To Anti-tumor Necrosis Factor Research Articles

Thalidomide Use and Outcomes in Pediatric Patients With Crohn Disease Refractory to Infliximab and Adalimumab

The aim of the study was to evaluate thalidomide as rescue therapy for pediatric patients with severe refractory Crohn disease (CD) who failed to respond to antitumor necrosis factor (TNF) biologic agents. A computerized database was used to identify children with CD who had failed conventional immunosuppression therapy and received thalidomide rescue therapy. Twelve patients, mean age at diagnosis 10 years, were identified. Eight children had disease localized to the ileum and colon and 4 to the gastroduodenal area and colon. Five cases were complicated by strictures and 7 by fistulae. Previous drug therapy included azathioprine/6-mercaptopurine (11/12), methotrexate (7/12), and anti-TNF biologics (12/12). Outcome measures were Harvey-Bradshaw Index, change in prednisone dose, hospitalizations, bowel resections, and incision and drainage procedures. Laboratory evaluations were calculated before and after 1 to 6 months of thalidomide. Mean Harvey-Bradshaw Index score improved from 11.8 to 3.9 (P = 0.0004), mean prednisone dose decreased from 13.9 to 2.3 mg/day (P = 0.001), mean number of hospitalizations decreased from 6.3 to 1.3 (P = 0.002), and erythrocyte sedimentation rate decreased from 35 to 14 mm/h (P = 0.02). The surgery rate pre-thalidomide was 0.031 and on thalidomide was 0.004. Of the 7 patients with fistulae, 5 had complete fistula closure, 1 had partial closure, and 1 showed no improvement. Adverse reactions that resulted in discontinuation of thalidomide are as follows: 42% peripheral neuropathy, 17% worsening of the CD, 8% dizziness, and 8% allergic reaction. All 5 patients who developed peripheral neuropathy had clinical resolution of the neurologic symptoms within 2 to 3 months after stopping thalidomide. Thalidomide is a potentially effective rescue therapy for severe refractory CD in children who fail to respond to anti-TNF medications.

Dermatomyositis in Patients with Rheumatoid Arthritis During Adalimumab Therapy

To the Editor: We read the recent letter by Brunasso, et al 1 with great interest. They reported that dermatomyositis (DM) developed after 4.5 years of adalimumab therapy in patients with rheumatoid arthritis (RA). We comment on development of myositis in patients with RA and whether it is actually related to anti-tumor necrosis factor (TNF) therapy. An association of polymyositis (PM)/DM with RA has long been well known2. RA can precede myositis, or it can develop after the diagnosis of PM/DM3. We previously reported 2 patients with RA who were not receiving anti-TNF therapy, but developed anti-Jo-1 antibody-positive … Address correspondence to Dr. Nagashima; E-mail: naga4ma{at}jichi.ac.jp

Tuberculous Peritonitis in a Patient with Rheumatoid Arthritis Treated with Infliximab

One of the severe adverse reactions to anti-tumor necrosis factor (TNF)-α therapy is the reactivation of tuberculosis. We present a case of tuberculous peritonitis in a 57-yearold woman with rheumatoid arthritis (RA) that appeared during treatment with infliximab. Confirming a diagnosis of tuberculous peritonitis is difficult and can be delayed because of the nonspecific symptoms, the rarity of the disease, and the low detection rate of mycobacteria in ascites fluid. This case illustrates that prompt anti-tuberculous therapy is needed for suspected cases of tuberculous peritonitis in RA patients treated with infliximab.

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organization: When to Start, When to Stop, Which Drug to Choose, and How to Predict Response?

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Response to Rituximab and Timeframe to Relapse in Rheumatoid Arthritis Patients

Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5 +/- 127.0 days for the RF+ patients versus 233.3 +/- 59.6 days for the RF- patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 +/- 1.076 in seropositive patients versus 0.94 +/- 1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF- counterparts, despite a significantly lower percentage of CD20+ cells. Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease

Inflammatory bowel disease (IBD), in particular Crohn's disease refractory to conventional therapy, fistulizing Crohn's disease and chronic active ulcerative colitis, generally respond well to anti-tumor necrosis factor (TNF) therapy. However, serious side effects do occur, necessitating careful monitoring of therapy. Potential side effects of anti-TNF therapy include opportunistic infections, which show a higher incidence when concomitant immunosuppression is used. Furthermore, antibody formation against anti-TNF is associated with decreased efficacy and an increased frequency of infusion reactions. The hypothesis of a slightly increased risk of lymphomas in IBD patients treated with anti TNF-therapy is debatable, since most studies lack the specific design to properly address this issue. Alarmingly, the occurrence of hepatosplenic T-cell lymphomas coincides with combined immunosuppressive therapy. Despite the potential serious side effects, anti-TNF therapy is an effective and relatively safe treatment option for refractory IBD. Future research is needed to answer important questions, such as the long-term risk of malignancies, safety during pregnancy, when to discontinue and when to switch anti-TNF therapy, as well as to determine the balance between therapeutic and toxic effects.

Is rituximab suitable for use as a first-line biologic therapy for RA?

Rituximab is approved for the treatment of patients with rheumatoid arthritis (RA) who are unresponsive to anti-tumor necrosis factor (TNF) therapy. McGonagle et al. presented a series of patients treated in everyday clinical practice with rituximab as the first biologic agent—that is, before anti-TNF therapy. The patients did well in terms of improvements in signs and symptoms of RA. There was one death that was probably a result of infection, but otherwise the rituximab therapy was well tolerated. Appropriately, the authors did not endorse rituximab as a first-line agent for RA patients in general, but concluded that rituximab was a reasonable option in situations where anti-TNF agents either could not be obtained, or where there was concern about their toxicity. We agree with the authors—there are circumstances where rituximab might be used in patients who have not received anti-TNF therapy, but there are insufficient data to support a change in the pre-eminent position of anti-TNF agents in the current standard of care.

The comparative effectiveness of methotrexate and anti-tumor necrosis factor therapy in psoriatic arthritis

Introduction: Methotrexate (MTX) is a cornerstone therapy in rheumatoid arthritis (RA), either as monotherapy or combined with another disease-modifying antirheumatic drug (DMARD) or a biologic agent [ 1 ]. MTX has also shown effectiveness in moderate to severe psoriasis with similar responses to those observed with cyclosporine [ 2 ]. Dermatologists often prescribe MTX intermittently to treat psoriasis because cutaneous infl ammation waxes and wanes and skin plaques do not result in chronic end-organ damage. In addition, many dermatologists are concerned about long-term MTX use and liver toxicity; therefore, patients are often monitored very closely, and the total cumulative dose often does not exceed 4 g. Regrettably, the effi cacy and safety of MTX for treatment of psoriatic arthritis (PsA) is unknown, even though this agent is widely prescribed for this condition. Two studies examined MTX in PsA. The fi rst small study used an unacceptably high dose of parenteral MTX [ 3 ], and the second trial was underpowered and underdosed [ 4 ]. This lack of data regarding MTX stands in contrast to anti-tumor necrosis factor (TNF) agents, where grade A evidence for the effi cacy of etanercept, infl iximab, and adalimumab with large effect sizes in PsA have been published [ 5 ]. Given the absence of high-quality clinical trial data in support of MTX, this observational study by Heiberg et al. was designed to compare the effi cacy of MTX and anti-TNF agents to treat PsA patients followed in a longitudinal registry.

A novel assay for screening patients for latent tuberculosis infection prior to anti-TNF therapy

Screening for latent tuberculosis (TB) infection (LTBI) prior to anti-tumor necrosis factor (TNF) therapy is complicated by the decreased sensitivity of the purified protein derivative tuberculin skin test in immunosuppressed patients, as well as the poor specificity of the tuberculin skin test in bacillus Calmette-Guérin (BCG)-vaccinated patients. Interferon-gamma-release assays that utilize specific TB antigens (e.g. ESAT-6/CFP-10) have greater specificity for LTBI, but their relative sensitivity is unknown in the setting of immune suppression. Dinser et al. evaluated a novel flow-cytometric interferon-gamma detection assay in 97 patients with inflammatory arthritis during LTBI screening for anti-TNF therapy. Overall, 39% of patients had purified protein derivative reactivity in vitro versus 14% cutaneously, and 16% exhibited reactivity in vitro to ESAT-6/CFP-10. The results suggest that flow cytometry using TB-specific antigens might eventually provide another tool for diagnosing LTBI in patients undergoing screening prior to anti-TNF or other immunosuppressive therapies. Further evaluation of the sensitivity and specificity of this novel whole-blood assay is warranted.

Immunosuppressant Medications and Mortality in Inflammatory Bowel Disease

This study examined whether treatment of Crohn's disease (CD) and ulcerative colitis (UC) with immunosuppressant medications was associated with an increased risk of death in the era prior to antitumor necrosis factor (TNF) therapies. This retrospective cohort study used data from the General Practice Research Database from 1987 to 1997. CD and UC patients were matched to controls on age, sex, and primary care practice. CD and UC patients were stratified according to whether they used immunosuppressant medications during follow-up. Cox proportional hazards models adjusted for comorbidities were used to define the relative hazard of death. Additional models examined the relative hazard of death with current use of corticosteroids or thiopurines. The cohort included 5,539 patients with CD, 8,910 patients with UC, and 41,624 controls. Patients with CD had an increased mortality (not immunosuppressant-treated CD hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.07-1.51; immunosuppressant-treated CD HR 2.44, 95% CI 1.84-3.25). Increased mortality was only observed among UC patients treated with immunosuppressant medications (HR 1.67, 95% CI 1.34-2.09). In both CD and UC, current corticosteroid therapy was associated with increased mortality (CD HR 2.48, 95% CI 1.85-3.31; UC HR 2.81, 95% CI 2.26-3.50). Current use of thiopurines was not associated with increased mortality (CD HR 0.83, 95% CI 0.37-1.86; UC HR 0.70, 95% CI 0.29-1.70). Patients treated with corticosteroids, but not thiopurines, are at increased risk of death, although this study could not clarify whether this was as a result of the medication or the underlying disease severity.

Drug-Induced Lupus due to Anti-Tumor Necrosis Factor α Agents

To evaluate the reported cases of drug-induced lupus erythematosus (DILE) due to anti-tumor necrosis factor (TNF) alpha therapy and to compare "classic" DILE with DILE secondary to anti-TNFalpha therapy. We also add 3 case reports related to 3 different anti-TNFalpha drugs to the literature. We searched the Medline database for cases published in English and evaluated 53 cases in 27 papers purported to be TNFalpha-induced DILE. We compared the clinical and laboratory features of cases that fulfilled our criteria for TNFalpha DILE to those of DILE due to non-TNFalpha drugs as found in standard texts. We also report the clinical and laboratory findings of our 3 patients with drug-induced lupus related to anti-TNFalpha drugs, 1 each in patients treated with adalimumab, etanercept, and infliximab. Of the 53 purported cases of DILE due to anti-TNFalpha therapy, we excluded 17 with cutaneous manifestations alone and 3 with overlap syndromes and mixed connective tissue disease. In the 33 cases that met our criteria for systemic DILE, 21 cases were due to infliximab, 10 cases were due to etanercept, and only 2 cases were related to adalimumab. TNFalpha-blocker-induced DILE cases had a higher prevalence of antibodies to double-stranded DNA, rash, and hypocomplementemia than DILE due to other drugs. Fever is common in both types of DILE. Renal disease, which is rare in classic DILE, has been reported in cases of TNFalpha DILE. TNFalpha DILE has significant clinical and laboratory manifestations which distinguish it from DILE due to drugs other than anti-TNF agents and may be difficult to diagnose in patients treated for autoimmune diseases. It is appropriate to consider whether all patients who are begun on anti-TNF therapy should have pretreatment serologic evaluation for systemic lupus erythematosus.

The Effect of Blockade of Tumor Necrosis Factor α on VLA-1+T-Cells in Rheumatoid Arthritis Patients

The alpha1beta1 integrin, very late antigen (VLA)-1, characterizes collagen adherent interferon (IFN) gamma producing memory T cells in inflamed synovium. We now report that the mean percentage of VLA-1+ T cells is significantly lower among peripheral blood mononuclear cells of rheumatoid patients responsive to antitumor necrosis factor (TNF) alpha therapy than of those with active disease not receiving therapy. Neutralization of TNFalpha during in vitro polyclonal activation of VLA-1- T cells reduced differentiation to expression of VLA-1 and inhibited secretion of IFNgamma, but did not affect integrin expression on in vivo differentiated VLA-1+ T cells. Moreover, synovial fluids of patients relapsing during and after therapy were enriched in VLA-1+ T cells and lines derived from VLA-1+ T cells in peripheral blood of treated patients retained collagen binding and secreted IFN gamma. Thus, whereas therapy decreases VLA-1+ T cells in rheumatoid arthritis patients, a subset is resistant and contributes to residual and recurring inflammation.

Rituximab

An important role for B cells in the immunopathogenesis of rheumatoid arthritis (RA) is recognized. Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody that transiently depletes CD20+ B cells. A single course of rituximab (two intravenous infusions of 1,000mg given two weeks apart) with a stable dose of methotrexate significantly improved all measures of disease activity, fatigue, and health-related quality of life relative to placebo with methotrexate. This was demonstrated in the REFLEX trial, a 24-week, randomized, double-blind, double-dummy, international, phase III study in 520 patients who had active RA despite ongoing treatment with methotrexate and had experienced an inadequate response to anti-tumor necrosis factor (TNF) therapy. Patients in REFLEX (or other studies) who responded to, and required further treatment after, an initial course of rituximab continued to respond to subsequent courses of the drug. A small subgroup of patients in REFLEX continued to respond to their first course of rituximab through 48 weeks of follow-up. Long-term treatment (up to 56 weeks) with one or more courses of rituximab in REFLEX significantly inhibited joint structural damage, the first time this effect has been reported in patients with an inadequate response to TNF inhibitors. Rituximab was generally well tolerated; the majority of adverse events were related to the first infusion of the drug, were mild to moderate in severity, and were easily managed. The adverse event profile of rituximab was unchanged after repeat courses.

Killing, letting die and euthanasia.

Medical ethicists debate whether or not the moral assessment of cases of euthanasia should depend on whether the patient is 'killed' or 'allowed to die'. The usual presupposition is that a clear distinction between killing and letting die can be drawn so that this substantive question is not begged. I contend that the categorisation of cases of instances of killing rather than as instances of letting die depends in part on a prior moral assessment of the case. Hence is it trivially rather than substantively true that the distinction has moral significance. But even if a morally neutral (ie non-question begging) distinction could be drawn, its application to the euthanasia controversy is problematic. I illustrate the difficulties of employing this distinction to reach moral conclusions by critically discussing Philippa Foot's recent treatment of euthanasia. I conclude that even if an act of euthanasia is an instance of killing, and there exists a prima facie moral duty not to kill, and no more stringent duty overrides this duty, one still cannot determine such an act to be morally impermissible.