Acuerdo de riesgo compartido basado en resultados de salud para el tratamiento de psoriasis moderada-grave con certolizumab pegol / Risk-sharing agreement based on health outcomes for the treatment of moderate-severe psoriasis with certolizumab pegol

Objetivo: aportar evidencia de la efectividad de certolizumab pegol (CZP) en la práctica clínica real en pacientes adultos afectados por psoriasis (PsO) en placas moderada-grave, dentro del contexto de un acuerdo de riesgo compartido (ARC). Métodos: estudio observacional retrospectivo a partir de las variables recogidas en un ARC en los pacientes adultos con PsO en placas moderada-grave tratados con CZP. Participaron 10 hospitales españoles donde se estableció el ARC. Se evaluó el porcentaje de pacientes que alcanzaron la respuesta clínica objetivo del ARC en la visita de seguimiento (semana 16): valor de Psoriasis Area and Severity Index (PASI) absoluto ≤3 para la población naive a biológicos, y ≤5 ante el fracaso previo a un único fármaco biológico. Además, se analizó la mejora en la puntuación de otras escalas: Body Surface Area (BSA), Dermatology Life Quality Index (DLQI), Physician’s Global Assesment (PGA) y Nail Psoriasis Severity Index (NAPSI). Se realizó un análisis descriptivo del total de la población y por subgrupos de pacientes (naive vs. no naive a biológico, hombre vs. mujer, y con vs. sin interrupción). Resultados: se incluyeron 66 pacientes, 12 hombres y 54 mujeres. El 90,9% alcanzaron la respuesta clínica objetivo, con una reducción media de 8 (−78,4%) puntos de PASI absoluto. Se observó una mejora en BSA, PGA, NAPSI y DLQI, con una reducción de 11,3 (−80,6%), 1,9 (−65,5%), 3,3 (−30,7%) y 9,0 (−66,4%) puntos del valor absoluto, respectivamente. Pese a no alcanzar el objetivo terapéutico establecido en el ARC en 6 pacientes (9%) (el coste del fármaco fue asumido por el laboratorio), solo 2 (3%) interrumpieron el tratamiento. Conclusión: nuestro estudio muestra que CZP resulta efectivo en la práctica clínica real en los pacientes con PsO en placas moderada-grave con una mejora de PASI absoluto y DLQI, así como de otras escalas, tanto para el total de la población como en los subgrupos analizados...(AU)

Objective: To provide evidence of the effectiveness of certolizumab pegol (CZP) in real clinical practice in adult patients with moderate-to-severe plaque psoriasis (PsO) in the context of a risk-sharing agreement (RSA). Methods: Retrospective observational study based on variables collected in the RSA for treatment with CZP of adult patients with moderate-severe plaque PsO. Ten Spanish hospitals where the RSA was implemented participated. The percentage of patients who achieved the target clinical response of the RSA at the follow-up visit (week 16) was evaluated: absolute Psoriasis Area and Severity Index (PASI) value ≤3 for biologic naïve population, and ≤5 in case of previous failure to a single biologic drug. In addition, the improvement in the scores of other scales included in the study was analyzed: Body Surface Area (BSA), Dermatology Life Quality Index (DLQI), Physician's Global Assessment (PGA), and Nail Psoriasis Severity Index (NAPSI). A descriptive analysis was performed for the total population and by patient subgroups (naive vs. non-naive to biologic, male vs. female, and with vs. without discontinuation). Results: Sixty-six patients were included, 12 men and 54 women. 90.9% achieved the target clinical response, with a mean reduction of 8 (−78.4%) absolute PASI points. Improvement was observed in BSA, PGA, NAPSI and DLQI, with a reduction of 11.3 (−80.6%), 1.9 (−65.5%), 3.3 (−30.7%) and 9.0 (−66.4%) absolute value points, respectively. Despite not achieving the therapeutic target set in the RSA in six patients (9%) (the cost of the drug was assumed by the laboratory), only two (3%) discontinued treatment. Conclusion: Our study shows that CZP is effective in real clinical practice in patients with moderate-severe plaque PsO, with an improvement in absolute PASI and DLQI, as well as other scales, both for the total population and in the subgroups analyzed. Nearly 91% of patients reached the therapeutic target fixed in the RSA...(AU)

Risk-sharing agreement based on health outcomes for the treatment of moderate–severe psoriasis with certolizumab pegol / Acuerdo de riesgo compartido basado en resultados de salud para el tratamiento de psoriasis moderada-grave con certolizumab pegol

Objetivo: aportar evidencia de la efectividad de certolizumab pegol (CZP) en la práctica clínica real en pacientes adultos afectados por psoriasis (PsO) en placas moderada-grave, dentro del contexto de un acuerdo de riesgo compartido (ARC). Métodos: estudio observacional retrospectivo a partir de las variables recogidas en un ARC en los pacientes adultos con PsO en placas moderada-grave tratados con CZP. Participaron 10 hospitales españoles donde se estableció el ARC. Se evaluó el porcentaje de pacientes que alcanzaron la respuesta clínica objetivo del ARC en la visita de seguimiento (semana 16): valor de Psoriasis Area and Severity Index (PASI) absoluto ≤3 para la población naive a biológicos, y ≤5 ante el fracaso previo a un único fármaco biológico. Además, se analizó la mejora en la puntuación de otras escalas: Body Surface Area (BSA), Dermatology Life Quality Index (DLQI), Physician’s Global Assesment (PGA) y Nail Psoriasis Severity Index (NAPSI). Se realizó un análisis descriptivo del total de la población y por subgrupos de pacientes (naive vs. no naive a biológico, hombre vs. mujer, y con vs. sin interrupción). Resultados: se incluyeron 66 pacientes, 12 hombres y 54 mujeres. El 90,9% alcanzaron la respuesta clínica objetivo, con una reducción media de 8 (−78,4%) puntos de PASI absoluto. Se observó una mejora en BSA, PGA, NAPSI y DLQI, con una reducción de 11,3 (−80,6%), 1,9 (−65,5%), 3,3 (−30,7%) y 9,0 (−66,4%) puntos del valor absoluto, respectivamente. Pese a no alcanzar el objetivo terapéutico establecido en el ARC en 6 pacientes (9%) (el coste del fármaco fue asumido por el laboratorio), solo 2 (3%) interrumpieron el tratamiento. Conclusión: nuestro estudio muestra que CZP resulta efectivo en la práctica clínica real en los pacientes con PsO en placas moderada-grave con una mejora de PASI absoluto y DLQI, así como de otras escalas, tanto para el total de la población como en los subgrupos analizados...(AU)

Objective: To provide evidence of the effectiveness of certolizumab pegol (CZP) in real clinical practice in adult patients with moderate-to-severe plaque psoriasis (PsO) in the context of a risk-sharing agreement (RSA). Methods: Retrospective observational study based on variables collected in the RSA for treatment with CZP of adult patients with moderate-severe plaque PsO. Ten Spanish hospitals where the RSA was implemented participated. The percentage of patients who achieved the target clinical response of the RSA at the follow-up visit (week 16) was evaluated: absolute Psoriasis Area and Severity Index (PASI) value ≤3 for biologic naïve population, and ≤5 in case of previous failure to a single biologic drug. In addition, the improvement in the scores of other scales included in the study was analyzed: Body Surface Area (BSA), Dermatology Life Quality Index (DLQI), Physician's Global Assessment (PGA), and Nail Psoriasis Severity Index (NAPSI). A descriptive analysis was performed for the total population and by patient subgroups (naive vs. non-naive to biologic, male vs. female, and with vs. without discontinuation). Results: Sixty-six patients were included, 12 men and 54 women. 90.9% achieved the target clinical response, with a mean reduction of 8 (−78.4%) absolute PASI points. Improvement was observed in BSA, PGA, NAPSI and DLQI, with a reduction of 11.3 (−80.6%), 1.9 (−65.5%), 3.3 (−30.7%) and 9.0 (−66.4%) absolute value points, respectively. Despite not achieving the therapeutic target set in the RSA in six patients (9%) (the cost of the drug was assumed by the laboratory), only two (3%) discontinued treatment. Conclusion: Our study shows that CZP is effective in real clinical practice in patients with moderate-severe plaque PsO, with an improvement in absolute PASI and DLQI, as well as other scales, both for the total population and in the subgroups analyzed. Nearly 91% of patients reached the therapeutic target fixed in the RSA...(AU)

Changes of Metabolic Biomarker Levels upon One-Year Anti-TNF-α Therapy in Rheumatoid Arthritis and Ankylosing Spondylitis: Associations with Vascular Pathophysiology.

BACKGROUND: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. PATIENTS AND METHODS: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. RESULTS: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months (p < 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids (p < 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p < 0.05). One-year anti-TNF treatment together with baseline leptin (p = 0.039) or CRP (p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes (p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime (p = 0.003). CONCLUSIONS: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology.

Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial.

PURPOSE: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. PATIENTS AND METHODS: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. RESULTS: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. CONCLUSIONS: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.

Anti-TNF containing regimens may be associated with increased risk of Clostridioides difficile infection in patients with underlying inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at greater risk for Clostridioides difficile infection (CDI). There remain controversial issues about the association of infliximab therapy in IBD patients and CDI. OBJECTIVE: The present work aimed to investigate the potential association between infliximab therapy and the risk of CDI in a group of Iranian patients with IBD. PATIENTS AND METHODS: A total of 140 IBD patients were enrolled, their fresh stool specimens were obtained and used for C. difficile detection. The presence of toxin-encoding genes of C. difficile isolates were examined by PCR. Demographic data, frequency of defecation, antibiotic usage, and IBD therapy were recorded. RESULTS: About half of the IBD patients had a history of antibiotic usage, mostly metronidazole (11.4 %) alone, and metronidazole + ciprofloxacin (16.4 %) as drug combination. C. difficile was isolated from 17.1 % (24/140) of the IBD patients, and more than 90 % of the isolates were found to be toxigenic having genotypes of tcdA+/tcdB+ (18/22, 81.8 %), tcdA+/tcdB- (3/22, 13.6 %) and tcdA-/tcdB+ (1/22, 4.5 %). Interestingly, we only found a significant relationship between the emergence of CDI and the use of infliximab in combinations with other drugs (P = 0.023). CONCLUSIONS: In conclusion, there was a considerable incidence of CDI in Iranian patients with IBD. Our study also demonstrated that anti-TNF containing regimens in combinations with other immunosuppressive medications potentially may influence susceptibility to CDI in a group of patients with underlying IBD. Furthermore, our findings recommend avoiding the prolonged use of infliximab along with other corticosteroids or immunomodulators. Further validation studies are needed to better understand the mechanisms that regulate TNF-mediated pathways in CDI pathogenesis among IBD patients.

Maintenance of clinical remission in early axial spondyloarthritis following certolizumab pegol dose reduction.

BACKGROUND: The best strategy for maintaining clinical remission in patients with axial spondyloarthritis (axSpA) has not been defined. C-OPTIMISE compared dose continuation, reduction and withdrawal of the tumour necrosis factor inhibitor certolizumab pegol (CZP) following achievement of sustained remission in patients with early axSpA. METHODS: C-OPTIMISE was a two-part, multicentre phase 3b study in adults with early active axSpA (radiographic or non-radiographic). During the 48-week open-label induction period, patients received CZP 200 mg every 2 weeks (Q2W). At Week 48, patients in sustained remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 at Weeks 32/36 and 48) were randomised to double-blind CZP 200 mg Q2W (full maintenance dose), CZP 200 mg every 4 weeks (Q4W; reduced maintenance dose) or placebo (withdrawal) for a further 48 weeks. The primary endpoint was remaining flare-free (flare: ASDAS ≥2.1 at two consecutive visits or ASDAS >3.5 at any time point) during the double-blind period. RESULTS: At Week 48, 43.9% (323/736) patients achieved sustained remission, of whom 313 were randomised to CZP full maintenance dose, CZP reduced maintenance dose or placebo. During Weeks 48 to 96, 83.7% (87/104), 79.0% (83/105) and 20.2% (21/104) of patients receiving the full maintenance dose, reduced maintenance dose or placebo, respectively, were flare-free (p<0.001 vs placebo in both CZP groups). Responses in radiographic and non-radiographic axSpA patients were comparable. CONCLUSIONS: Patients with early axSpA who achieve sustained remission at 48 weeks can reduce their CZP maintenance dose; however, treatment should not be completely discontinued due to the high risk of flare following CZP withdrawal. TRIAL REGISTRATION NUMBER: NCT02505542, ClinicalTrials.gov.

A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNFα-Blockade in Rheumatoid Arthritis Patients.

Objectives: To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment. Methods: Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust and underwent synovial sampling of an actively inflamed joint using ultrasound-guided needle biopsy before commencing certolizumab-pegol and after 12-weeks. At 12-weeks, patients were categorized as responders if they had a DAS28 fall >1.2. A minimum of 6 samples was collected for histological analysis. Based on H&E and immunohistochemistry (IHC) staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages) patients were categorized into three distinct synovial pathotypes (lympho-myeloid, diffuse-myeloid, and pauci-immune). Results: At baseline, as per inclusion criteria, DAS28 mean was 6.4 ± 0.9. 94.6% of the synovial tissue was retrieved from the wrist or a metacarpophalangeal joint. Histological pathotypes were distributed as follows: 58% lympho-myeloid, 19.4% diffuse-myeloid, and 22.6% pauci-immune. Patients with a pauci-immune pathotype had lower levels of CRP but higher VAS fatigue compared to lympho- and diffuse-myeloid. Based on DAS28 fall >1.2, 67.6% of patients were deemed as responders and 32.4% as non-responders. However, by categorizing patients according to the baseline synovial pathotype, we demonstrated that a significantly higher number of patients with a lympho-myeloid and diffuse-myeloid pathotype in comparison with pauci-immune pathotype [83.3% (15/18), 83.3 % (5/6) vs. 28.6% (2/7), p = 0.022) achieved clinical response to certolizumab-pegol. Furthermore, we observed a significantly higher level of post-treatment tender joint count and VAS scores for pain, fatigue and global health in pauci-immune in comparison with lympho- and diffuse-myeloid patients but no differences in the number of swollen joints, ESR and CRP. Finally, we confirmed a significant fall in the number of CD68+ sublining macrophages post-treatment in responders and a correlation between the reduction in the CD20+ B-cells score and the improvement in the DAS28 at 12-weeks. Conclusions: The analysis of the synovial histopathology may be a helpful tool to identify among clinically indistinguishable patients those with lower probability of response to TNFα-blockade.

Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease.

BACKGROUND: Biologic therapies in patients with Crohn's disease often yield low clinical and endoscopic remission rates. After multiple failed therapies, combining two biologic therapies is possibly the sole medical alternative to recurrent surgery. However, data on this approach are limited. AIMS: To assess the efficacy and safety of concomitant use of two biologic therapies in the largest cohort to date of refractory Crohn's disease patients. METHODS: Data were extracted from Crohn's disease patients started on dual biologic therapy at two referral centres. Biologics utilised include infliximab, adalimumab, vedolizumab, ustekinumab, certolizumab and golimumab. The primary outcome was endoscopic improvement (>50% reduction in Simplified Endoscopic Score-Crohn's disease [SES-CD] or explicitly stated). Endoscopic remission (SES-CD < 3 or stated), clinical response (Crohn's disease-patient-reported outcome-2 score [PRO2] reduced by 8), clinical remission (PRO2 < 8), and C-reactive protein (CRP) were also assessed. RESULTS: A total of 22 patients with 24 therapeutic trials of dual biologic therapy were identified. The majority of patients had prior surgical resections (91%), stricturing (59%) or penetrating (36%) phenotype, and perianal fistulas (50%). Median number of prior failed biologics was 4. Endoscopic improvement occurred in 43% of trials and 26% achieved endoscopic remission. Fifty per cent had clinical response and 41% achieved clinical remission. There were significant post-treatment reductions in median SES-CD (14.0 [12.0-17.5] to 6.0 [2.5-8.0], P = 0.0005], PRO-2 (24.1 [20.3-27.0] to 13.4 [4.6-21.8], P = 0.002] and CRP (17.0 [11.0-24.0] to 9.0 [4.0-14.0], P = 0.02). Presence of perianal fistulas decreased from 50% to 33%. Adverse events occurred in 13% of trials. CONCLUSION: Dual biologic therapy was associated with clinical, biomarker and endoscopic improvements in selected patients with refractory Crohn's disease who failed multiple biologics. Further studies are needed to validate this approach.

A multicenter, open-label study to evaluate the safe and effective use of a new electromechanical auto-injection device for self-injection of certolizumab pegol.

BACKGROUND: ava® is a new reusable electromechanical auto-injector (e-Device) with disposable, single-use certolizumab pegol (CZP) dispensing cartridges. METHODS: RA0098 (NCT03357471) was a US, multicenter, open-label, phase 3 study designed to assess whether the e-Device can be used safely and effectively by self-injecting patients. CZP pre-filled syringe (PFS) self-injecting patients (≥18 years) diagnosed with rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, plaque psoriasis, and Crohn's disease received training and self-injected CZP using the e-Device at 2 visits. The primary outcome was the proportion of patients able to self-inject safely and effectively at Visit 2, defined as: 1) complete dose delivery, and 2) no adverse events related to the e-Device precluding its continued use. RESULTS: 65/67 patients (97.0%) completed the study, 64/65 (98.5%) performed safe and effective self-injection at Visit 2, and 67/67 (100%) performed safe and effective self-injection at Visit 1. Patient satisfaction and self-confidence increased over the two visits. Overall, patients reported a preference for the e-Device (58/65; 89.2%) compared to a PFS (4/65; 6.2%). CONCLUSIONS: Patients were able to safely and effectively self-inject CZP using the e-Device and most preferred ava® over a PFS. No safety-related findings impacting the benefit-risk ratio of CZP were identified.

A pilot study examining patient preference and satisfaction for ava®, a reusable electronic injection device to administer certolizumab pegol.

Background: Anti-tumor necrosis factor (anti-TNF) adherence is suboptimal. ava®, a reusable electromechanical self-injection device (e-Device) developed for certolizumab pegol (CZP) administration, aims to overcome some barriers to increase adherence. This study evaluates patient experience of the e-Device and its training materials and determines patient device preference.Methods: CZP-treated patients were recruited from the Netherlands, Denmark and Sweden. Patients completed a pre-injection Assessment of Self-Injection (ASI) questionnaire investigating self-injection perception. After training, patients administered 3 consecutive self-injections using the e-Device, patient experience of each was assessed using the post-injection ASI. An additional questionnaire evaluated training materials. After Injection 3, patients indicated their preference: the e-Device or their previous device.Results: 59 patients participated; most rated the e-Device highly for satisfaction, self-confidence and ease of use. The (negative) feelings and pain and skin reactions domains had low ratings. Post-injection ASI domain scores were similar following each of the 3 e-Device injections. Training materials were rated highly (video: 8.4/10; step-by-step guide: 8.4/10). 57.1% (32/56) patients preferred the e-Device over their previous self-injection device.Conclusions: Patients were satisfied with the e-Device and most preferred it over other self-injection devices. By improving patient experience, the e-Device may help increase medication adherence.

Patient Satisfaction with CIMZIA® (Certolizumab Pegol) AutoClicks® in the UK.

INTRODUCTION: The CIMZIA® AutoClicks® pre-filled pen (CZP PFP) was developed to overcome barriers to self-injection, by improving self-injection confidence, reducing fear associated with needle use, and supporting patients with impaired dexterity. The purpose of this research was to gather feedback on injection experience and the usefulness of training materials. METHODS: Eligible patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) were at least 18 years of age and initiated onto the CZP PFP. Routine self-injection training and support were provided by trained specialist nurses. Patient experience (pain and skin reactions, confidence, satisfaction, and ease of use) was evaluated at visits 1-3 using an amended version of the self-injection assessment questionnaire (SIAQ) v2.0. Nurse and patient feedback on the training materials, and nurse opinions on patient self-injection after self-injection at visit 1, were also collected. RESULTS: Of 355 patients invited to participate, 196 provided informed consent and 79 participated in all three visits. Patients generally found the CZP PFP easy to use, and self-confidence and satisfaction were high. From visit 1 to visit 3, there was a numerical trend towards improvement in all three aspects of patient experience, most notably in both confidence and satisfaction. After self-injection at visit 1, confidence around safe patient self-injection was higher among nurses than among patients. Meanwhile, "pain and skin reactions" remained low at all visits. Patients thought the training materials contained sufficient information and were easy to understand and useful. CONCLUSION: After training, patients generally found the device easy to use and showed high confidence and satisfaction with self-injection. Some patients may have been competent (based on nurse opinion), but initially lacked self-confidence. Increasing self-injection experience, together with patient training and continued support, may have facilitated high patient confidence and satisfaction, thereby potentially overcoming some of the barriers to self-injection.

Exposure-Response Relationship of Certolizumab Pegol and Achievement of Low Disease Activity and Remission in Patients With Rheumatoid Arthritis.

Anti-tumor necrosis factor (anti-TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti-TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C-reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure-response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 µg/ml at week 12, and ≥ 17.6 µg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.

Factors associated with successful discontinuation of certolizumab pegol in early rheumatoid arthritis.

AIM: The Certolizumab-Optimal Prevention of joint damage for Early Rheumatoid Arthritis (C-OPERA) study demonstrated that in methotrexate (MTX)-naïve early RA patients with poor prognostic factors, 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year optimized MTX therapy brings radiographic and clinical benefits through 2 years even after stopping CZP. This exploratory analysis aimed to identify factors at baseline and at CZP discontinuation associated with successful CZP discontinuation. METHODS: MTX-naïve early RA patients with poor prognostic factors entered C-OPERA (NCT01451203), a multicenter, randomized controlled trial. Patients were randomized to CZP + MTX (n = 159) or PBO + MTX (n = 157); those who completed the 1-year, double-blind period received MTX alone in Year 2 (CZP + MTX→MTX, n = 108; PBO + MTX→MTX, n = 71). Association between factors at baseline or at discontinuation of CZP and clinical/radiographic outcomes were evaluated by multiple logistic regression analysis. Predictive value cut-offs were calculated using receiver operating characteristic analysis. RESULTS: Sex (male) and low baseline Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR) were associated with simple disease activity index (SDAI) remission (≤3.3), whereas high baseline DAS28-ESR and modified total Sharp score (mTSS) were associated with clinically relevant radiographic progression (yearly progression mTSS > 3) at Week 104 (across both treatment arms). Low DAS28-ESR (<2.1) and rheumatoid factor (RF; <74 IU/mL) at discontinuation of CZP were associated with SDAI remission at Week 104. At Week 104, SDAI remission was achieved by 75.0% (42/56) of patients with low DAS28-ESR and RF at discontinuation, compared to 15.4% (2/13) of patients with high DAS28-ESR and RF. CONCLUSION: Patients with low RF and low disease activity after treatment with CZP + MTX may be able to discontinue CZP without risk of loss of response.

Development of hypocomplementemic urticarial vasculitis during certolizumab pegol treatment for rheumatoid arthritis: A case report.

WHAT IS KNOWN AND OBJECTIVE: Tumour necrosis factor-α-blocking agents potentially cause vasculitis. However, no study has reported on the association between hypocomplementemic urticarial vasculitis (HUV) and certolizumab pegol (CZP) usage. CASE DESCRIPTION: We present the first case of HUV development during CZP treatment for rheumatoid arthritis. Hypocomplementemic urticarial vasculitis improved after CZP was discontinued and the dose of oral prednisolone was increased. WHAT IS NEW AND CONCLUSION: Clinicians should be aware about the potential development of HUV during CZP treatment, which is presumed to be safe considering its unique structural characteristics that differ from those of other tumour necrosis factor-α-blocking agents.

Psoriasis and pregnancy in the biologic era, a feared scenario. What do we do now?

Psoriasis is a chronic, multifactorial inflammatory disease; its clinical severity can vary widely. Treatment of severe cases during pregnancy is of special interest. To date there is scarce information available and most data comes from other medical specialties that use similar treatments. Immunosuppressors are strongly discouraged during pregnancy and breastfeeding. Amongst biologic agents, anti-TNFα having been the longest on the market has allowed for the most experience. It is known that transplacental transport of these drugs does not occur until gestational week 22, once organogenesis is completed. Within this group certolizumab pegol, seems to be the safest choice, as its molecular structure does not cross the placental barrier. Beyond pregnancy, it is important to take into account these drugs' half-life and passage to breast milk, as well as its impact on neonatal immunization.

Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: a proof-of-concept study.

OBJECTIVE: Evaluate the efficacy and safety of dual neutralisation of interleukin (IL)-17A and IL-17F with bimekizumab, a monoclonal IgG1 antibody, in addition to certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) and inadequate response (IR) to certolizumab pegol. METHODS: During this phase 2a, double-blind, proof-of-concept (PoC) study (NCT02430909), patients with moderate-to-severe RA received open-label CZP 400 mg at Weeks 0, 2 and 4, and 200 mg at Week 6. Patients with IR at Week 8 (Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP))>3.2) were randomised 2:1 to CZP (200 mg every 2 weeks (Q2W)) plus bimekizumab (240 mg loading dose then 120 mg Q2W) or CZP plus placebo. The primary efficacy and safety variables were change in DAS28(CRP) between Weeks 8 and 20 and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Of 159 patients enrolled, 79 had IR at Week 8 and were randomised to CZP plus bimekizumab (n=52) or CZP plus placebo (n=27). At Week 20, there was a greater reduction in DAS28(CRP) in the CZP-IR plus bimekizumab group compared with the CZP-IR plus placebo group (99.4% posterior probability). The most frequent TEAEs were infections and infestations (CZP plus bimekizumab, 50.0% (26/52); CZP plus placebo, 22.2% (6/27)). CONCLUSIONS: PoC was confirmed based on the rapid decrease in disease activity achieved with 12 weeks of CZP plus bimekizumab. No unexpected or new safety signals were identified when neutralising IL-17A and IL-17F in patients with RA concomitantly treated with CZP, but the rate of TEAEs was higher with dual inhibition.

A safety review of recent advancements in the treatment of psoriasis: analysis of clinical trial safety data.

INTRODUCTION: The management of psoriasis can include oral medications and injectable biologics. Safety data of these various treatment options are important to consider when choosing the right treatment for the patient. AREAS COVERED: This review evaluates the safety of newer treatments approved for psoriasis, including interleukin-(IL)-17 inhibitors, IL-23/p19 inhibitors, ustekinumab, certolizumab pegol and apremilast, using phases III and IV clinical trial data. EXPERT OPINION: Even as treatment of psoriasis becomes safer, it is important to recognize both common and uncommon adverse effects of treatment. Common adverse effects are similar across treatment options, including upper respiratory infection and injection-site reaction. Serious adverse effects occur less frequently and specific to the psoriasis treatment option, such as inflammatory bowel disease and candida infections with IL-17 inhibitors, tuberculosis with certolizumab pegol, and psychiatric events with apremilast. While IL-23/p19 inhibitors may have a slightly better safety profile than other biologics, long-term data are limited. The conclusions that can be drawn from clinical trial safety data are limited given that many clinical trials are not large enough to detect rare safety events. Data from registries provide important complementary information on long-term safety but there are limitations including a lack of randomized assignment between drug treatments.

HLA-B27 spondyloarthritis and spotted fever rickettsiosis: case-based review.

Rickettsia rickettsii, a tick borne disease, is the pathogen responsible for inducing Rocky Mountain Spotted Fever (RMSF), an illness that can progress to fulminant multiorgan failure and death. We present a case where R. rickettsii, acquired on a camping trip, precipitated a flare of peripheral arthritis and episcleritis in an HLA-B27 positive patient. Although Yersinia, Salmonella, Mycobacteria, Chlamydia, Shigella, Campylobacter, and Brucella have been previously associated with HLA-B27 spondyloarthritis, this unusual case demonstrates that obligate intracellular rickettsial organisms, and specifically, R. rickettsii, can also induce flares of HLA-B27 spondyloarthritis. Rickettsial infections in general can rapidly become fatal in both healthy and immunosuppressed patients, and thus, prompt diagnosis and therapy are required.