Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Characteristics and treatment of pyoderma gangrenosum in inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum is a serious cutaneous complication seen in approximately 1 % of patients with inflammatory bowel disease (IBD). Oral corticosteroids are the mainstay treatment, although the evidence supporting their use is weak. AIMS: The purpose of this study was to investigate the characteristics of pyoderma gangrenosum associated with Crohn's disease or ulcerative colitis and which treatments are prescribed in Spanish clinical practice. METHODS: In this retrospective, observational study, the medical records from all patients with IBD and a diagnosis of pyoderma gangrenosum attended by the gastroenterology departments of 12 Spanish hospitals were reviewed. Data on patient demographics and characteristics, underlying IBD and treatment, and pyoderma gangrenosum characteristics, treatment, and outcome were collected and analyzed. RESULTS: The data from 67 patients were analyzed (41 [61.2 %] women, 41 [61.2 %] with Crohn's disease, 25 [37.3 %] with ulcerative colitis, and 1 [1.5 %] with indeterminate disease). The underlying disease was in remission in approximately one-third of patients at the time of presentation of pyoderma gangrenosum. Healing was achieved in all patients (in 3 without any systemic therapy). Oral corticosteroids were taken by 51 patients (76.1 %), almost always as first-line treatment, although definitive healing was attained in 19 (28.4 %). Biologic agents such as infliximab and adalimumab were taken by 31 patients (46.3 %) at some point (first-line in 6 patients [9.0 %]), with definitive healing in 29 patients (93.5 %). CONCLUSIONS: Oral corticosteroid therapy remains the most common treatment for pyoderma gangrenosum associated with inflammatory bowel disease. Biologic therapies such as infliximab and adalimumab should also be considered.

Effectiveness and Safety of the Switch from Remicade® to CT-P13 in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: To evaluate the clinical outcomes in patients with IBD after switching from Remicade® to CT-P13 in comparison with patients who maintain Remicade®. METHODS: Patients under Remicade® who were in clinical remission with standard dosage at study entry were included. The 'switch cohort' [SC] comprised patients who made the switch from Remicade® to CT-P13, and the 'non-switch' cohort [NC] patients remained under Remicade®. RESULTS: A total of 476 patients were included: 199 [42%] in the SC and 277 [58%] in the NC. The median follow-up was 18 months in the SC and 23 months in the NC [p < 0.01]. Twenty-four out of 277 patients relapsed in the NC; the incidence of relapse was 5% per patient-year. The cumulative incidence of relapse was 2% at 6 months and 10% at 24 months in this group. Thirty-eight out of 199 patients relapsed in the SC; the incidence rate of relapse was 14% per patient-year. The cumulative incidence of relapse was 5% at 6 months and 28% at 24 months. In the multivariate analysis, the switch to CT-P13 was associated with a higher risk of relapse (HR = 3.5, 95% confidence interval [CI] = 2-6). Thirteen percent of patients had adverse events in the NC, compared with 6% in the SC [p < 0.05]. CONCLUSIONS: Switching from Remicade® to CT-P13 might be associated with a higher risk of clinical relapse, although this fact was not supported in our study by an increase in objective markers of inflammation. The nocebo effect might have influenced this result. Switching from Remicade® to CT-P13 was safe.

Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.

BACKGROUND: Onset during old age has been reported in upto 10% of total cases of inflammatory bowel disease (IBD). AIM: To evaluate phenotypic characteristics and the use of therapeutic resources in patients with elderly onset IBD. METHODS: Case-control study including all those patients diagnosed with IBD over the age of 60 years since 2000 who were followed-up for >12 months, identified from the IBD databases. Elderly onset cases were compared with IBD patients aged 18 to 40 years at diagnosis, matched by year of diagnosis, gender and type of IBD (adult-onset). RESULTS: One thousand three hundred and seventy-four elderly onset and 1374 adult-onset cases were included (62% ulcerative colitis (UC), 38% Crohn's disease (CD)). Among UC patients, elderly onset cases had a lower proportion of extensive disease (33% vs 39%; P < 0.0001). In CD, elderly onset cases showed an increased rate of stenosing pattern (24% vs 13%; P < 0.0001) and exclusive colonic location (28% vs 16%; P < 0.0001), whereas penetrating pattern (12% vs 19%; P < 0.0001) was significantly less frequent. Regarding the use of therapeutic resources, there was a significantly lower use of corticosteroids (P < 0.0001), immunosuppressants (P < 0.0001) and anti-TNFs agents (P < 0.0001) in elderly onset cases. Regarding surgery, we found a significantly higher surgery rate among elderly onset UC cases (8.3% vs 5.1%; P < 0.009). Finally, elderly onset cases were characterised by a higher rate of hospitalisations (66% vs 49%; P < 0.0001) and neoplasms (14% vs 0.5%; P < 0.0001). CONCLUSIONS: Elderly onset IBD shows specific characteristics and they are managed differently, with a lower use of immunosuppressants and a higher rate of surgery in UC.

[Primary intraosseous hemangioma of the orbit: report of two cases]. / Hemangioma intraóseo primario de la órbita: a propósito de dos casos.

Primary intraosseous hemangioma, though rarely affect the bones of the orbit, should be considered in the differential diagnosis when a patient presents an enlarging mass fixed to the bone in the orbit or signs of progressive painless proptosis. Assessing the exact site and extent of the hemangioma by means of a CT scan and MRI and establishing the vascular origin of the lesion, is critical in the therapeutical planning, since an inadequate management may result in a severe hemorrhage. Progressive proptosis and contour deformity require surgical treatment. Two cases of patients with primary intraosseus hemangioma of the supra-lateral orbital rim are reported. A bony healthy margin excision was performed, followed by immediate reconstruction of the orbit with calvarial bone grafts fixed with resorbable plates. After three-year follow-up there have not been evidence of local recurrence, and the functional and aesthetic results obtained have been very satisfactory.

[Frontal sinus obliteration using tibial bone graft and platelet-rich plasma for the treatment of chronic osteomyelitis]. / Obliteración del seno frontal mediante injerto de tibia y plasma reco en plaquetas para el tratamiento de la osteomielitis crónica.

OBJECTIVES: The more successfully surgical treatment for the treatment of chronic frontal sinusitis complicated with chronic osteomielitis, is the cleaning and curettage of the sinus with obliteration of the sinus cavity and nasofrontal duct. Several autologous and alloplastics materials are used for this obliteration. MATERIAL AND METHODS: We report the case of a patient previously operated on because of frontal sinus plasmocytoma who developed frontal sinusitis with chronic osteomielitis and cutaneous suppuration. He received surgical treatment with frontal sinus curettage and obliteration with tibial bone graft and platelet-rich plasma (PRP). Symptoms disappeared and there were no complications or recurrence. CONCLUSIONS: Obliteration of the frontal sinus with tibial bone graft and PRP after sinus cleaning and curettage can be a good alternative in the treatment of chronic frontal sinus osteomielitis.

Hepatocarcinoma: diagnóstico y resección con radiofrecuencia quirúrgica / HEPATOCARCINOMA: DIAGNOSIS AND RESECTION WITH SURGICAL RADIO FREQUENCY

Objetivo: Presentar metodología diagnostica y resección atípica, con fines curativos de hepatocarcinoma. Caso clínico: Femenina de 82 años, con múltiples antecedentes entre el que se destaca, hepatitis a virus C de 15 años de evolución, que presenta por estudios complementarios alta sospecha de hepatocarcinoma, se realiza laparotomía exploradora con resección atípica de tumor en segmento 5 y 6 con radiofrecuencia quirúrgica y colecistectomía con colangiografía intraoperatoria. Cursa post operatorio sin complicaciones con alta sanatorial al 8vo dia. Conclusion: Hay que sospechar esta patología en pacientes con antecedentes de hepatopatía viral, plantear screening adecuado para un diagnóstico temprano y la mejor resolución adaptada a cada paciente. Dentro de las opciones terapéuticas encontramos la radiofrecuencia quirúrgica como una buena herramienta, con índice bajo de complicaciones

Objective: To present diagnostic methodology and atypical resection, for curative purposes of hepatocarcinoma. Clinical case: An 82-year-old female, with multiple history factors, among them, hepatitis C virus of 15 years of evolution, which presents high suspicion of hepatocarcinoma due to complementary studies, exploratory laparotomy is performed with atypical resection of tumor in segments 5 and 6 with surgical radiofrequency and cholecystectomy with intraoperative cholangiography. Post-operative course without complications with sanatorial discharge on the 8th day. Conclusion: This pathology must be suspected in patients with history of viral liver disease. We suggest an adequate screening for an early diagnosis and the best resolution adapted to each patient. Among the therapeutic options we find surgical radiofrequency as a good tool, with a low rate of complications

Tuberculosis in Anti-Tumour Necrosis Factor-treated Inflammatory Bowel Disease Patients After the Implementation of Preventive Measures: Compliance With Recommendations and Safety of Retreatment.

BACKGROUND AND AIMS: Despite having adopted preventive measures, tuberculosis (TB) may still occur in patients with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor (anti-TNF). Data on the causes and characteristics of TB cases in this scenario are lacking. Our aim was to describe the characteristics of TB in anti-TNF-treated IBD patients after the publication of the Spanish TB prevention guidelines in IBD patients and to evaluate the safety of restarting anti-TNF after a TB diagnosis. METHODS: In this multicentre, retrospective, descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary. RESULTS: We collected 50 TB cases in anti-TNF-treated IBD patients, 60% male, median age 37.3 years (interquartile range [IQR] 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated and 26% extrapulmonary. In 30 patients (60%), TB cases developed despite compliance with recommended preventive measures; *not performing 2-step TST (tuberculin skin test) was the main failure in compliance with recommendations. In 17 patients (34%) anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation. CONCLUSIONS: Tuberculosis could still occur in anti-TNF-treated IBD patients despite compliance with recommended preventive measures. A significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.

[Antisynthetase syndrome without myositic disease: a case report]. / Síndrome antisintetasa sin afectación miosítica: a propósito de un caso.

Antisynthetase syndrome is a rare disorder, included among the idiopathic inflammatory myopathies, characterized by the presence of antisynthetase antibodies. We present a case of a patient with a suggestive clinical stage of interstitial lung disease, skin and articular disease, but without muscle involvement, with the presence of anti Jol antibodies.

Noradrenergic and opioidergic influences on the antinociceptive effect of clomipramine in the formalin test in rats.

Although tricyclic antidepressants are especially useful in the treatment of chronic pain conditions, most of the work about its mechanism of action has been made on acute pain tests. The present study was aimed at studying the role played by noradrenergic and opioidergic influences on the antinociceptive activity of subchronically administered clomipramine in the formalin test (a tonic pain model) in rats. Clomipramine produced antinociception after 7 days, administration (2.5 mg/kg/day), an effect equivalent to that obtained by acute morphine (5 mg/kg). The antinociceptive effect of clomipramine was inhibited by the following: nonspecific blocking of alpha 1- and alpha 2-adrenoceptors by phentolamine, specific blocking of alpha 1-adrenoceptors by prazosin; stimulation of alpha 2 receptors by clonidine; and blocking of the opioid receptors by naloxone. Blocking the alpha 2-receptors with yohimbine did not antagonize the effect of clomipramine. These results suggest that clomipramine produces antinociception in this test, partly via the participation of the endogenous opioid system and partly by further activating or potentiating previously activated noradrenergic pathways which are involved in the control of pain information.

Antagonism of the stimulant and depressant effects of ethanol in rats by naloxone.

The action of naloxone (0.5 and 2 mg/kg IP) on the behavioural effects of a low (2 g/kg PO) and a high dose (4 g/kg PO) of ethanol was studied in rats. Ethanol at the low dose increased spontaneous motility, enhancing open-field external ambulations and reducing shuttle-box latency. All these effects were antagonized by naloxone. Ethanol at the high dose produced by hypomotility, decreasing open-field external ambulations and impairing shuttle-box performance. In this case, naloxone also reduced the ethanol effect, but its action was less consistent. Therefore, although mechanisms other than a specific opioid receptor blockade by naloxone must be considered, an involvement of opioid peptides in the effects of ethanol cannot be discounted.

Modulation of neuropathic pain in rats by intrathecally injected serotonergic agonists.

The involvement of spinal cord serotonergic influences in the development of autotomy, a proposed behavioural model of denervation pain, was studied in rats subjected to sciatic and saphenous nerve transection 5 min after intrathecal injection of 100 or 200 mu g of several serotonergic receptor subtype agonists. Injection of 8-OH-DPAT, m-CPP, 2-m-5-HT and a low dose of 5-HT, significantly shifted one or more of the parameters describing autotomy to less intense behaviour. In contrast, the injection of CGS-12066B and DOI intensified autotomy. These results suggest both a modulatory role for spinal cord serotonin in the events occurring shortly after neurectomy and new therapeutic approaches for the prevention of certain pain syndromes, such as phantom limb pain.

Anti-inflammatory drugs suppress injury-induced NADPH-d activity in CA1 pyramidal neurones.

Inducibility of NADPH-diaphorase (NADPH-d) or nitric oxide synthase (NOS) has been demonstrated in pyramidal neurones of the hippocampus, but the mechanisms of this induction are not known. The present study aimed to assess the role of anti-inflammatory drugs in injury-induced production of NADPH-d/NOS in CA1 pyramidal neurones. We found that either a steroid, dexamethasone or a non-steroid, indomethacin, prevents induction of these enzymes. We also found that NO is not necessary for the induction. None of the three drugs used had detectable effect on the neurones which contain constitutive NADPH-d/NOS.

Chronic amitriptyline decreases autotomy following dorsal rhizotomy in rats.

In the rat, unilateral dorsal cervicothoracic rhizotomy (C5-T1), a proposed model of chronic pain, resulted in autotomy of the ipsilateral limb. The self-mutilation lesions were evaluated daily by means of an autotomy score from the 1st to the 80th postoperatory day. The onset of lesions was variable and attained the maximum degree 8-9 weeks after the dorsal roots section. Chronic administration of amitriptyline (5 and 10 mg/kg/day, i.p., over 30 days), started on the 10th day after rhizotomy, decreased autotomy behavior, an effect which persisted 20 days after treatment withdrawal, and lengthened almost two-fold the lag time between rhizotomy and appearance of lesions. A more pronounced effect was observed with the lowest dose of amitriptyline suggesting the existence of a therapeutic window. Possible mechanisms for the antinociceptive effect of amitriptyline in this model are discussed.

Light-induced arousal affects simultaneously EEG and heart rate variability in the rat.

In awaken rats, ECG and EEG were simultaneously analysed in order to quantify the cortical EEG and beat-to-beat heart rate variability (HRV) in response to light onset. The HRV bands LF (40-200 mHz), MF (200-600 mHz) and HF (600-2500 mHz) and the EEG bands delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz) and beta (13-32 Hz) were assessed. Light onset induced a significant arousal reaction in the EEG, manifested by a global decrease in total spectral power and a shift towards theta and beta bands, while total HRV spectral power increased, with a shift to the sympathetic-related MF band. This simultaneous changes in HRV and EEG induced by light onset could be triggered by the same common factor that controls both oscillatory responses.

Nitric oxide mediates neuropathic pain behavior in peripherally denervated rats.

The involvement of spinal cord nitric oxide (NO) in the development of autotomy, a proposed behavioral model of denervation pain, was studied in sciatic and saphenous nerves transected rats injected intrathecally, 10-15 min prior to neurectomies, with NG-nitro-L-arginine methyl ester (L-NAME, 20-500 nmol), NG-nitro-D-arginine methyl ester (D-NAME, 500 nmol), L- or D-arginine (5 mumol), and 8-bromoguanosine 3':5'-cyclic monophosphate sodium salt (8-Br-cGMP, 100 and 200 nmol). Self-inflicted lesions were scored daily for 8 weeks. The main effects on autotomy were: (1) a significant suppression in rats injected with L-NAME (500 nmol), but not with D-NAME; (2) a significant potentiation after L-arginine, but not D-arginine; and (3) a significant potentiation with 8-Br-cGMP, which was blocked by co-administration of L-NAME. These findings indicate that autotomy in rats can be modulated by blocking or enhancing nitroxidergic transmission at lumbosacral level, and suggest new therapeutic approaches for the prevention of certain pain syndromes, such as phantom limb pain.

Autotomy in rats following peripheral nerve transection is attenuated by preceding formalin injections into the same limb.

The influence of an evolving painful inflammatory lesion on the development of autotomy, a behavioural model of denervation pain, was studied in rats suffering sciatic and saphenous nerves transection 30 or 60 min, and 1, 3, 7 or 14 days after being injected with formalin (50 microl, 5%, s.c). Hindpaws pressure and heat nociceptive thresholds and volume of the injected paw were assessed, in non-operated rats, at the above time-points. The main effects on autotomy were: (1) a significant attenuation when formalin injection preceded the neurectomies by 1 day or more, a period characterized by hypalgesia of the injected paw to both mechanical (during the first week) and thermal (spanning up to the third day after formalin) stimuli and inflammation (lasting for 14 days); (2) a significantly earlier onset when formalin was injected 30 min before neurectomies. Possible mechanisms linking nociceptive responsiveness and inflammation to the development of autotomy are discussed.

Pharmacological study of the muscle paralyzing activity of the juice of the banana trunk.

Extracts of the juice of the banana trunk were assayed in the isolated phrenic nerve-diaphragm muscle preparation of the rat. The chemical composition of those producing muscular paralysis was then studied. As active extracts mainly consisted of monopotassium oxalate, the effect of this compound on the muscle preparation was investigated and compared with that of the active extracts. The pattern of muscular paralysis induced by monopotassium oxalate was the same as that seen with the juice extracts. Likewise inhibition of contractions of the tibialis muscle was observed in vivo after intra-arterial administration of both the crude concentration of the juice and monopotassium oxalate. These findings suggest that monopotassium oxalate could be responsible for the muscular paralysis caused by the juice of banana trunk.

Temporary sedation with midazolam for control of severe incident pain.

Incident pain frequently complicates cancer-related pain. Its treatment is sometimes very difficult due to poor responsiveness to opioids. Two cases are presented in which a temporary or intermittent sedation with midazolam was successfully used to control excruciating incident pain.