Rapidity of clinical response to adalimumab and improvement of quality of life in luminal Crohn's disease: RAPIDA study

ObjectiveNo studies evaluating the rapidity of response to biological therapies are available for Crohn's disease (CD). The aim of this study was to evaluate rapidity of onset of clinical response and impact on quality of life (QoL) of adalimumab therapy in adult anti-TNF-naïve patients with moderately-to-severely active CD.Patients and methodsRAPIDA was an open-label, single-arm, prospective, multicenter clinical trial. Adult patients with moderately-to-severely active luminal CD, anti-TNF-naïve, and unresponsive to conventional therapy were treated with adalimumab. Clinical disease activity, QoL and inflammatory biomarkers were measured at day 4, and weeks 1, 2, 4, and 12 after treatment initiation.ResultsEighty-six patients were included in the intention-to-treat (ITT) analyses. Clinical disease activity was reduced from a median of 9.0 points to 6.0 points at day 4. Clinical response (≥ 3-point reduction in the Harvey-Bradshaw Index, HBI) was achieved by 61.6% (d4) and 75.6% (w1) of patients in the ITT population (median 2.5 days) and with non-responder imputation (NRI), by 55.8% and 53.4%, respectively. The proportion of patients in clinical remission (HBI < 5) at weeks 2 and 4 in the ITT population was 54.7% and 62.8%, respectively (median 7.0 days), and 38.4% and 45.3% in the NRI population. All QoL scores significantly improved and inflammatory biomarkers significantly decreased from day 4 onwards (p < 0.0001).ConclusionRapid clinical response and remission, improvement in QoL and fatigue, and a reduction of inflammatory biomarkers were achieved with adalimumab as early as day 4 in adult anti-TNF-naïve patients with moderately-to-severely active CD.     

Pyloric stenosis associated Crohn's disease responding to adalimumab therapy

Gastroduodenal Crohn’s disease (CD) is rare and the response to standard medical therapy is often poor. Anti-tumor necrosis factor therapy has revolutionised the treatment of CD. We present a patient with pyloric stenosis associated with CD which improved with Adalimumab therapy. We recommend considering anti-tumor necrosis factor therapy in symptomatic gastroduodenal CD.     

Stevens-Johnson syndrome complicating adalimumab therapy in Crohn＇s disease

The anti-tumor necrosis factor （TNF）α medications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. With the increasing number of patients receiving anti-TNFα agents, however, less common adverse reactions will occur. Cutaneous eruptions complicating treatment with an anti-TNFα agent are not uncommon, occurring in around 20% of patients. Adalimumab, a fully humanized antibody against TNFα, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody, infliximab. We, however, report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn＇ s disease （CD）. In this case report, a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis, peripheral rash and desquamation, fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy. Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded. The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome. Desquamating skin reactions have now been described in three of the TNFα antagonists （infliximab, etanercept and adalimumab）. These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents, especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.     

Evaluation of bone mineral density, bone turnover markers, the OPG/RANKL system and sTNF-RI in Crohn's disease

Introduction

Patients with Crohn's disease are at risk of developing osteoporosis, a disease in which the inflammatory process seems to be gaining importance. We performed a cross-sectional study to evaluate bone metabolism, osteoclastogenic factors [receptor activator of NF-kB ligand (RANK-L) and osteoprotegerin (OPG)] and soluble tumor necrosis factor-α receptor I (sTNF-RI) in patients with Crohn's disease and to correlate the findings with the degree of disease activity.

Method

Sixty-four patients with Crohn's disease from the province of Granada (Spain) were included in this study. Bone mineral density (BMD) was studied through dual X-ray absorptiometry. Immunoassay was used to assess markers of bone formation [bone alkaline phosphatase (bALP) and osteocalcin (OC)] and bone resorption [tartrate resistant acid phosphatase (TRAP) and carboxyterminal telopeptide of type I procollagen (CTX)] as well as RANKL, OPG and sTNF-RI.

Results

The percentage of patients with a Z-score ≤-2 in the femoral neck or lumbar spine was 20.3% and was higher in patients with active disease, although this difference was not significant. This percentage was only higher in patients receiving corticosteroids (11.1 vs. 9.1%; P = .001). Patients with the highest disease activity had higher TRAP levels. No significant differences were found in BMD but significant differences were found in TRAP levels with respect to C-reactive protein concentrations. No association was found between levels of OPG, RANKL and sTNF-RI and BMD or disease activity.

Conclusions

A substantial proportion of our patients had low BMD. Levels of bone turnover markers suggested higher bone resorption, possibly in relation to disease activity, without a compensatory increase in bone formation.     

Effectiveness of infliximab after adalimumab failure in Crohn's disease

AIM: To evaluate the effectiveness of infliximab as a second-line therapy in Crohn’s disease patients after adalimumab failure.METHODS: A historical cohort study in a community-based gastroenterology practice evaluated Crohn’s disease patients treated with infliximab (induction plus maintenance) after adalimumab failure. Patients were identified using a large Spanish database (ENEIDA).RESULTS: We included 15 Crohn’s disease patients who received infliximab after adalimumab failure. Five patients discontinued adalimumab due to loss of response, 3 due to adverse events and 7 due to partial response. After infliximab therapy was started, all patients who had interrupted adalimumab due to loss of efficacy regained response. All patients who discontinued adalimumab due to adverse events responded to infliximab and maintained this response; one of these patients had an uneventful course on infliximab, but 2 developed adverse events. None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab.CONCLUSION: Switching from adalimumab to infliximab may be useful in patients who develop adverse effects or loss of response, however, the benefit of infliximab in primary nonresponders was not established.     

Utility of infliximab therapy in severe enterorrhagia associated with Crohn's disease. Report of three cases

Severe lower gastrointestinal (GI) bleeding is an infrequent complication in Crohn's disease.We report the cases of three patients with Crohn's disease, localized in distinct areas, who developed severe enterorrhagia requiring multiple transfusions. All three patients responded favorably to infliximab administration, which resolved the life-threatening hemorrhages and avoided emergency surgical resection, which had seemed inevitable.Based on this clinical experience and a review of the literature comparing infliximab with other pharmacological options, we believe that this drug should be the treatment of choice in patients with Crohn's disease who develop severe lower gastrointestinal bleeding. This strategy can, in some cases, avoid surgery if the bleeding stops due to rapid healing of the deep mucosal lesions causing the hemorrhagic episode.     

Loss of response and need for adalimumab dose intensification in Crohn's disease: a systematic review

The objective of this study was to review loss of response and need for adalimumab dose intensification in adult and pediatric patients with Crohn's disease. Studies were identified through the electronic databases of MEDLINE and the annual meetings of Digestive Disease Week, of the United European Gastroenterology Week, and of the American College of Gastroenterology and the European Crohn's and Colitis Organization meetings. Studies evaluating loss of efficacy and/or need for dose intensification were included. Thirty-nine studies were included. The mean percentage of loss of response to adalimumab among primary responders was 18.2% and the annual risk was 20.3% per patient-year. The mean percentage of patients who required dose intensification among primary responders to adalimumab was 37% and the annual risk was 24.8% per patient-year. When considering initial responders and patients with primary non-response, the mean percentage of patients who needed an adalimumab dose escalation was 21.4% and the annual risk was 24.4% per patient-year. Pooled analysis showed that dose escalation permitted response to be regained in 71.4% and remission in 39.9% of patients. Predictors for loss of response or dose escalation were male gender, current/former smoker status, family history of inflammatory bowel disease, isolated colonic disease, extra-intestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline Crohn's Disease Activity Index, concomitant corticosteroid use, no deep remission at week 12, low serum trough concentrations of adalimumab, previous infliximab non-response and being previously treated with an anti-tumor necrosis factor agent. Overall, around one fifth of adult patients require dose intensification and experience a loss of response after initiation of adalimumab therapy. Adalimumab dose escalation permits response to be regained in the majority of patients.     

Nefritis túbulo-intersticial aguda en paciente con espondiloartritis axial HLA-B27 en tratamiento con adalimumab

Antagonists of tumor necrosis factor-alpha (ATNF) are used for the treatment of multiple diseases such as psoriatic arthritis, Crohn's disease, ankylosing spondylitis and juvenile idiopathic arthritis, usually, when they are refractory to first-line treatment¹. The use of ATNF has been associated with the induction of autoimmune diseases such as systemic lupus erythematosus-like disease, vasculitis, sarcoidosis-like diseases and, recently, acute granulomatous tubulointerstitial nephritis. We report a case of acute nongranulomatous tubulointerstitial nephritis in an HLA-B27-positive patient with axial spondyloarthritis and Crohn's disease being treated with adalimumab.     

Successful use of adalimumab for treating fistulizing Crohn＇s disease with pyoderma gangrenosum： Two birds with one stone

Crohn＇s disease （CD） is a chronic relapsing and remitting autoinflammatory disorder of the gastrointestinal tract that has many intestinal and extraintestinal complications. The purpose of treatment is long-term remission, reduction of complications, and improvement of patients＇ quality of life. In many cases, this can be quite challenging and it is necessary to have a well thought out management strategy. We present the case of a 38-year-old woman with fistulizing CD that manifested as diffuse abdominal pain and bloody diarrhea accompanied by arthralgia. In addition, there were ulcerative lesions surrounded by cutaneous inflammation and erythema on her extremities, indicative of pyoderma gangrenosum. The patient was treated with high doses of parenteral methylprednisolone without any improvement and was started on adalimumab. A positive response to adalimumab therapy was observed： after 2 mo of therapy, the ulcerative skin lesion healed completely and the enterogastric fistula was closed affcer 5 mo adalimumab treatment. Adalimumab might be a suitable initial as well as maintenance therapy in patients with complicated CD.     

Successful use of adalimumab for treating fistulizing Crohn's disease with pyoderma gangrenosum: Two birds with one stone

Crohn's disease (CD) is a chronic relapsing and remitting autoinflammatory disorder of the gastrointestinal tract that has many intestinal and extraintestinal complications. The purpose of treatment is long-term remission, reduction of complications, and improvement of patients' quality of life. In many cases, this can be quite challenging and it is necessary to have a well thought out management strategy. We present the case of a 38-year-old woman with fistulizing CD that manifested as diffuse abdominal pain and bloody diarrhea accompanied by arthralgia. In addition, there were ulcerative lesions surrounded by cutaneous inflammation and erythema on her extremities, indicative of pyoderma gangrenosum. The patient was treated with high doses of parenteral methylprednisolone without any improvement and was started on adalimumab. A positive response to adalimumab therapy was observed: after 2 mo of therapy, the ulcerative skin lesion healed completely and the enterogastric fistula was closed after 5 mo adalimumab treatment. Adalimumab might be a suitable initial as well as maintenance therapy in patients with complicated CD.     

Effect of adalimumab on work productivity and indirect costs in moderate to severe Crohn's disease: a meta-analysis

OBJECTIVE:

To assess the effect of adalimumab on work productivity and indirect costs in patients with Crohn’s disease (CD) using a meta-analysis of clinical trials.

METHODS:

Study-level results were pooled from all clinical trials of adalimumab for moderate to severe CD in which work productivity outcomes were evaluated. Work Productivity and Activity Impairment Questionnaire outcomes (absenteeism, presenteeism and total work productivity impairment [TWPI]) were extracted from adalimumab trials. Meta-analyses were used to estimate pooled averages and 95% CIs of one-year accumulated reductions in work productivity impairment with adalimumab. Pooled averages were multiplied by the 2008 United States national average annual salary ($44,101) to estimate per-patient indirect cost savings during the year following adalimumab initiation.

RESULTS:

The four included trials (ACCESS, CARE, CHOICE and EXTEND) represented a total of 1202 employed adalimumab-treated patients at baseline. Each study followed patients for a minimum of 20 weeks. Pooled estimates (95% CIs) of one-year accumulated work productivity improvements were as follows: −9% (−10% to −7%) for absenteeism; −22% (−26% to −18%) for presenteeism; and −25% (−30% to −20%) for TWPI. Reductions in absenteeism and TWPI translated into per-patient indirect cost savings (95% CI) of $3,856 ($3,183 to $4,529) and $10,964 ($8,833 to $13,096), respectively.

CONCLUSION:

Adalimumab provided clinically meaningful improvements in work productivity among patients with moderate to severe CD, which may translate into substantial indirect cost savings from an employer’s perspective.     

Evaluation of adalimumab therapy in multidisciplinary strategy for perianal Crohn's disease patients with infliximab failure

BackgroundInfliximab has improved the management of perianal Crohn's disease, but intolerance and loss of efficacy can occur. The use of a second antibody can be less effective.ObjectiveOur aim was to determine if the use of adalimumab, based on a multidisciplinary strategy, can enhance outcomes for patients with fistulizing disease and infliximab failure.Material and methodsSixteen patients with perianal disease and infliximab failure were treated with adalimumab. Complex fistulas were assessed using magnetic resonance imaging (MRI). Patients with severe conditions as determined by radiology were examined under anesthesia, and seton placement was performed when appropriate. Setons were removed when external discharge had ceased and there was no radiological evidence of fistula activity.ResultsNine patients (56%) underwent MRI. Setons were inserted in seven (43%). The baseline perianal disease activity index (PDAI) decreased after 4 weeks and remained at similar levels 24 and 48 weeks after treatment. The complete response rate was 50% after four weeks and 87.5% of these patients remained in remission after 48 weeks of treatment.ConclusionsFor patients with Crohn's perianal fistulas and infliximab failure, adalimumab as a multidisciplinary approach to management, using MRI to guide surgical drainage when necessary, results in a favourable response and low recurrence rate.     

Dose de-escalation to adalimumab 40 mg every three weeks in patients with inflammatory bowel disease—A multicenter,retrospective, observational study

Background

Data about the outcomes after adalimumab dose de-escalation in inflammatory bowel disease (IBD) are scarce.

Efficacy of treatment intensification with adalimumab,etanercept and infliximab in rheumatoid arthritis: A systematic review of cohort studies with focus on dose

Objectives

To summarize the empirical evidence regarding the effect of treatment intensification on clinical outcomes in patients with rheumatoid arthritis treated with one of the TNF-α-inhibitors, adalimumab, etanercept or infliximab.

Methods

A systematic search of the bibliographic databases Embase, Medline, Web of Science and Cochrane Central identifying articles concerning treatment with adalimumab, etanercept or infliximab in adult patients with rheumatoid arthritis exposed to dose increase or shortening of dosing intervals was performed. Longitudinal cohorts, both clinical trials and observational studies, were included. ACR and EULAR response criteria and DAS28 were the preferred outcome measures.

Results

Out of 1135 records, eleven studies were included in the final evidence synthesis. One article concerned all the three TNF-α-inhibitors, eight used infliximab, one adalimumab and one etanercept. According to GRADE, evidence was weakened in particular by the lack of control groups, and for treatment intensification with adalimumab and etanercept, no conclusions could be drawn. With infliximab, two trials of high quality revealed contradictory results, but six studies described an improved clinical outcome following intensified treatment strategies. Some studies (2/2) also indicated that for infliximab, frequency increase was superior to dose increase.

Conclusions

Available studies indicate that intensifying treatment with infliximab in rheumatoid arthritis patients, preferably by increasing the frequency of drug administration, may lead to improved clinical outcome in some patients, but the evidence is weak. There is an urgent need for prospectively designed cohort studies to be able to draw a final conclusion.     

Low serum trough levels are associated with post-surgical recurrence in Crohn's disease patients undergoing prophylaxis with adalimumab

BackgroundWhether therapeutic drug monitoring of biologic therapy can predict the efficacy of adalimumab to prevent postoperative Crohn's disease recurrence is unknown.AimTo investigate whether adalimumab trough levels and anti-adalimumab antibodies correlate with endoscopic and clinical outcomes in a series of patients treated with prophylactic adalimumab monotherapy after resective surgery.MethodsPost hoc analysis of a randomized, mesalamine-controlled trial. Adalimumab trough levels and antibodies were analysed every 8 weeks for 2 years using an homogeneous mobility shift assay.ResultsAt two years, 1/6 patient had clinical recurrence and 1/6 patient had endoscopic and clinical recurrence. At baseline (9.5 vs. 14.4 mcg/mL) and during follow-up [7.5 (4.4–9.8) vs. 13.9 (8.9–23.6) mcg/mL, p < 0.01], median adalimumab trough levels in patients with clinical or endoscopic recurrence were lower than in those who maintained remission. Persistent antibodies-against-adalimumab were detected in the patient with both endoscopic and clinical recurrence.ConclusionMeasurement of adalimumab trough levels and anti-adalimumab antibodies after surgery could be useful to further reduce postoperative recurrence.     

Clinical and endoscopic outcomes of patients with colonic Crohn's disease treated with 5-aminosalicylates as monotherapy

BackgroundIn spite of the lack of evidence regarding the clinical benefits of oral 5-aminosalicylic acid (5-ASA) compounds in Crohn's disease (CD), these drugs are frequently used in daily clinical practice, particularly for colonic CD. Our aim is to assess the use and clinical outcomes of 5-ASA of those patients with colonic CD treated with 5-ASA as monotherapy.MethodsPatients diagnosed with isolated colonic CD and treated with 5-ASA but never exposed to immunosuppressants or biologicals were identified from the local databases of five referral centres. A retrospective review of clinical and endoscopic outcomes was performed.ResultsOut of 545 patients with isolated colonic CD, 106 (19%) were treated with oral 5-ASA in monotherapy as maintenance therapy. The median follow-up was 144 months (interquartile range [IQR], 48–234). Almost all of the patients (92%) presented an inflammatory pattern and 11% developed perianal disease. Half of the patients had already received 5-ASA at diagnosis, and the median duration of 5-ASA treatment was 107 months (IQR 22.5–187). Endoscopic remission, as defined by the absence of ulcers at the last complete colonoscopy, was observed in 65% of those patients undergoing at least one colonoscopy during follow-up. Male gender and extraintestinal manifestations were associated with a lower likelihood of achieving endoscopic remission. Nine patients required colectomy, but mostly soon after CD diagnosis.Conclusions5-ASA seems to be of benefit in the long-term in one fifth of patients with colonic CD as the only maintenance therapy and should be considered in fragile patients with Crohn's colitis.     

Systemic amyloidosis in inflammatory bowel disease

Systemic amyloidosis comprises a group of diseases that develop as a consequence of an abnormal accumulation of different proteins in several organs, altering their function. Secondary amyloidosis develops after the accumulation of serum amyloid A protein (an acute phase reactant), mainly in the course of chronic inflammatory conditions such as rheumatologic diseases, familial Mediterranean fever, or tuberculosis. Inflammatory bowel disease (IBD) may also cause secondary amyloidosis. However, little is known about the true prevalence, risk factors, and clinical outcomes of amyloidosis among IBD patients. A few studies suggest that amyloidosis is more prevalent in Crohn's disease than in ulcerative colitis, mainly occurring in patients with an extensive, long-lasting, and penetrating disease pattern. In this article we review the available data on secondary amyloidosis and IBD, focusing on prevalence, risk factors, clinical presentation and therapeutic measures.     

Efficacy and safety of adalimumab in Canadian patients with moderate to severe Crohn's disease: results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn's DiseaSe (ACCESS) trial

OBJECTIVE:

To evaluate open-label adalimumab therapy for clinical effectiveness, fistula healing, patient-reported outcomes and safety in Canadian patients with moderate to severe Crohn’s disease (CD) who were either naive to or previously exposed to antitumour necrosis factor (anti-TNF) therapy.

METHODS:

Patients with moderate to severe CD (CD activity index [CDAI] score of greater than 220, or Harvey-Bradshaw index [HBI] of 7 or greater) were eligible. Patients received open-label adalimumab as induction (160 mg and 80 mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly. Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada.

RESULTS:

Of the 304 patients enrolled, 160 were infliximab experienced, while 144 were anti-TNF naive. HBI remission (HBI score of 4 or lower) at week 24 was achieved by 53% of anti-TNF-naive and 36% of infliximab-experienced patients (P<0.01; P<0.001 for both groups for all visits versus baseline). Fistula healing rates at week 12 were 48% for anti-TNF-naive patients, and 26% for infliximab-experienced patients. At week 24, fistula healing rates were significantly greater for the anti-TNF-naive group (60% versus 28%; P<0.01). Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients. Serious infections occurred in 2% of patients.

CONCLUSIONS:

Adalimumab therapy induced and sustained steroid-free remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD. Clinically meaningful rates of fistula healing were also observed. Improvements in patient-reported outcomes were sustained throughout the 24-week study period.     

Relevance of dynamic studies with magnetic resonance enterography in Crohn's disease

IntroductionA proper quantification of the inflammatory activity in Crohn's disease (CD) lesions is needed to establish the appropriate management for each patient. The aim of this study is to evaluate the inflammatory activity of affected segments in small bowel lesions using dynamic studies of magnetic resonance enterography (MRE) in patients undergoing surgery, and their correlation with the level of inflammation and histological fibrosis of the surgical piece.MethodsA prospective, consecutive, observational, clinical study was conducted that included all the patients with small bowel CD that underwent surgery in this center between March 2011 and September 2013. Diagnosis was established according to Lennard–Jones criteria and the Montreal classification. All the patients underwent MRE within three months before surgery, using a routine protocol involving Liver Acquisition with Volume Acceleration-Extended Volume (LAVA-XV) sequence for the dynamic studies before intravenous administering of gadolinium and 30, 70, 120, and 420 s after administering this. The results allowed the designing of graphics with different uptake patterns. The Chiorean classification was used in the histological analysis, as well as a modified version published previously by this study group.ResultsA total of 28 patients with 47 lesions were analyzed. There was a significant correlation between both curve patterns, including the modified Chiorean classification (P < 0.0001) as well as the level of inflammation (P < 0.0001) and fibrosis (P < 0.002). Inflammatory patterns of dynamic studies are related to histological findings with 80.9% accuracy (sensitivity = 75.7%; specificity = 100%).ConclusionThere is a high correlation between dynamic enhancement studies and the level of inflammatory activity. MRE is a suitable tool to differentiate between inflammatory and fibrotic lesions, making it useful to decide the appropriate management of each patient.