11.6 ± 3.8 mg/week with folic acid logic drugs (infliximab, etanercept, rituximab, and adali- supplementation; two were taking hydroxychloroquine at a dose of 300 or mumab), which were all discontinued for adverse events 400 mg/day; and four were taking prednisone 2.5–7.5 mg/day. The patients had also been treated with intravenously administered TCZ 8 mg/kg every 4 weeks or inefficacy. During follow-up, her ANA titers fluctuated for a mean ± SD of 43.4 ± 32.4 months. ACPA anti-citrullinated peptide antibodies, from negative to positive values and vice versa (maximum ANA anti-nuclear antibodies, dsDNA anti-double stranded DNA, F females, M titer recorded 1.160), whereas anti-dsDNA and other males, RF rheumatoid factor, SD standard deviation, TCZ tocilizumab Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 4 of 6 ab c de f Fig. 1 Subcutaneous nodules on the dorsal surface of the hands of five patients with rheumatoid arthritis treated with tocilizumab. The nodules tended to cluster and ulcerate (c–e), and were surrounded by an erythematous halo (f) that was associated with local pain and disability ulcerate and released a serous but not purulent fluid, and a peripheral layer of epithelioid macrophages, lym- and perilesional inflammation and local pain greatly af- phocytes, and histiocytes. There is some evidence that fected their quality of life. the nodules may arise as a T helper (Th)1-mediated re- As there are still no standardized guidelines, this med- sponse, and highly express cytokines such TNF-α, IL-10, ical event was managed in various ways, including the IL-15, IL-18, and IL-12 [5, 6] but, interestingly, IL-17 tapering or discontinuation of MTX (two cases), the ad- does not seem to be involved in their pathogenesis. ministration of steroids (one case), the addition of HCQ Granulomatous responses are related to the activation of or colchicine (one case), the use of antibiotics to prevent Th1 lymphocytes and macrophages favoured by the local infective complications (three cases), and surgery with a production of cytokines such as IL-2 and TNF-α, histological examination that revealed a granulomatous whereas IL-17 seems to be mainly involved in lymph pattern compatible with rheumatoid nodules (one case). node organization and in the formation of germinal cen- However, neither pharmacological nor surgical treatment ters [7]; IL-17 is therefore associated with Th2 and B was completely effective as the nodules tended to recur lymphocyte activation and antibody production that de- and increased in number and size. In one case, TCZ was pend on a distinct immune pathway. By preventing the permanently discontinued because of poor clinical effi- maturation of Th-17 lymphocytes and the subsequent cacy; the patient was switched to an anti-TNF agent release of IL-17, TCZ may shift the immunological (golimumab) and is still being followed up. balance toward a more pronounced Th1 response that Subcutaneous nodulosis is the most frequently en- indirectly promotes rheumatic nodulosis, although cur- countered extra-articular manifestation of RA, and oc- rently available data are contrasting [8–10]. curs in up to 35% of patients [3]. The nodules typically The use of MTX (and sometimes azathioprine, leflu- develop on the dorsal surface of the fingers, the elbows nomide, and anti-TNF agents) may accelerate the growth or Achilles tendons, although they may also involve the of pre-existing nodules [11–14]. Drug-induced subcuta- lungs or vocal chords, and are often associated with high neous nodules have the same clinical and histological RF or ACPA titers, and a more aggressive and erosive characteristics as RA-related nodules, but the mechan- course of RA. A genetic substrate, cigarette smoking, ism by means of which the drugs favor subcutaneous and male gender have been controversially associated nodulosis while controlling articular symptoms is still with the risk of developing nodulosis [4]. The nodules unclear. Genetic susceptibility has been described in are usually characterized histologically by a granuloma- patients carrying the polymorphic variants of methionine tous process, with a central area of fibrinoid necrosis synthase reductase (MTR) or haplotype HLA-DRB1*0401 Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 5 of 6 [15, 16], and some authors have demonstrated that treat- Availability of data and materials Please contact author for data requests. ment with MTX is associated with the reactivation of Ep- stein–Barr virus, which may be responsible for the Authors’ contributions development of lymphoproliferative disorders or subcuta- RT conceived of the study, drafted the manuscript, and collected clinical and iconographic data; MCG, MCD, and AB collected clinical data; FA and PS neous nodules [17]. The concomitant use of colchicine, participated in the design and coordination of the study and helped to draft sulfasalazine, or HCQ seems to improve the course of the the manuscript. All authors read and approved the final manuscript. complication, and is therefore recommended in cases in Ethics approval and consent to participate which the discontinuation of MTX is contraindicated [11]. Not applicable. Anti-TNF-α biologic therapy (for example, infliximab and etanercept) is commonly used in the management of RA, Consent for publication Written informed consent was obtained from the patients for publication of especially in patients who are MTX-resistant. There have this case report and any accompanying images. A copy of the written been reports of accelerated subcutaneous and lung nodu- consents is available for review by the Editor-in-Chief of this journal. losis in patients with RA, developing early after starting Competing interests infliximab or etanercept, perhaps as a result of new auto- The authors declare that they have no competing interests. immune phenomena triggered by the neutralization of TNF-α [12, 18]. Publisher’sNote To the best of our knowledge, there are no data con- Springer Nature remains neutral with regard to jurisdictional claims in cerning accelerated subcutaneous nodulosis during treat- published maps and institutional affiliations. ment with TCZ. Some reports have even highlighted the Author details usefulness of TCZ in treating lung nodulosis induced by 1 Department of Rheumatology, ASST Fatebenefratelli-Sacco, via GB Grassi n. previous treatment with anti-TNF agents [1], and there 74, 20157 Milan, Italy. Rheumatology Unit, University of Messina, via Consolare Valeria 1, 98100 Messina, Italy. is one case report indicating its beneficial effect on olec- ranon subcutaneous nodules in a patient with RA [2]. Received: 21 July 2017 Accepted: 12 April 2018 Given its biological properties, TCZ reduces the burden of systemic inflammation and prevents extra-articular References manifestations, endothelial dysfunction, and vasculitis, 1. Andres M, Vela P, Romera C. Marked improvement of lung rheumatoid but there are some published reports describing the oc- nodules after treatment with tocilizumab. Rheumatology (Oxford). 2012; 51(6):1132–4. currence of dermatological complications such as leuko- 2. Al Attia HM, Abushawish M. Treatment with tocilizumab leads to the cytoclastic vasculitis and toxidermia [19, 20]. disappearance of olecranon rheumatoid nodules. Int J Dermatol. 2012; We have observed a visible worsening of subcutaneous 51(2):197–8. 3. Tilstra JS, Rheumatoid Nodules LDW. Dermatol Clin. 2015;33(3):361–71. nodulosis in 8.3% of the 60 patients receiving TCZ treat- 4. Mattey DL, Dawes PT, Fisher J, Brownfield A, Thomson W, Hajeer AH, et al. ment at our center, which may be related to a change in Nodular disease in rheumatoid arthritis: association with cigarette smoking the immune response toward more pronounced Th1 acti- and HLA-DRB1/TNF gene interaction. J Rheumatol. 2002;29(11):2313–8. 5. Hessian PA, Highton J, Kean A, Sun CK, Chin M. Cytokine profile of the vation. In addition, in our cohort of patients treated with rheumatoid nodule suggests that it is a Th1 granuloma. Arthritis Rheum. TCZ, there have also been three cases (5%) with subcuta- 2003;48(2):334–8. neous nodulosis which, however, remained stable during 6. Stamp LK, Easson A, Lehnigk U, Highton J, Hessian PA, Different T. cell subsets in the nodule and synovial membrane: absence of interleukin-17A the treatment. Further studies are required to clarify the in rheumatoid nodules. Arthritis Rheum. 2008;58(6):1601–8. mechanisms of pathogenesis underlying this association, 7. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, et al. and the real incidence of this little known event. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 2011;35(6):986–96. 8. Pesce B, Soto L, Sabugo F, Wurmann P, Cuchacovich M, Lòpez MN, Sotelo PH, . Effect of interleukin-6 receptor blockade on the balance between Conclusions regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exp Immunol. 2013;171(3):237–42. In conclusion, we report for the first time five cases of 9. Thiolat A, Semerano L, Pers YM, Biton J, Lemeiter D, Portales P, et al. accelerating subcutaneous nodulosis in patients with RA Interleukin-6 receptor blockade enhances CD39+ regulatory T cell intravenously treated with TCZ. All five patients suffering development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol. 2014;66(2):273–83. from pre-existing rheumatic nodulosis experienced its 10. Guggino G, Giardina AR, Raimondo S, Giardina G, Sireci G, Dieli F, et al. severe progression with local inflammation and ulceration. Targeting IL-6 signalling in early rheumatoid arthritis is followed by Th1 and Our data suggest that a clearer understanding of RA may Th17 suppression and Th2 expansion. Clin Exp Rheumatol. 2014;32(1):77–81. 11. Patatanian E, Thompson DF. A review of methotrexate-induced accelerated allow the identification of subtypes not previously appreci- nodulosis. Pharmacotherapy. 2002;22:1157–62. ated, finally leading to personalized therapies. However, 12. Mackley CL, Ostrov BE, Ioffreda MD. Accelerated cutaneous nodulosis during given the apparently protective effect of TCZ on the infliximab therapy in a patient with rheumatoid arthritis. J Clin Rheumatol. 2004;10(6):336–8. extra-articular manifestations of RA, the association be- 13. Braun MG, Van Rhee R, Becker-Capeller D. Development and/or increase of tween its use and the development/worsening of subcuta- rheumatoid nodules in RA patients following leflunomide therapy. Z neous nodulosis deserves further investigations. Rheumatol. 2004;63(1):84–7. Talotta et al. Journal of Medical Case Reports (2018) 12:154 Page 6 of 6 14. Chao J, Parker BA, Zvaifler NJ. Accelerated cutaneous nodulosis associated with aromatase inhibitor therapy in a patient with rheumatoid arthritis. J Rheumatol. 2009;36(5):1087–8. 15. Berkun Y, Abou Atta I, Rubinow A, Orbach H, Levartovsky D, Aamar S, et al. 2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis. J Rheumatol. 2007;34(8):1664–9. 16. Ahmed SS, Arnett FC, Smith CA, Ahn C, Reveille JD. The HLA- DRB1*0401 allele and the development of methotrexate-induced accelerated rheumatoid nodulosis: a follow-up study of 79 Caucasian patients with rheumatoid arthritis. Medicine (Baltimore). 2001;80(4):271–8. 17. Shimoura N, Fukunaga A, Nagai H, Oka M, Nishigori C. Epstein-Barr virus- associated methotrexate-induced accelerated rheumatoid nodulosis. Acta Derm Venereol. 2015;95(1):100–1. 18. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum. 2002;47(4):445–9. 19. Sakaue S, Sumitomo S, Kubo K, Fujio K, Yamamoto K. Tocilizumab-induced leucocytoclastic vasculitis in a patient with rheumatoid arthritis. Rheumatology (Oxford). 2014;53(8):1529–30. 20. Fechtenbaum M, Banse C, Boyard-Lasselin P, Goëb V. Toxidermia under treatment with tocilizumab for rheumatoid arthritis. Joint Bone Spine. 2015;82(1):69–70.

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Journal of Medical Case ReportsSpringer Journals

Published: Jun 3, 2018

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