Efficacy and safety of certolizumab pegol in pregnant women with uveitis. Recommendations on the management with immunosuppressive and biologic therapies in uveitis during pregnancy.

OBJECTIVES: Clinicians often face the challenge of providing effective and safe therapy for pregnant women with uveitis. Certolizumab pegol (CZP) differs from other anti-TNFα agents due to its limited placental transfer. In this study we assessed the efficacy of CZP in pregnant women with uveitis. We also provided information on outcomes of pregnant women and neonates exposed to CZP. METHODS: We carried out a multicentre study of women with uveitis who received CZP during pregnancy and their neonates. The main visual outcomes were visual acuity (VA), intraocular inflammation and corticosteroid-sparing effect. Pregnancy outcomes, maternal and neonatal infections and congenital malformations were also assessed. RESULTS: We studied 14 women (23 affected eyes); mean age of 34.3±5.5 years. The underlying diseases were spondyloarthritis (n=7), idiopathic (n=2), and Vogt-Koyanagi-Harada, rheumatoid arthritis, juvenile idiopathic arthritis, punctate inner choroidopathy and Behçet's disease (1 each). The patterns of ocular involvement were anterior (n=10), posterior (n=2), intermediate (n=1), panuveitis (n=1). Cystoid macular oedema was present in one patient (1 eye). Uveitis was bilateral in nine cases and chronic in seven patients. CZP was started before getting pregnant in ten patients and after conceiving in four. All patients achieved or maintained ocular remission throughout pregnancy. Fifteen healthy infants were born. Only one woman presented a mild infection during pregnancy. Neither infections nor malformations were observed in neonates after a follow-up of 6 months. Six infants were breastfed and all of them received scheduled vaccinations without complications. CONCLUSIONS: Certolizumab pegol is effective and safe in women with uveitis during pregnancy.

Tocilizumab in giant cell arteritis: differences between the GiACTA trial and a multicentre series of patients from the clinical practice.

OBJECTIVES: A potential point of concern among clinicians is whether results derived from the clinical trials can be reasonably applied or generalised to a definable group of patients seen in real world. It can be the case of the GiACTA study that is a phase III randomised controlled trial of tocilizumab (TCZ) in giant cell arteritis (GCA). To address this question, we compared the clinical features and the responses to TCZ from the GiACTA trial patients with those from a series of GCA seen in the daily clinical practice. METHODS: Comparative study of clinical features between patients from the GiACTA trial (overall n=251) and those from a multicentre series of real-world GCA patients undergoing TCZ therapy (n=134). The diagnosis of GCA in the GiACTA trial was established by the ACR modified criteria whereas in the series of real-world patients it was made by using the ACR criteria, a positive biopsy of temporal artery or the presence of imaging techniques consistent with large-vessel vasculitis in individuals who presented cranial symptoms of GCA. GiACTA trial patients received subcutaneous TCZ (162 mg every 1 or 2 weeks) whereas those from the clinical practice series were treated using standard IV dose (8 mg/kg/month) or subcutaneous (162 mg/week). RESULTS: Real-life patients undergoing TCZ were older with longer disease duration and higher values of ESR and had received conventional immunosuppressive therapy (mainly methotrexate) more commonly than those included in the GiACTA trial. Despite clinical differences, TCZ was equally effective in both GiACTA trial and clinical practice patients. However, serious infections were more commonly observed in GCA patients recruited from the clinical practice. CONCLUSIONS: Despite clinical differences with patients recruited in clinical trials, data from real-life patients confirm the efficacy of TCZ in GCA.

Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases: multicentre study of 80 patients.

OBJECTIVES: To evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID). METHODS: Multicentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year. RESULTS: We studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet's disease (n=10), psoriatic arthritis (n=8), Crohn's disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1), CONCLUSIONS: CZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.

Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients.

Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Our aim was to assess the efficacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves' Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age ± standard deviation 51 ± 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone (n = 43), or selenium (n = 11). GO disease was moderate (n =29) or severe (n = 19) and dysthyroid optic neuropathy (DON) (n = 7). TCZ was used in monotherapy (n = 45) or combined (n = 3) at a dose of 8 mg/kg IV every four weeks (n = 43) or 162 mg/s.c. every week (n = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 ± 0.25 vs. 0.9 ± 0.16; p = 0.0001), CAS (4.64 ± 1.5 vs. 1.05 ± 1.27; p = 0.0001) and intraocular pressure (IOP) (19.05 ± 4.1 vs. 16.73 ± 3.4 mmHg; p = 0.007). After a mean follow-up of 16.1 ± 2.1 months, low disease activity (CAS ≤ 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity (n = 25) or inefficacy (n = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.

Tartrate-resistant acid phosphatase 5b, but not periostin, is useful for assessing Paget's disease of bone.

BACKGROUND: Periostin is a matricellular protein with a preferential location in cortical bone and periosteal tissue, and tartrate-resistant acid phosphatase 5b (TRAP5b) is a marker of osteoclast numbers. In Paget's disease of bone (PDB), there is increased cortical thickening and probably increased periosteal apposition, along with increased osteoclast numbers. OBJECTIVES: To analyse if circulating periostin is a biomarker for PDB, and if it is associated with disease activity and involvement of long bones that represent major cortical contribution. Also, to analyse whether TRAP5b, a scarcely explored bone resorption marker, is useful in the assessment of PDB. PATIENTS AND METHODS: We recruited 42 patients with PDB (13F/29M; 71 ±â€¯11.6 yrs). 71.4% had active disease, 66.6% had polyostotic disease and 54.8% had long bone involvement. Blood and urine samples were taken between 8:00 and 10:00 A.M. after an overnight fast. Periostin and TRAP5b were measured in serum, using commercial ELISA assays (Biomedica and IDS, respectively). Serum total ALP, PINP, CTX, bone ALP and urinary NTX were measured. Reference values for periostin and TRAP5b were obtained from 45 healthy subjects. RESULTS: Serum periostin did not differ between patients and controls (989.4 ±â€¯173.2 vs. 966.9 ±â€¯195.4 pMol/L, p = 0.572). No significant differences were observed between patients with and without active disease (964.5 ±â€¯168.8 vs.1051.6 ±â€¯175.6 pMol/L, p = 0.143), involvement or not of long bones (1022.2 ±â€¯145.8 vs 949.7 ±â€¯198.2 pMol/L, p = 0.181) and monostotic or polyostotic disease (963.8 ±â€¯198.7 vs 1002.2 ±â€¯161.4 pMol/L, p = 0.505). There were significant correlations between serum periostin and all bone turnover markers (bone ALP, PINP, uNTX, sCTX and TRAP5b) in PDB patients with active disease, but not in the inactive PDB group. Serum TRAP5b was significantly higher in PDB patients than in controls (4.43 ±â€¯1.76 vs. 3.21 ±â€¯1.02 U/L, p < 0.001), in those with active disease (4.98 ±â€¯1.76 vs. 3.07 ±â€¯0.72 U/L, p < 0.001) and in patients with polyostotic disease than in those with monostotic disease (4.81 ±â€¯1.79 vs 3.68 ±â€¯1.5 U/L, p = 0.005). TRAP5b levels were not influenced by previous bisphosphonate treatment (4.14 ±â€¯1.42 vs. 4.84 ±â€¯2.02 U/L, p = 0.206). CONCLUSIONS: Periostin is not useful for assessing PDB, whilst TRAP5b, which has been a scarcely explored bone turnover marker until now, may be useful in the analysis of this disease, providing new information on the resorption process. In addition, periostin levels correlate with all classical BTMs in active PDB, suggesting that this marker may reflect periosteal and cortical metabolism in accelerated bone turnover states.

Tocilizumab in giant cell arteritis. Observational, open-label multicenter study of 134 patients in clinical practice.

OBJECTIVE: Tocilizumab (TCZ) has shown efficacy in clinical trials on giant cell arteritis (GCA). Real-world data are scarce. Our objective was to assess efficacy and safety of TCZ in unselected patients with GCA in clinical practice Methods: Observational, open-label multicenter study from 40 national referral centers of GCA patients treated with TCZ due to inefficacy or adverse events of previous therapy. Outcomes variables were improvement of clinical features, acute phase reactants, glucocorticoid-sparing effect, prolonged remission and relapses. A comparative study was performed: (a) TCZ route (SC vs. IV); (b) GCA duration (≤6 vs. >6 months); (c) serious infections (with or without); (d) ≤15 vs. >15 mg/day at TCZ onset. RESULTS: 134 patients; mean age, 73.0 ± 8.8 years. TCZ was started after a median [IQR] time from GCA diagnosis of 13.5 [5.0-33.5] months. Ninety-eight (73.1%) patients had received immunosuppressive agents. After 1 month of TCZ 93.9% experienced clinical improvement. Reduction of CRP from 1.7 [0.4-3.2] to 0.11 [0.05-0.5] mg/dL (p < 0.0001), ESR from 33 [14.5-61] to 6 [2-12] mm/1st hour (p < 0.0001) and decrease in patients with anemia from 16.4% to 3.8% (p < 0.0001) were observed. Regardless of administration route or disease duration, clinical improvement leading to remission at 6, 12, 18, 24 months was observed in 55.5%, 70.4%, 69.2% and 90% of patients. Most relevant adverse side-effect was serious infections (10.6/100 patients-year), associated with higher doses of prednisone during the first three months of therapy. CONCLUSION: In clinical practice, TCZ yields a rapid and maintained improvement of refractory GCA. Serious infections appear to be higher than in clinical trials.

Why people with fibromyalgia persist in activity despite the increasing pain? A Delphi Study of the content of the Clinic Scale of Persistence in Activity in Fibromyalgia.

BACKGROUND AND OBJECTIVE: There is evidence of the relevance of fear, anxiety and avoidance of activity in the maintenance of pain in fibromyalgia. Recently, an opposite pattern based on the persistence in activity has been described. To date, the cognitions that impede modifying this pattern are unknown. Therefore, the aim of this study is to reach consensus on the content of an instrument that assesses those cognitions. MATERIAL AND METHODS: A Delphi method was applied to reach consensus on the content of the Clinic Scale of Persistence in Activity in Fibromyalgia (CCAP-FM). RESULTS: After three rounds of consultation, an acceptable consensus was reached. Those items that received an average rating of relevance lower than 5/10 and that at least the 75% of experts recommended removing were excluded. The preliminary questionnaire of persistence in activity was composed of 30 items. CONCLUSIONS: The consensus on the content of the CCAP-FM will allow advancing towards the assessment of the relation between the modification of the cognitions responsible for the maintenance of the persistence in activity and the clinical improvement in people with fibromyalgia.

[Pharmacologic treatment of fibromyalgia: Towards chemical neuromodulation]. / Tratamiento farmacológico de la fibromialgia: hacia la neuromodulación química.

Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients.

¿Por qué las personas con fibromialgia persisten en la actividad a pesar del dolor creciente?: estudio Delphi sobre el contenido del Cuestionario Clínic de Persistencia en la Actividad en Fibromialgia / Why people with fibromyalgia persist in activity despite the increasing pain? A Delphi Study of the content of the Clinic Scale of Persistence in Activity in Fibromyalgia

Introducción. Existen sólidas pruebas de la relevancia del miedo, la ansiedad y la evitación de la actividad en el mantenimiento del dolor en la fibromialgia. Recientemente se ha descrito un modelo opuesto basado en la persistencia en la actividad. Actualmente desconocemos las cogniciones que dificultan la modificación de este patrón de comportamiento. Por consiguiente, el objetivo del estudio es la definición consensuada del contenido de un instrumento que las evalúa. Material y métodos. Mediante consulta prospectiva a expertos se consensuó el contenido del Cuestionario Clínic de Persistencia en la Actividad en la Fibromialgia (CCAP-FM). Resultados. Tras 3 rondas de consulta se alcanzó un acuerdo aceptable. Se excluyeron los ítems que obtuvieron una valoración media consensuada de relevancia inferior a 5/10 y que al menos el 75% de los expertos recomendó eliminar. El cuestionario preliminar de persistencia en la actividad quedó compuesto por 30 ítems. Conclusiones. La definición del contenido del CCAP-FM permitirá iniciar el proceso de evaluación de la relación entre la modificación de las cogniciones responsables del mantenimiento de la persistencia en la actividad y la mejoría clínica de las personas con fibromialgia(AU)

Background and objective. There is evidence of the relevance of fear, anxiety and avoidance of activity in the maintenance of pain in fibromyalgia. Recently, an opposite pattern based on the persistence in activity has been described. To date, the cognitions that impede modifying this pattern are unknown. Therefore, the aim of this study is to reach consensus on the content of an instrument that assesses those cognitions. Material and methods. A Delphi method was applied to reach consensus on the content of the Clinic Scale of Persistence in Activity in Fibromyalgia (CCAP-FM). Results. After three rounds of consultation, an acceptable consensus was reached. Those items that received an average rating of relevance lower than 5/10 and that at least the 75% of experts recommended removing were excluded. The preliminary questionnaire of persistence in activity was composed of 30 items. Conclusions. The consensus on the content of the CCAP-FM will allow advancing towards the assessment of the relation between the modification of the cognitions responsible for the maintenance of the persistence in activity and the clinical improvement in people with fibromyalgia(AU)

Tratamiento farmacológico de la fibromialgia: hacia la neuromodulación química / Pharmacologic treatment of fibromyalgia: towards chemical neuromodulation

La fibromialgia (FM) es una patología crónica, cuyo síntoma principal es el dolor, el cual no responde a los analgésicos tradicionales. Las características clínicas y los diferentes hallazgos neurofisiológicos en estos pacientes apuntan a un proceso de sensibilización central del sistema nociceptivo como eje fisiopatológico central en esta enfermedad. El conocimiento del funcionamiento del sistema nociceptivo y de su comportamiento en esta enfermedad nos ha aportado en los últimos años nuevas posibilidades en el abordaje terapéutico. Así, están siendo desarrollados fármacos con un mecanismo de acción diferencial, que pueden ejercer una modulación de la actividad del sistema nociceptivo capaz de producir analgesia donde otros fármacos han fracasado. Diferentes fármacos con capacidad de incrementar la actividad de las bioaminas implicadas en los procesos de inhibición nociceptiva y otros dirigidos a ejercer una disminución de la excitabilidad del sistema, a través de los canales iónicos, están siendo probados con beneficio en los pacientes con FM y pueden conformar un perfil farmacológico neuromodulador más racional en esta enfermedad. En este artículo se revisan las diferentes estrategias farmacológicas con evidencia científica y se apuntan algunas líneas de futuro que fortalezcan el cambio terapéutico que se está produciendo en el abordaje farmacológico de estos pacientes (AU)

Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients (AU)