Miscellaneous RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. ORIGINAL RESEARCH Long-­term follow-­up of certolizumab pegol in uveitis due to immune-­ mediated inflammatory diseases: multicentre study of 80 patients José Luis Martín-­Varillas ‍ ‍,1 Lara Sanchez-­Bilbao,2 Vanesa Calvo-­Río,2 Alfredo Adán,3 Inés Hernanz,3 Adela Gallego-­Flores,4 Emma Beltran-­Catalan ‍ ‍,5 Sonia Castro-­Oreiro,6 Patricia Fanlo,7 Alvaro Garcia Martos,8 Ignacio Torre,9 Miguel Cordero-­Coma,10 Juan Ramon De Dios,11 Ángel García-­Aparicio,12 Marisa Hernández-­Garfella,13 Amalia Sánchez-­Andrade,14 Andrea García-­Valle,15 Olga Maiz,16 Roberto Miguélez,17 Sergio Rodríguez-­Montero,18 Ana Urruticoechea,19 Raúl Veroz,20 Arantxa Conesa,21 Cristina Fernández-­Carballido ‍ ‍,22 Vega Jovaní,23 Jose J Mondejar,24 Olga Martínez González,25 Patricia Moya Alvarado,26 Susana Romero-­Yuste,27 Paula Rubio-­Muñoz,28 Eva Peña-­Sainz-­Pardo,29 Marta Garijo-­Bufort,30 Rosalía Demetrio-­Pablo,31 José L Hernández ‍ ‍,32,33 Ricardo Blanco ‍ ‍2 To cite: Martín-­Varillas JL, ABSTRACT Sanchez-­Bilbao L, Calvo-­Río V, WHAT IS ALREADY KNOWN ON THIS TOPIC Objectives To evaluate effectiveness and safety of et al. Long-­term follow-­up certolizumab pegol (CZP) in uveitis due to immune-­ ⇒ Antitumour necrosis factor-α (anti-­TNF-α) drugs of certolizumab pegol in have substantially improved the management of pa- mediated inflammatory diseases (IMID). uveitis due to immune-­ tients with uveitis refractory to conventional immu- mediated inflammatory Methods Multicentre study of CZP-­treated patients with IMID uveitis refractory to conventional immunosuppressant. nosuppressive therapy, especially adalimumab and diseases: multicentre study of 80 patients. RMD Open Effectiveness was assessed through the following ocular infliximab; however, evidence on other anti-­TNF-α 2022;8:e002693. doi:10.1136/ parameters: best-­corrected visual acuity, anterior chamber drugs, such as certolizumab pegol (CZP), is scarce. rmdopen-2022-002693 cells, vitritis, macular thickness and retinal vasculitis. WHAT THIS STUDY ADDS These variables were compared between the baseline, and first week, first, third, sixth months, first and second year. ⇒ This study provides real-­world clinical practice ef- JLH and RB are joint senior Results We studied 80 (33 men/47 women) patients (111 fectiveness of CZP in patients with refractory uveitis authors. in multiple immune-­mediated inflammatory diseas- affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet’s es, even in those patients with insufficient response Received 25 August 2022 disease (n=10), psoriatic arthritis (n=8), Crohn’s disease to other anti-­TNF-α drugs. Accepted 31 October 2022 (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis HOW THIS STUDY MIGHT AFFECT RESEARCH, (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), PRACTICE OR POLICY relapsing polychondritis (n=1), Conclusions CZP seems to be effective and safe in uveitis ⇒ We can increase the therapeutic armamentarium in related to different IMID, even in patients refractory to the ocular affectation of several diseases with diffi- previous biological drugs. cult management. © Author(s) (or their Likewise, uveitis was reported in 30%–70% employer(s)) 2022. Re-­use INTRODUCTION of patients with sarcoidosis.4 Similarly, in permitted under CC BY-­NC. No Non-­infectious uveitis (NIU) is a common commercial re-­use. See rights axial spondyloarthritis (SpA) or juvenile idio- and permissions. Published and severe clinical manifestation occurring pathic arthritis (JIA), acute anterior uveitis by BMJ. in a wide spectrum of immune-­ mediated is the predominant extra-­ articular manifes- For numbered affiliations see inflammatory diseases (IMID), leading to tation, with a prevalence of 12%–33% and end of article. visual loss at a variable rate. In Behçet’s 10%–20%, respectively.5–8 Other systemic Correspondence to disease (BD), it has been estimated that up inflammatory conditions such as Crohn’s Dr José L Hernández; to 35%–90% of patients may develop uveitis, disease (CD) or ulcerative colitis (UC) may ​hernandezjluis@​gmail.​com including the presence of retinal vasculitis.1–3 present with ocular impairment.9 Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693    1 RMD Open RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. However, the increasing development of biological Malignancy or systemic infectious diseases were therapy has led to a significant improvement in the excluded before anti-­ TNF-α initiation, as previously ocular prognosis of patients with IMID. Drugs targeting described.16 17 21 22 tumour necrosis factor (TNF)-α such as adalimumab CZP was administered at the standard dose of 400 mg (ADA) and infliximab (IFX) have been the most at baseline and weeks 2 and 4, then continued as 400 studied group.10 ADA has been approved by European mg injections monthly, or 200 mg injections every other Medicines Agency (EMA) and Food and Drug Admin- week. istration (FDA) for non-­infectious non-­anterior uveitis, According to SUN classification, remission was estab- based on two phase III trials (VISUAL I and VISUAL lished in absence of signs of ocular inflammation for at II),11 12 and long-­ term follow-­ up solid data on these least 3 months. Relapses or flares were defined as the patients are reported (VISUAL III).13 Although IFX is presence of inflammatory ocular activity in patients who only authorised in Japan (PDMA) for use in Behçet’s had reached remission.28 29 Flares on the same eye were uveoretinitis,14 15 data on effectiveness and safety profile considered separate only if the interval between them in Caucasian patients with NIU refractory to conven- was >3 months.23 tional immunosuppressive therapy are widely demon- Before CZP initiation, all patients signed written strated.16–22 Nevertheless, there is limited evidence informed consent since the prescription of CZP was an to support the use of other anti-­TNF-α drugs, such as off-­label indication by the EMA for the treatment of non-­ certolizumab pegol (CZP) or golimumab (GOL), for infectious and non-­anterior uveitis. ocular complications in patients with IMID, and the current focus is mainly on SpA uveitis.23–25 Outcome variables CZP is a Fab fragment of a recombinant humanised To determine effectiveness, the intraocular inflamma- anti-­TNF-α antibody expressed in Escherichia coli and tion, macular thickness, visual acuity and the sparing conjugated to polyethylene glycol conferring pharmaco- effect of glucocorticoids were assessed. These variables kinetic and pharmacodynamic advantages over drugs of were recorded at baseline (CZP initiation), first week, first the same family.26 In addition, CZP may be a therapeutic month, third month, sixth month and first and second option in pregnant women as it lacks the Fc-­region which years. Intraocular inflammation included the following prevents it from crossing the placental barrier.27 features: anterior or posterior chamber inflammation, Taking all these considerations into account, we aimed vitritis, retinal vasculitis, papillitis and macular thickness. to evaluate the long-­term effectiveness and safety of CZP The degree of intraocular inflammation was evaluated therapy in a large series of Caucasian patients with refrac- according to the SUN Working Group.28 Vitritis was tory uveitis due to several IMIDs. assessed by the Nussenblatt scale.29 Fluorescein angiography (FA) was performed to eval- uate the presence of retinal vasculitis. Retinal vasculitis was defined as retinal angiographic leakage, staining PATIENTS AND METHODS and/or occlusion on FA.30 Design, enrolment criteria and definitions To assess the macular thickness, high-­definition optical We conducted a national multicentre observational study coherence tomography (OCT), using a Cirrus HD-­OCT on 80 patients with IMID with refractory uveitis treated (Carl Zeiss, Dublin, California, USA), was performed. with CZP. Patients who had received CZP between January Scans were obtained using the 512×128 scan pattern. 2015 and January 2020 were selected and followed-­up at Macular thickening was defined as a macular thickness the Uveitis Units from several Spanish hospitals. >250 µm. Anatomical classification of uveitis was performed The best-­corrected visual acuity (BCVA) was estimated according to the Standardisation of Uveitis Nomencla- using the Snellen chart. For the present study, 20/20 ture (SUN) Working Group.28 (normal vision) was expressed as 1.0 and 0/20 as 0.0. All the patients had uveitis refractory to corticosteroids As another effectiveness outcome, flares before and and had previously received at least one conventional after CZP initiation were compared. synthetic immunosuppressive drug. The conventional immunosuppressive drugs and dosages used before CZP Statistical analysis initiation were as follows: azathioprine (AZA) (100– Variables were tested for normality by the Kolmogorov-­ 150 mg/day orally), methotrexate (MTX) (7.5–25 mg/ Smirnov test. Results were expressed as mean±SD for vari- week subcutaneously or orally), ciclosporin A (CsA) ables with a normal distribution, or as median and IQR (3–6 mg/kg/day orally), mycophenolate mofetil (MMF) (25th, 75th) for those not normally distributed. Paired (2–3 g/day orally), leflunomide (LFN) (20 mg/day sample T-­test or Wilcoxon signed-­rank test were used to orally), cyclophosphamide (CFM) (500–1000 mg/m2/ compare continuous variables over different time points. month intravenously) and salazopyrine (SSZ) (1000– The following variables were assessed and compared 2000 mg/day orally). In case of severe uveitis, the ther- between baseline and first week, first month, third apeutic scheme included three consecutive pulses of month, sixth month, first year and second year: BCVA, methylprednisolone (MP), 500–1000 mg/day. anterior chamber cells, vitritis, retinal vasculitis, macular 2 Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693 Miscellaneous RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. thickness (OCT) and glucocorticoid-­sparing effect. The Table 1 Main general features of a series of 80 incidence of uveitis flares was reported as the incidence patients with refractory uveitis due to immune-­mediated rate (IR) per 100 patients-­year in both groups (before inflammatory diseases (IMID) treated with certolizumab and after CZP onset) and incidence rate ratio (IRR), with pegol (CZP) their Poisson 95% CI. Analyses were performed using No. of patients/eyes affected, n/n 80/111 IBM SPSS software V.28 (IBM, Armonk, New York, USA). Statistical significance was considered as a p value <0.05 Age, mean (SD), years 41.6±11.7 in all the calculations. Sex, male/female, n/n (%) 33/47 (41.2/58.8) Time between IMID diagnosis and CZP 72 (35–144) initiation, median (IQR) RESULTS Baseline features of the study sample Patients initiating CZP due to 20 (25) pregnancy, n (%) Eighty Caucasian patients (111 affected eyes) with refrac- tory uveitis to conventional treatment who received CZP Underlying IMID, n (%) as a therapeutic alternative agent were included in the  Spondyloarthritis 43 (53.7) study. The mean age at CZP initiation was 41.6±11.7 years  Behçet’s disease 10 (12.5) and 58.8% were women. In 20 patients, in addition to  Psoriatic arthritis 8 (10) the presence of refractory uveitis, the desire for preg-  Crohn’s disease 4 (5) nancy was the reason for CZP initiation. The underlying diseases were: SpA (n=43), BD (n=10), psoriatic arthritis  Sarcoidosis 2 (2.5) (n=8), CD (n=4), sarcoidosis (n=2), JIA (n=1), reactive  Juvenile idiopathic arthritis 1 (1.3) arthritis (n=1), rheumatoid arthritis (n=1), relapsing  Reactive arthritis 1 (1.3) polychondritis (n=1), TINU (n=1), pars planitis (n=1),  Rheumatoid arthritis 1 (1.3) birdshot (n=1) and idiopathic uveitis (n=6). Anterior uveitis was the most frequent ocular pattern (n=61). The  Relapsing polychondritis 1 (1.3) main demographic and clinical data of the whole series  TINU 1 (1.3) are summarised in table 1.  Pars planitis 1 (1.3)  Birdshot choroidopathy 1 (1.3) Previous immunosuppressive therapy before CZP initiation Besides oral glucocorticoids (mean prednisone dose;  Idiopathic uveitis 6 (7.5) 13.9±11.6 mg/day) and before the initiation of biological Ocular parameters at CZP initiation therapy, patients had received the following conventional  AC cells count, median (IQR) 1 [1.0–1.75) immunosuppressive agents: MTX (n=38), SSZ (n=28),  Patients who present vitritis, n (%) 14 (17.5) AZA (n=14), CsA (n=10), LFN (n=3), MMF (n=4) and  BCVA, mean (SD) 0.68±0.27 CFM (n=1). MP intravenous pulses were administered to four patients due to the severity of ocular impairment.  OCT, mean (SD) 297.48±48.19 Moreover, 52 subjects (63%) were on previous biolog-  Patients who present retinal 3 (3.8) ical therapy with a median of 21–3 drugs per patient. The vasculitis, n (%) most frequent biological drug used was ADA (n=48), Uveitis pattern, n (%) followed by IFX (n=32), GOL (n=15), etanercept (n=7),  Bilateral/Unilateral 31/49 (38.7/61.3) tocilizumab (n=5), rituximab (n=1), anakinra (n=1) and  Anterior 61 (76.3) secukinumab (n=1) (figure 1).  Intermediate 4 (5.0) Certolizumab therapy: effectiveness  Posterior 7 (8.8) CZP was initiated as monotherapy in 39 patients and  Panuveitis 7 (8.8) combined with another conventional immunosuppres- sive agent in the remaining 41, as follows: MTX (n=23), BCVA, best-­corrected visual acuity; OCT, optical coherence tomography. AZA (n=9), SSZ (n=7), CsA (n=1) and HCQ (n=1) (table 2). In 28 patients, CZP was administered as the first biological agent. The main outcome variables assessed in the study eyes with an improvement of AC cell count according to (intraocular inflammation, macular thickness, BCVA) SUN criteria and vitritis was increased to 100% in both showed a rapid and maintained improvement from the cases in the second year. Concerning the three patients first week and throughout the follow-­up (figure 2). who had retinal vasculitis at the beginning of the study, a The mean BCVA increased from a mean value of rapid and sustained improvement was observed, with no 0.64±0.27 before the initiation of biological therapy to new episodes at the end of the study. Furthermore, of the 0.88±0.21 in the second year (p<0.001) (figure 2A). Simi- three patients who had choroiditis at CZP initiation, only larly, all patients experienced an improvement in the one was active at the end of the follow-­up. Furthermore, parameters of ocular inflammation. The percentage of we observed a significant decrease in macular thickness Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693 3 RMD Open RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. Figure 1 Flow chart of the biological treatments received in the 80 patients with refractory uveitis in different immune-­ mediated inflammatory diseases (IMID). ADA, adalimumab; CZP, certolizumab pegol; ETA, etanercept; GOL, golimumab; GEVO, gevokizumab; IFX, infliximab; IMID, immune-­mediated inflammatory; RTX, rituximab; SECU, secukinumab; TCZ, tocilizumab. measured by OCT from 297.5±48.1 µm at baseline to anti-­TNF-α drugs is based on observational studies with 266.1±36.2 µm in the second year (p<0.001) (figure 2B). a low level of evidence, and usually, these agents are As another effectiveness parameter, number of flares 2 reserved for situations in which ADA is contraindicated years before and after CZP initiation were recorded and or ineffective. compared. The IR of flares before CZP was 1.23 (95% CI To the best of our knowledge, this multicentre study 1.06 to 1.42) per 100 patients-­year and 0.34 (95% CI 0.25 represents the largest series of multiple patients with to 0.44) per 100 patients-­year after CZP initiation. The IMID with refractory uveitis on CZP therapy in a real-­ IR difference was 0.89 (95% CI 0.70 to 1.09) (p<0.0001). world clinical setting. The main reason for prescribing The IRR was 3.64 (95% CI 2.67 to 5.04) (p<0.0001). CZP was poor control of ocular inflammation and in We also found a rapid decrease in the median gluco- addition, in 20 patients, desire for pregnancy. CZP was corticoid dose from the start of CZP (10 (5–27.5) mg/ effective in most cases, with a statistically significant rapid day) to the end of the follow-­up (3.1 (0–8.7) mg/day and maintained improvement of all ocular parameters (p<0.001) (figure 2C). during a 2-­year follow-­up. Moreover, we have observed a glucocorticoid-­ sparing effect, showing a significant Certolizumab therapy: follow-up data and safety profile decrease in the median oral prednisone dose from 10 After a median follow-­up of 2412–36 months, 95% of patients mg/day at IFX initiation to 3 mg/day after 2 years of achieved ocular remission. CZP was discontinued in 16 therapy. These results are in keeping with the scarcely (20%) patients due to maintained remission (n=3), insuf- available literature addressing the effectiveness of CZP ficient ocular response (n=4) and incomplete response in uveitis. In this regard, a Spanish observational study of extraocular manifestations (n=9). In this latter group, conducted by Llorenç et al reported complete remission six patients had recurrent episodes of peripheral arthritis of patients with chronic uveitis treated with CZP and (psoriatic arthritis (n=2), SpA (n=2), reactive arthritis prior failure to anti-­ TNF-α drugs.31 Similarly, Prieto-­ (n=1) and relapsing polychondritis (n=1)), two patients Peña et al described a series of 14 pregnant women with were diagnosed with CD with recurrent episodes of intes- different IMIDs and uveitis treated with CZP with consis- tinal ulcers and one patient with sarcoidosis due to persis- tent effectiveness and safety data and no adverse fetal tence of skin lesions (panniculitis). events.32 Of the 76 patients who maintained ocular remission, We also studied, as an effectiveness end point, the optimisation of treatment was performed in 12 of them mean number of flares before and after CZP initiation, by increasing the CZP administration interval to 200 mg and we observed a marked significant reduction of 75%. every 4 weeks, with no reported worsening. No severe In this line, several studies support our data. Rudwaleit side effects were reported in any of the patients included et al observed a three time-­lower rate of uveitis flares in in the study. comparison with the placebo group in a series of SpA treated with CZP for 24 weeks.33 Likewise, Tosi et al also DISCUSSION reported a significant reduction of ocular flares in 11 The optimal therapeutic scheme for NIU remains a chal- patients with longstanding refractory uveitis treated with lenge for rheumatologists and ophthalmologists. Despite CZP.34 Besides, a subanalysis of the multicentre phase the advances in biological therapies, current effectiveness IV C-­VIEW study showed a reduction in the number of data in this field only support the use of ADA in cases anterior uveitis flares in patients with SpA after 48 weeks where conventional therapy is insufficient to control the of follow-­up.23 Subsequently, a 2-­ year extension study disease (EMA and FDA approved).11 12 The use of other obtained similar consistent results.35 4 Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693 Miscellaneous RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. Table 2 Treatment schedule and long-­term follow-­up of a series of 80 patients with refractory uveitis due to immune-­mediated inflammatory diseases (IMID) treated with certolizumab pegol (CZP) Conventional immunosuppressant 60 (75) before CZP initiation, n (%)  Ciclosporin 10 (12.5)  Azathioprine 14 (17.5)  Methotrexate 38 (47.5)  Salazopyrin 28 (35.0)  Cyclophosphamide 1 (1.3)  Mycophenolate 4 (5.0)  Leflunomide 3 (3.8)  Pulses of intravenous MP 4 (5.0) Biological treatment before CZP 52 (63) initiation, n (%)  No. of biological drugs per patient, 2(1–3) median (IQR)  Adalimumab 48 (60)  Infliximab 32 (40)  Etanercept 7 (8.8)  Golimumab 15 (18.8)  Tocilizumab 5 (6.3)  Rituximab 1 (1.3)  Secukinumab 1 (1.3)  Gevokizumab 1 (1.3) Mean dose of prednisone at CZP 16.9±10.8 initiation (mg/day), mean±SD CZP regimen  Monotherapy/Combination, n (%) 39/41 (48.8/51.2)  Ciclosporin 1 (1.3)  Azathioprine 9 (11.3)  Methotrexate 23 (28.8)  Salazopyrine 7 (8.8)  Hydroxychloroquine 1 (1.3) Follow-­up time since CZP initiation 24 (12–36) (months), median (IQR)  Optimisation, n (%) 12 (15)  Reason for withdrawal, n (%) 16 (20)    Remission 3 (3.8)    Ocular inefficacy 4 (5)    Extraocular inefficacy 9 (11.3) Side effects    0 (0.0) MP, methylprednisolone. Figure 2 Rapid and maintained improvement following the initiation of certolizumab pegol (CZP). (A) Best-­corrected Up to 95% of the patients achieved ocular remission visual acuity (BCVA); (B) macular thickness (optical until the end of follow-­up, and three patients were able to coherence tomography (OCT)) (data from patients with discontinue treatment without new ocular events. Once macular involvement); (C) glucocorticoid-­sparing effect remission was achieved, CZP treatment was optimised in following CZP therapy (mg/day) (data from patients who a not negligible percentage of patients, by increasing the received prednisone at any time during follow-­up). Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693 5 RMD Open RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. 13 administration interval to 200 mg every 4 weeks, and no Ophthalmology, General University Hospital Consortium of Valencia, Valencia, relapses occurred. These data are consistent with those Spain 14 Rheumatology, University Hospital Lucus Augusti, Lugo, Spain found in optimisation studies involving other anti-­TNF-α 15 Rheumatology, Complejo Asistencial de Palencia, Palencia, Spain agents such as ADA or IFX.22 36 16 Rheumatology, Hospital of Donostia, San Sebastian, Spain However, four patients did not achieve adequate ocular 17 Rheumatology, Hospital Universitario de Mostoles, Mostoles, Spain 18 control. Additionally, poor control of extraocular symp- Rheumatology, Hospital Virgen de Valme, Sevilla, Spain 19 Rheumatology, Hospital Can Misses, Eivissa, Illes Balears, Spain toms led to discontinuation of treatment in another nine 20 Rheumatology, Hospital de Merida, Merida, Spain patients. 21 Rheumatology, Hospital General Universitari de Castello, Castellon de la Plana, Noteworthy, more than half of the patients (63%) Spain 22 had received biological treatment before CZP initiation, Rheumatology, Hospital Universitario San Juan de Alicante, Sant Joan d'Alacant, with a median of 21–3 drugs per patient. This reflects the Spain 23 Rheumatology, Hospital General Universitario de Alicante, Alicante, Spain severity of the different diseases and their refractori- 24 Ophthalmology, Hospital General Universitario de Alicante, Alicante, Spain ness to multiple therapies. In addition, it is important to 25 Rheumatology, Hospital Universitario de Salamanca, Salamanca, Spain 26 emphasise that all of them had received at least one anti-­ Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 27 TNF-α as a first-­line agent or subsequently. In patients Rheumatology, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain with rheumatoid arthritis, it has been postulated that in 28 Rheumatology, Fundació Hospital de l'Esperit Sant, Barcelona, Spain the case of a failure of the anti-­TNF-α drug failure, the 29 Pediatric, Hospital Universitario 12 de Octubre, Madrid, Spain most useful strategy is switching to another therapeutic 30 Rheumatology, Hospital de Sagunto, Sagunto, Spain 31 target.37 Nevertheless, it seems that in patients with uveitis Ophthalmology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain it may be feasible to use other drugs of the same family as 32 Internal Medicine, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, shown in our study. Spain Concerning CZP safety, no serious, or moderate 33 Medicine and Psychiatry Department, Universidad de Cantabria, Santander, Spain or mild adverse events were reported in our series. However, in the subanalysis of the C-­VIEW study, five Contributors JLM-­V: conception or design of the work; data collection; data analysis and interpretation; drafting the article; critical revision of the article; patients reported serious adverse effects such as vestib- final approval of the version to be published. LS-­B: conception or design of the ular disorder, sarcoidosis or prostate cancer.23 35 Similarly, work; data collection; data analysis and interpretation; drafting the article; critical and in agreement with previous studies, no pregnancy revision of the article. VC-­R: conception or design of the work; data analysis and interpretation; drafting the article. AA, AG-­F, EB-­C, SC-­O, PF, AGM, IT, MC-­C, JRDD, complications or congenital malformations attributable AG-­A, MH-­G, AS-­A, AG-­V, OM, RM, SR-­M, AU, RV, AC, CF-­C, VJ, JJM, OMG, PMA, to CZP were reported.38–40 SR-­Y, PR-­M, EP-­S-­P, MG-­B, RD-­P: conception or design of the work; data collection; Our study has several limitations mainly inherent to drafting the article. JLH: conception or design of the work; data analysis and interpretation; statistical analysis; drafting the article; critical revision of the article; its observational nature, the lack of a control group, final approval of the version to be published. RB: conception or design of the work; the relatively low number of optimised patients and the data analysis and interpretation; drafting the article; critical revision of the article; final approval of the version to be published. heterogeneity of the underlying IMID with different uveitis patterns. For these reasons, further randomised Funding This work was also partially supported by RETICS Programmes, RD08/0075 (RIER) and RD12/0009/0013 from 'Instituto de Salud Carlos III' (ISCIII) controlled trials comparing conventional immunosup- (Spain). pressive drugs and other anti-­TNF-α agents are required. Competing interests JLM-­V received grants/research support from AbbVie, Nevertheless, it is very difficult to perform studies on Pfizer, Lilly, Celgene, Janssen, and UCB Pharma. VC-­R received grants/research refractory uveitis with large populations, especially since support from MSD and Roche and had consultation fees/participation in the company-­sponsored speaker’s bureau from AbbVie, Lilly, Celgene, Grünenthal and the development and approval of biosimilar drugs. There- UCB Pharma. LS-­B received grants/research support from Roche, Lilly and Pfizer. fore, future valuable information will probably come EB-­C had consultation fees/participation in the company-­sponsored speaker’s bureau from AbbVie, Amgen, Janssen, MSD, Pfizer, Lilly, Novartis y UCB. PF from observational multicentre studies, such as ours. received grants/research supports from Sobi and Novartis and had consultation In conclusion, our results suggest that CZP seems to fees/participation in the company-­sponsored speaker’s bureau from Sobi and be effective and safe, in the short-­term and long-­term, in Novartis. AGM received consultation fees from Novartis and Amgem and sponsored speaker’s bureau from Novartis, Jansen, Amgen, UCB and Grünenthal. MC-­C was a Caucasian patients with IMID with refractory uveitis. lecturer for AbbVie, Merck Sharp & Dohme, Allergan and UCB. He also participated in Advisory Boards for AbbVie and Allergan. He also had travel grants from Author affiliations AbbVie, UCB and Allergan. RV had consultation fees/participation in the company-­ 1 Rheumatology, Hospital Comarcal de Laredo, Laredo, Spain sponsored speaker’s bureau from AbbVie, Pfizer, MSD, UCB, Gebro, Celgene, 2 Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Janssen, Bristol Myers, Lilly, Galápagos, Amgen. CF-­C received honoraria for Spain lectures/presentations from AbbVie, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer 3 and UCB; consulting fees from AbbVie, Janssen, Lilly, Novartis and UCB and support Ophthalmology, Hospital Clinic de Barcelona, Barcelona, Spain 4 for attending meetings from AbbVie, Galapagos, Janssen, Lilly, Novartis, Roche Rheumatology, University Hospital Complex Badajoz, Badajoz, Spain and UCB. JLH received grants/research support from Amgen and participation in 5 Rheumatology, Hospital del Mar, Barcelona, Spain company-­sponsored speaker’s bureau from Amgen, MSD and Novartis. RB received 6 Rheumatology, Joan XXIII University Hospital in Tarragona, Tarragona, Spain grants/research support from AbbVie, MSD and Roche, and had consultation fees/ 7 Internal Medicine, Complejo Hospitalario de Navarra, Pamplona, Spain participation in a company-­sponsored speaker’s bureau from AbbVie, Pfizer, Roche, 8 Rheumatology, Hospital Universitario del Tajo, Aranjuez, Spain Bristol Myers, Janssen and MSD. 9 Rheumatology, Hospital de Basurto, Basurto, Spain Patient consent for publication Not applicable. 10 Ophthalmology, Complejo Asistencial Universitario de Leon, Leon, Spain Ethics approval This study was approved by Ethics Committee: CEIm Cantabria 11 Department of Rheumatology, Araba University Hospital, Vitoria-­Gasteiz, Spain (reference number: JLM-­CER-­2020-­01). Participants gave informed consent to 12 Rheumatology, Hospital Universitario de Toledo, Toledo, Spain participate in the study before taking part. 6 Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693 Miscellaneous RMD Open: first published as 10.1136/rmdopen-2022-002693 on 6 December 2022. Downloaded from http://rmdopen.bmj.com/ on November 6, 2023 by guest. Protected by copyright. Provenance and peer review Not commissioned; externally peer reviewed. in Behçet's disease: an open-­label trial. Arthritis Rheum 2005;52:2478–84. Data availability statement No data are available. 19 Niccoli L, Nannini C, Benucci M, et al. Long-­Term efficacy of Open access This is an open access article distributed in accordance with the infliximab in refractory posterior uveitis of Behcet's disease: a Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 24-­month follow-­up study. Rheumatology 2007;46:1161–4. permits others to distribute, remix, adapt, build upon this work non-­commercially, 20 Bou R, Adán A, Borrás F, et al. Clinical management algorithm of and license their derivative works on different terms, provided the original work is uveitis associated with juvenile idiopathic arthritis: interdisciplinary properly cited, appropriate credit is given, any changes made indicated, and the panel consensus. Rheumatol Int 2015;35:777–85. use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 21 Riancho-­Zarrabeitia L, Calvo-­Río V, Blanco R, et al. Anti-­TNF-α therapy in refractory uveitis associated with sarcoidosis: Multicenter ORCID iDs study of 17 patients. Semin Arthritis Rheum 2015;45:361–8. 22 Martín-­Varillas JL, Atienza-­Mateo B, Calvo-­Rio V, et al. Long-­Term José Luis Martín-­Varillas http://orcid.org/0000-0001-6147-6633 follow-­up and optimization of infliximab in refractory uveitis due to Emma Beltran-­Catalan http://orcid.org/0000-0001-8070-6916 Behçet disease: national study of 103 white patients. J Rheumatol Cristina Fernández-­Carballido http://orcid.org/0000-0002-0910-4944 2021;48:741–50. José L Hernández http://orcid.org/0000-0002-6585-8847 23 van der Horst-­Bruinsma I, van Bentum R, Verbraak FD, et al. The Ricardo Blanco http://orcid.org/0000-0003-2344-2285 impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients with axial spondyloarthritis: 48-­week interim results from C-­VIEW. RMD Open 2020;6:e001161. 24 Lopalco G, Emmi G, Gentileschi S, et al. Certolizumab Pegol REFERENCES treatment in Behcet’s disease with different organ involvement: A 1 Sakane T, Takeno M, Suzuki N, et al. Behçet’s Disease. N Engl J multicenter retrospective observational study. Modern Rheumatology Med Overseas Ed 1999;341:1284–91. 2017;27:1031–5. 2 Taylor SRJ, Singh J, Menezo V, et al. Behçet disease: visual 25 Palmou-­Fontana N, Calvo-­Río V, Martín-­Varillas JL, et al. Golimumab prognosis and factors influencing the development of visual loss. in refractory uveitis associated to juvenile idiopathic arthritis: Am J Ophthalmol 2011;152:1059–66. multicentre study of 7 cases and literature review. Clin Exp 3 Tugal-­Tutkun I, Onal S, Altan-­Yaycioglu R, et al. Uveitis in Rheumatol 2018;36:652–7. Behçet disease: an analysis of 880 patients. Am J Ophthalmol 26 Pasut G. Pegylation of biological molecules and potential benefits: 2004;138:373–80. pharmacological properties of certolizumab pegol. BioDrugs 4 Rothova A. Ocular involvement in sarcoidosis. Br J Ophthalmol 2014;28:15–23. 2000;84:110–6. 27 Porter C, Armstrong-­Fisher S, Kopotsha T, et al. Certolizumab pegol 5 Stolwijk C, van Tubergen A, Castillo-­Ortiz JD, et al. Prevalence does not bind the neonatal Fc receptor (FcRn): consequences for of extra-­articular manifestations in patients with ankylosing FcRn-­mediated in vitro transcytosis and ex vivo human placental spondylitis: a systematic review and meta-­analysis. Ann Rheum Dis transfer. J Reprod Immunol 2016;116:7–12. 2015;74:65–73. 28 Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of 6 de Winter JJ, van Mens LJ, van der Heijde D, et al. Prevalence of uveitis Nomenclature for reporting clinical data. Results of the first peripheral and extra-­articular disease in ankylosing spondylitis International workshop. Am J Ophthalmol 2005;140:509–16. versus non-­radiographic axial spondyloarthritis: a meta-­analysis. 29 Nussenblatt RB, Palestine AG, Chan C-­C, et al. Standardizatlon of Arthritis Res Ther 2016;18:196. vitreal inflammatory activity in intermediate and posterior uveitis. 7 Foster CS. Diagnosis and treatment of juvenile idiopathic arthritis-­ Ophthalmology 1985;92:467–71. associated uveitis. Curr Opin Ophthalmol 2003;14:395–8. 30 Tugal-­Tutkun I, Onal S, Altan-­Yaycioglu R, et al. Uveitis in 8 Heiligenhaus A, Niewerth M, Ganser G, et al. Prevalence and Behçet disease: an analysis of 880 patients. Am J Ophthalmol complications of uveitis in juvenile idiopathic arthritis in a population-­ 2004;138:373–80. based nation-­wide study in Germany: suggested modification of the 31 Llorenç V, Mesquida M, Sainz de la Maza M, et al. Certolizumab current screening guidelines. Rheumatology 2007;46:1015–9. pegol, a new anti-­TNF-α in the armamentarium against ocular 9 Harbord M, Annese V, Vavricka SR, et al. The first European inflammation. Ocul Immunol Inflamm 2016;24:167–72. evidence-­based consensus on extra-­intestinal manifestations in 32 Prieto-­Peña D, Calderón-­Goercke M, Adán A, et al. Efficacy and inflammatory bowel disease. J Crohns Colitis 2016;10:239–54. safety of certolizumab pegol in pregnant women with uveitis. 10 Schwartzman S. Advancements in the management of uveitis. Best recommendations on the management with immunosuppressive and Pract Res Clin Rheumatol 2016;30:304–15. biologic therapies in uveitis during pregnancy. Clin Exp Rheumatol 11 Jaffe GJ, Dick AD, Brézin AP, et al. Adalimumab in patients with 2021;39:105–14. active noninfectious uveitis. N Engl J Med 2016;375:932–43. 33 Rudwaleit M, Rosenbaum JT, Landewé R, et al. Observed incidence 12 Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitis following Certolizumab pegol treatment in patients with of uveitic flare in patients with inactive non-­infectious uveitis axial spondyloarthritis. Arthritis Care Res 2016;68:838–44. controlled by corticosteroids (visual II): a multicentre, double-­ 34 Tosi GM, Sota J, Vitale A, et al. Efficacy and safety of certolizumab masked, randomised, placebo-­controlled phase 3 trial. The Lancet pegol and golimumab in the treatment of non-­infectious uveitis. Clin 2016;388:1183–92. Exp Rheumatol 2019;37:680–3. 13 Suhler EB, Adán A, Brézin AP, et al. Safety and efficacy of 35 van der Horst-­Bruinsma IE, van Bentum RE, Verbraak FD, adalimumab in patients with noninfectious uveitis in an ongoing et al. Reduction of anterior uveitis flares in patients with axial open-­label study: visual III. Ophthalmology 2018;125:1075–87. spondyloarthritis on certolizumab pegol treatment: final 2-­year 14 Ohno S, Umebayashi I, Matsukawa M, et al. Safety and efficacy results from the multicenter phase IV C-­VIEW study. Ther Adv of infliximab in the treatment of refractory uveoretinitis in Behçet’s Musculoskelet Dis 2021;13:1759720X211003803. disease: a large-­scale, long-­term postmarketing surveillance in 36 Martín-­Varillas JL, Calvo-­Río V, Beltrán E, et al. Successful Japan. Arthritis Res Ther 2019;21:2. optimization of adalimumab therapy in refractory uveitis due to 15 Ohno S, Nakamura S, Hori S, et al. Efficacy, safety, and Behçet's disease. Ophthalmology 2018;125:1444–51. pharmacokinetics of multiple administration of infliximab in Behçet's 37 Gottenberg J-­E, Brocq O, Perdriger A, et al. Non-­TNF-­Targeted disease with refractory uveoretinitis. J Rheumatol 2004;31:1362–8. biologic vs a second anti-­TNF drug to treat rheumatoid arthritis 16 Calvo-­Río V, Blanco R, Beltrán E, et al. Anti-­TNF-α therapy in in patients with insufficient response to a first anti-­TNF drug: a patients with refractory uveitis due to Behçet's disease: a 1-­year randomized clinical trial. JAMA 2016;316:1172–80. follow-­up study of 124 patients. Rheumatology 2014;53:2223–31. 38 Uma M. Pregnancy concerns in women with inflammatory bowel 17 Santos-­Gómez M, Calvo-­Río V, Blanco R, et al. The effect of biologic disease. Gastroenterol Hepatol 2015;11:273–5. therapy different from infliximab or adalimumab in patients with 39 Clowse MEB, Scheuerle AE, Chambers C, et al. Pregnancy refractory uveitis due to Behçet's disease: results of a multicentre outcomes after exposure to Certolizumab pegol: updated results open-­label study. Clin Exp Rheumatol 2016;34:S34–40. from a pharmacovigilance safety database. Arthritis Rheumatol 18 Tugal-­Tutkun I, Mudun A, Urgancioglu M, et al. Efficacy of infliximab 2018;70:1399–407. in the treatment of uveitis that is resistant to treatment with the 40 Kiely PDW. Biologic efficacy optimization—a step towards combination of azathioprine, cyclosporine, and corticosteroids personalized medicine. Rheumatology 2016;55:780–8. Martín-­Varillas JL, et al. RMD Open 2022;8:e002693. doi:10.1136/rmdopen-2022-002693 7