|BackgroundInfliximab is a monoclonal antibody that binds to and inhibits tumor necrosis factor alpha, a cytokine that plays an important role in a variety of inflammatory processes, including induction of pro-inflammatory cytokines, enhancement of leukocyte migration, activation of neutrophil and eosinophil activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and chondrocytes. Elevated concentrations of TNF alpha have been found in the joints of rheumatoid arthritis patients and the stools of Crohn’s disease patients, and correlate with elevated disease activity. In Crohn’s disease, treatment with infliximab reduced infiltration of inflammatory cells and TNF alpha production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propia able to express TNF alpha and interferon gamma. In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion, chemoattraction, and tissue degradation.
The patient selection criteria outlined above were derived from the FDA-approved prescribing information for Remicade, the studies that were presented to the FDA in support of the pre-market approval application, and studies in the peer-reviewed published medical literature.
Infliximab is an intravenous medication that is indicated for the reduction in the number of enterocutaneous fistulas in patients with fistulating Crohn’s disease. The safety and efficacy of infliximab in fistulizing Crohn’s disease was demonstrated in a randomized, controlled study of patients with fistulizing Crohn’s disease of at least three months duration. Initial therapy consists of three doses of infliximab (5mg/kg) given at 0, 2 and 6 weeks. Retreatment with infliximab is covered.
Infliximab is also indicated for the reduction in signs and symptoms of active Crohn’s disease in patients who have had an inadequate response to conventional therapies (corticosteroids, sulfasalazine, mesalamine, olsalazine, or 6-mercaptopurine). The safety and efficacy of infliximab for patients with active Crohn’s disease was demonstrated in a randomized controlled clinical trial. In clinical studies of infliximab for active Crohn’s disease, all patients had experienced an inadequate response to prior conventional therapies, including corticosteroids, 5-aminosalicylates (5-ASA), and/or 6-mercaptupurine/ azathioprine (6-MP/AZA). Initial therapy consists of a single infusion of infliximab (5mg/kg). In clinical studies, there was no evidence of a dose response; doses higher than 5 mg/kg did not result in a greater proportion of responders. Retreatment with infliximab may be necessary and is covered. Although the optimal frequency of retreatment is uncertain, there is preliminary evidence to suggest that the optimal interval frequency of retreatments is 8-week intervals.
Consistent with FDA-approved product labeling, infliximab, in combination with methotrexate, is considered medically necessary for the reduction of signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate monotherapy. The safety and efficacy of infliximab for rheumatoid arthritis was demonstrated in a 30-week-long, multicenter, randomized, controlled clinical study involving rheumatoid arthritis patients who had failed to adequately respond to 6 or more months of methotrexate monotherapy. When used for treatment of rheumatoid arthritis, infliximab is administered intravenously in 3 mg/kg doses at zero, two and six weeks and then every eight weeks thereafter. Infliximab may be administered as frequently as every four weeks in patients with an inadequate response to less frequent dosing. However, in clinical trials, higher doses and/or more frequent administrations did not result in higher response rates.
There are currently three biological response modifiers for rheumatoid arthritis currently on the market: infliximab (Remicade) and etanercept (Enbrel) act by inhibiting tumor-necrosis factor, and anakinra (Kineret) acts by blocking interleukin-1. However, there are no published direct comparative studies of these drugs to determine whether any one is more safe or effective than another. Although the three currently available biological response modifiers differ in structure, mechanism of action and pharmacokinetics, they each have proven effective in reducing the signs and symptoms of rheumatoid arthritis and in slowing and even arresting the progression of radiographic damage. Infliximab requires intravenous administration by a health care professional; by contrast, both etanercept and anakinra are self-administered by subcutaneous injection.
Conventional treatment options for patients with severe corticosteroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently limited by toxicity, or colectomy. Studies have shown that infliximab, improves clinical, endoscopic, and histologic outcomes in patients with severely active ulcerative colitis refractory to conventional therapy, allowing corticosteroid sparing and reducing the need for colectomy. This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade. Two Phase III randomized, placebo-controlled clinical trials have demonstrated efficacy of infliximab in inducing and maintaining clinical response and remission of refractory moderate to severe ulcerative colitis (Rutgeerts, et al., 2005; Sandborn, et al., 2005). In these clinical trials, subjects with moderate to severe ulcerative colitis that was refractory to at least one standard therapy were randomly assigned to infliximab in doses of 5 mg per kg or 10 mg per kg, or to placebo. In one clinical trial involving 364 subjects with moderate to severe ulcerative colitis (Sandborn, et al., 2005), 62 percent of subjects in the 10 mg group and 69 percent of subjects in the 5 mg group had a clinical response at 8 weeks, compared to 37 percent of subjects in the placebo group (p < 0.001 for both). At that time, 32 percent of subjects in the 10 mg group and 39 percent of subjects in the 5 mg group were in clinical remission, versus 15 percent of subjects in the placebo group. (p = 0.002 and p < 0.001, respectively). By 30 weeks, 51 percent of the 10 mg group and 52 percent of the 5 mg group achieved clinical response versus 30 percent of placebo-treated subjects (p = 0.002 and p < 0.001). At that time, 37 percent of the 10 mg group and 34 percent of the 5 mg group were in clinical remission, versus 16 percent of the placebo group (p < 0.001 and p = 0.001).
In a second clinical trial involving 364 subjects with moderate to severe ulcerative colitis (Sandborn, et al., 2005), 69 percent of subjects in the 10 mg group and 65 percent of subjects in the 5 mg group had a clinical response at 8 weeks, compared to 29 percent of subjects in the placebo group (p < 0.001 for both). At that time, 28 percent of subject in the 10 mg group and 34 percent of subjects in the 5 mg group were in clinical remission, versus 6 percent of subjects in the placebo group (p < 0.001 for both). By 30 weeks, 60 percent of subjects in the 10 mg group and 47 percent of subjects in the 5 mg group had a clinical response, compared to 26 percent of subjects receiving placebo (p < 0.001 for both). At that time, 36 percent of subjects in the 10 mg group and 26 percent of subjects in the 5 mg group were in clinical remission, compared to 11 percent in the placebo group (p < 0.001 and p = 0.003).
Additional studies are needed to evaluate the optimal timing and duration of infliximab therapy, the utility of adjuvant medical treatments during infliximab therapy, and the long-term safety and comparative efficacy of the various treatments for ulcerative to better define the role of infliximab in the treatment of this condition. Other TNF antagonists for ulcerative colitis in various phases of investigation include the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide.
Two published randomized controlled trials have reported on significant reductions in disease activity in patients with ankylosing spondylitis and other spondyloarthropathies who were treated with infliximab. Spondyloarthropathy (literally arthritis of the spine) may be associated with ankylosing spondylitis, Reiter syndrome, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease, or may be idiopathic (undifferentiated spondyloarthropathy). Van den Bosch, et al. (2002) reported on a 12-week long clinical study involving forty patients with active spondyloarthropathy who were randomly assigned to receive an intravenous loading dose (weeks 0, 2, and 6) of 5 mg/kg infliximab or placebo. Both patient and physician global assessments of disease activity on a visual analog scale improved significantly in the infliximab group compared with the baseline value, with no improvement in the placebo group. As early as week 2 and sustained up to week 12, there was a highly statistically significant difference between the values for these two endpoints in the infliximab versus the placebo group. In most of the other assessments of disease activity (laboratory measures, assessments of specific peripheral and/or axial disease), significant improvements were observed in the infliximab group compared with the baseline value and compared with placebo. There was one severe drug-related adverse event, in which a patient developed disseminated tuberculosis.
Braun, et al. (2002) reported the results of a 12-week randomized placebo-controlled clinical trial involving 35 patients with active ankylosing spondylitis treated with intravenous 5mg/kg infliximab infusion (at weeks 0, 2 and 6) and 35 patients assigned to placebo. Eighteen (53%) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50% compared with three (9%) of 35 on placebo (difference 44% [95% CI 23-61], p<0.0001). Function and quality of life also improved significantly on infliximab but not on placebo (p<0.0001 and p<0.0001, respectively). The investigators reported that treatment with infliximab was generally well tolerated, but three patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia.
These randomized controlled trials confirm the findings of an open label study of infliximab in 21 patients with active spondyloarthropathy who received a maintenance regimen of 5 mg/kg infliximab every 14 weeks, 19 of whom were followed for one year (Kruithof, et al., 2002). The investigators reported that, after each re-treatment a sustained significant decrease of all disease manifestations was observed. Before re-treatment, symptoms recurred in 3/19 (16%) at week 20, in 13/19 (68%) at week 34, and in 15/19 (79%) at week 48. Twelve minor infectious episodes were observed in this cohort.
Based on limited evidence, the U.S. Pharmacopeial Convention (2003) has concluded that psoriatic arthritis and psoriasis are accepted indications for infliximab. A controlled clinical study (Chaudhari, et al., 2001) has demonstrated the short-term effectiveness of infliximab in plaque psoriasis. In a controlled clinical trial in which patients and investigators were blinded for the first 10 weeks, participants were assigned to either of two doses of infliximab (5 mg/kg or 10 mg/kg at baseline, 2 weeks, and 6 weeks) or to placebo. Nineteen of 22 patients assigned to infliximab achieved good or better physician’s overall assessments, compared with two of 11 patients assigned to placebo. In initial studies, remissions seemed to be durable, with many patients improving for six months or longer.
Based on the evidence of efficacy of infliximab in a variety of spondyloarthropathies where tumor necrosis factor plays a role, the U.S. Pharmacopeial Convention (2003) has concluded that reactive arthritis and inflammatory bowel disease arthritis are accepted off-label indications for infliximab.
Evidence suggests that infliximab may be effective in juvenile rheumatoid arthritis. A randomized, controlled clinical study found a nonsignificant trend in favor of infliximab in polyarticular juvenile idiopathic arthritis (Ruperto, et al., 2007). In this multicenter, randomized, placebo-controlled study, 122 children with persistent polyarticular juvenile idiopathic arthritis despite prior methotrexate therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received methotrexate plus infliximab 3 mg/kg through week 44, or methotrexate plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44. The investigators reported that a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), but the between-group difference in this primary efficacy end point was not statistically significant (p = 0.12). The investigators reported that, by week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients.
An open-label extension of this study of juvenile idiopathic arthritis concluded that infliximab was safe and effective in the long-term, but had a high discontinuation rate (Ruperto, et al., 2010). Seventy-eight of the 122 subjects (64%) entered this open-label extension study. Of these, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (8 patients) or patient/physician/sponsor requirement (8 patients). The authors reported that infliximab at a mean dose of 4.4 mg/kg per infusion was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At four years, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24%, and 13%, respectively.
There is limited evidence of infliximab’s effectiveness in persons with chronic pulmonary sarcoidosis who remain symptomatic despite treatment with steroids or immunosuppressants. Baughman, et al. (2005) reported on a randomized controlled clinical trial comparing two doses of infliximab (3 or 5 mg/kg) to placebo in 138 patients with chronic (greater than 1 year duration) sarcoidosis who remain symptomatic (American Thoracic Society dyspnea score greater than 1) despite treatment with 3 or more months of prednisone (10 mg or more) or immunomodulator therapy or both, with evidence of parenchymal disease (Stage II or II) on chest x-ray, and a forced vital capacity (FVC) of > 50% to < 75% predicted. The investigators reported significant (delta 2.5%, p = 0.038) improvement in the percent of predicted FVC at week 24, the primary study endpoint, in the combined infliximab groups. The results did not differ significantly between infliximab doses. The investigators reported that subgroup analysis demonstrated greater benefit in patients with more extensive sarcoidosis disease burden, duration, activity, and severity.
Infliximab is under investigation as a treatment for uveitis. Current evidence is limited to case reports and uncontrolled case series. In the largest series of infliximab for uveitis published to date, Suhler and colleagues (2005) reported that at 10 weeks’ follow-up, 18 of 23 patients were considered successfully treated. Those successfully treated for 1 year fell to 7 of 14 eligible patients, with 5 not completing the 1 year of treatment because of significant adverse effects. An editorial by Robert Nussenblatt of the National Eye Institute (Nussenblatt, 2005) that accompanied this report noted, however, that only 4 of 23 patients demonstrated an improvement in their visual acuity of 2 lines or better. “Perhaps the most striking part of the report is the litany of adverse effects associated with the administration of this medication” (Nussenblatt, 2005).
Commenting on the available literature on infliximab for uveitis, Nussenblatt (2005) stated: “More than 60 publications have appeared in the literature to date describing the effects of infliximab in the treatment of uveitis. This large number reflects a serious problem that needs to be addressed in this field. While small, often single, case reports are important in generating hypotheses, these studies seem to produce not hypotheses but merely more of the same case reports. Further, the reports use criteria that are not standardized, so comparing one study to another is difficult to do. This is the case for the present study as well.”
Well designed clinical studies are necessary for assessing the effectiveness and safety of infliximab in uveitis. It should also be noted that another tumor necrosis factor inhibitor, etanercept, showed apparently positive results in the treatment of uveitis in case reports and uncontrolled case series, but subsequently published controlled clinical trials demonstrated no significant benefit (Foster, et al., 2003; Smith, et al., 2005).
Kahn et al (2006) reported their experience in using infliximab for the treatment of childhood uveitis. A total of 17 children (3 males, 14 females) with chronic uveitis were administered high-dose infliximab (10 to 20 mg/kg/dose). Main outcome measure was the ability to eliminate all signs of intra-ocular inflammation. All 17 patients showed a dramatic, rapid response, with no observed inflammation in 13 patients after the second infusion, and 4 patients requiring 3 to 7 infusions to achieve disease quiescence. Additional immunosuppressives and topical glucocorticoids were tapered when patients achieved no intra-ocular inflammation. The authors noted that in this series, high-dose infliximab was a rapidly effective, well-tolerated therapeutic agent for the treatment of chronic, medically refractory, non-infectious uveitis. Moreover, they stated that larger, randomized, controlled studies will provide a better understanding of the dose, interval, and duration of treatment needed and will provide data on long-term safety.
A phase II clinical trial by Suhler and associates (2009) reported the 2-year follow-up data of patients with refractory uveitis treated with intravenous infliximab as part of a prospective clinical trial. Their 1-year data, published in 2005 (Suhler, 2005) reported reasonable initial success, but an unexpectedly high incidence of adverse events. Of their 23 patients, 7 developed serious adverse events, including 3 thromboses, 1 malignancy, 1 new onset of congestive heart failure, and 2 cases of drug-induced lupus. Of patients who received at least 3 injections of infliximab, 75 % also developed elevated antinuclear antibody titers, although the significance of this is unknown. The protocol initially permitted 1 year of therapy, but was extended to 2 years midway through the study. Longer-term follow-up data were also collected for patients who continued with infliximab therapy after study completion. Of the 31 patients who received infliximab in this study, approximately 75 % had an initial favorable response, and the drug was effective in select patients for 2 to 4 years. Of 23 patients who demonstrated initial success at 10 weeks, 15 completed 1 year in the study and 8 completed 2 years of therapy, 7 in the study and 1 outside the study protocol prior to its extension to 2 years. Three patients developed a drug-related lupus-like illness. Two developed fatal solid malignancies, which were considered by the authors to have an unclear relation to the drug. There were no further cases of congestive heart failure or venous thrombosis. Unfortunately, 2 of the 7 patients who completed 2 years of the study were ultimately lost to follow-up, and another 2 patients who completed the 1-year protocol were also lost to follow-up. It may be, in fact, that the risk of long-term adverse effects is even higher than reported in this article. The study by Suhler is difficult to interpret because of the small size, lack of comparision group, and substantial loss to followup.
In an accompanying editorial of theafore-mentioned article, Goldstein (2009) noted that Suhler et al (2009) are to be congratulated for adding to the literature on the use of TNF inhibitors in uveitis. The editorialist stated that, while the trial is small and is neither randomized nor controlled, the data are collected in a prospective fashion, with at least 2 years of follow-up. Although infliximab was not universally successful at controlling inflammation in this series, it was effective in selected patients, with 60 % of patients retained in the study per year. This series also demonstrated that while infliximab is well-tolerated in terms of immediate treatment-limiting adverse effects, significant late toxicity may occur. Furthermore, Goldstein noted that the rate of adverse events reported by Suhler et al (2009) is much higher than reported in retrospective uveitis series. Because this is a prospective trial, its results may be more clinically relevant than those from retrospective series and may offer the clinician a more accurate estimate of the risks associated with the use of infliximab in patients with uveitis. Clinical trials of infliximab for uveitis are currently ongoing.
A clinical trial has demonstrated that infliximab is superior to placebo in the treatment of pyoderma gangrenosum. Pyoderma gangrenosum is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. Pyoderma gangrenosum is treated by managing the underlying cause. Topical and oral steroids are used. If resistant, oral dapsone or minocycline, and occasionally cyclosporine is used. Brooklyn, et al. (2006) reported on the results of a randomized controlled trial of infliximab. Patients 18 years of age and older with pyoderma gangrenosum were randomized to receive infliximab at 5 mg per kilogram (n = 13) or placebo (n = 17). Patients were assessed two weeks later and, during the open label portion of the study, nonresponders were offered open labeled infliximab, and were reassessed four weeks later. At week 2, significantly more patients in the infliximab group had improved (46 percent (6/13) compared with the placebo group (6 percent (1/17) (p = 0.025). Overall, 29 patients received infliximab with 69 percent (20/29) demonstrating a clinical beneficial response. Remission rate at week 6 was 21 percent (6/29). There was no response in 31 percent (9/29) of patients. The authors concluded that infliximab is superior to placebo in the treatment of pyoderma gangrenosum.
A systematic evidence review in BMJ Clinical Evidence found that the effectiveness of infliximab in treatment of herniated disc is unknown (Jordan, et al., 2008). The assessment identified one randomized controlled clinical trial of 41 people with acute or subacute sciatic pain, caused by herniated discs confirmed by magnetic resonance imaging, comparing infliximab, given as a single intravenous infusion) versus control (saline infusion over 2 hours) (Korhonen, et al., 2005). The randomized controlled trial found no significant difference between infliximab and control in leg or back pain score improvements at 12 weeks or median reduction in back pain score at 12 weeks. The trial also found no significant difference between groups in reduction of Oswestry Disability Index scores, median cumulative sick leave, or the proportion of people undergoing discectomy.
There is insufficient scientific evidence regarding the clinical value of measurements of serum levels of infliximab and/or HACA for patients receiving infliximab therapy.
In a double-blind, placebo-controlled, phase III clinical trial, Maini and colleagues (1999) examined if infliximab would provide additional clinical benefit to patients who had active RA despite receiving methotrexate. A total of 428 patients who had active RA and had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomized to placebo (n = 88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for greater than or equal to 6 months, range 10 to 35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. At 30 weeks, the American College of Rheumatology (ACR)-20 response criteria, representing a 20 % improvement from baseline, were achieved in 53, 50, 58, and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20 % of patients receiving placebo plus methotrexate (p < 0.001 for each of the four infliximab regimens versus placebo). A 50 % improvement was achieved in 29, 27, 26, and 31 % of infliximab plus methotrexate in the same treatment groups, compared with 5 % of patients on placebo plus methotrexate (p < 0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group. The authors concluded that during 30 weeks, treatment with infliximab plus methotrexate was more effective than methotrexate alone in patients with active RA not previously responding to methotrexate.
The protocol in the study by Maini et al (1999) pre-specified that pharmacokinetic data would be analyzed in the first 200 subjects. However, the number of subjects with human anti-chimeric antibodies (HACA) formation was not stated. Because of the murine component of the antibody, patients receiving infliximab can develop HACA that are associated with an increased rate of infusion reactions. Pharmacokinetic measurements were actually performed in 197 patients and results were consistent with the previously defined half-life of 8 to 12 days. It should be noted that HACA formation could not be measured in patients receiving infliximab since the drug interferes with the assay. However, 27 patients who discontinued treatment before 30 weeks were tested for HACA formation, and 3 patients (11 %) tested positive for HACA (2 with a titer of 1/10 and 1 with a titer of 1/40). The rate of HACA formation in patients with CD treated with infliximab is reported to be 13 %, but this rate appears to be less if a patient is on concurrent immunosuppressive therapy (Hanauer, 1999; Sanborn and Hanauer, 2002). It is unclear whether serum infliximab levels may decline more rapidly in the presence of HACA resulting in reduced effectiveness of infliximab therapy.
St Clair, et al. (2002) examined the relationship between serum concentrations of infliximab and clinical improvement from RA following infliximab treatment. Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multi-center, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the safety and effectiveness of infliximab therapy. Serum levels of infliximab were measured by enzyme-linked immunosorbent assay. Dose-response trends were analyzed using generalized logistic regression techniques. Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial. At week 54, 26 % of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (p < 0.001). Increased magnitude of ACR response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR-20 criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (p < 0.001), as was less progression of radiographical joint damage (p = 0.004), providing support for a dose-response relationship. Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg. The authors concluded that these results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.
In the study by St. Clair, et al. (2002), the relatively low proportion of ACR-50 responders in patients receiving 3mg/kg every 8 weeks may be due to inadequate exposure to infliximab during the course of therapy. The trough serum levels of infliximab at 54 weeks varied more than 100-fold in this group suggesting marked differences among patients in exposure to infliximab. The basis for this individual variability is unclear, but HACA and/or metabolic differences may offer some explanations. However, it is unlikely that HACA are the sole reason for the rapid clearance of serum infliximab in this group of patients. After completion of the study, HACA were detected in 25 patients (8.5 %) with analyzable samples. These antibodies were distributed across all infliximab-treated groups. The appropriate serum samples were available for measuring HACA in 19 of 21 patients from the group that received 3mg/kg every 8 weeks; and this group of patients had undetectable trough levels of infliximab. Of these 19 subjects, only 6 were HACA-positive, and 2 had inconclusive results. Therefore, metabolic factors probably are responsible for the rapid clearance of infliximab in some patients.
The relationship between clinical improvement and trough serum levels of infliximab bears clinical implications. Although there was a trend towards a slightly higher proportion of serious side effects in the group receiving 3mg/kg every 4 weeks compared with the group receiving 3mg/kg every 8 weeks (16 % versus 11 %), this incidence was no higher than that observed in the placebo-controlled group (21 %). Presently, there is a lack of evidence to identify which patients might benefit from a dose increase based on any clinical, laboratory, or radiographical factors. Additionally, the relationship between trough serum levels of infliximab and clinical improvement is imprecise. At 54 weeks, 6 (21 %) of the 28 patients in the study attained ACR-50 or better despite trough serum infliximab levels of less than 0.1 ug/ml. Thus, trough serum levels of infliximab are not, by themselves reliable predictors of treatment response. St Clair, et al. (2002) stated that they would not advocate the routine measurement of serum infliximab levels for this reasons. It should also be noted that poor or lack of response to infliximab therapy may be the result of a particular disease characteristics (e.g., joint inflammation not primarily driven by TNF-alpha) or other host factors that preclude an adequate response to treatment.
The clinical significance of HACA formation, if any, has yet to be established. HACA is associated with an increased frequency of infusion reactions, although overall, the presence of HACA is poorly predictive of infusion reactions (Smith, et al., 2005). Guidelines from the Canadian Consensus Group on the Use of Infliximab in Crohn’s Disease (Panaccione, 2001) note that most infusion reactions are easily dealt with by stopping the infusion and restarting at a decreased rate. Furthermore, formation of antibodies to infliximab can be prevented by coadministration of infliximab with methotrexate or other immunosuppressants (Panaccione, 2004). It should be noted that HACA-positive patients who received repeated treatment with infliximab have demonstrated sustained clinical benefit and have tolerated such treatment well even though they may be more likely to experience an infusion reaction to the administration of infliximab.
Measurement of anti-histone antibodies has been employed for monitoring of infliximab therapy. However its clinical value has yet to be established. Allanore et al (2004) examined autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab. These investigators included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide. They tested the sera of the patients for anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30. Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after 3 infusions. At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19 % versus 42 %, p = 0.009). At week 30, the frequency of patients with ANA had increased from 29 % to 69 % (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0 % to 3 % for IgG (NS) and from 0 % to 32 % for IgM (p < 0.001); the frequency of anti-histone IgG detection had increased from 22 % to 32 % (p = 0.04) and that of IgM detection, from 18 % to 79 % (p < 0.001). No lupus-like syndrome was observed. RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001). No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy. The authors concluded that Infliximab therapy lead to the selective and delayed induction of autoantibodies. This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.
Elkayam and colleagues (2005) noted that therapy with TNFa blocking agents has been associated with increased rate of ANA and rare cases of lupus like syndromes. The objective of this study was to prospectively analyze a wide array of autoantibodies in RA patients before and 14 weeks after starting infliximab. In this study, 26 consecutive active RA patients participated. All treated with infliximab at a dosage of 3 mg/kg on week 0, 2, 6 and every 8 weeks, along with weekly low dose methotrexate. Patients were evaluated at week 0 and 14. Clinical assessment included the number of tender and swollen joints, duration of morning stiffness, adverse events (AE) (including SLE-like) and ESR. Sera were collected before the 1st infusion of infliximab at week 0 and 14. The autoantibodies studied were: fluorescent ANA, anti dsDNA, IgG and IgM anti-cardiolipin (ACA), anti-histone- H1 and C (H1, H2A, H2B, H3, H4), anti-SSA, -SSB, -ENA, -scleroderma 70, -thyroid peroxidase (TPO) and -neutrophilic cytoplasmatic (ANCA) antibodies. Of 26 patients, 17 were women. A significant decrease in duration of morning stiffness, number of tender and swollen joints and ESR were observed between week 0 and 14. During follow-up (mean of 20.5 +/- 7.3 months), 9 patients stopped infliximab due to inefficacy or AE (most of them after the 4th infusion). Two patients developed lupus-like phenomena. ANA was found positive at baseline in 7 out of 26 patients. In 5 of them, an increase in the titer of ANA was observed at week 14. ANA negative turned positive for 8 patients. A significant increase of anti-cardiolipin (ACA)-IgM levels was observed in 8 patients and of ACA-IgG in 6, in parallel with ANA seroconversion. The mean level of anti dsDNA) -IgG significantly increased from 66 +/-3 3 to 93 +/- 68 IU/ml, in 4 patients to pathological levels. Four patients demonstrated an increase in anti-histone H1. Levels of ANCA, anti-ENA, -SSA, -SSB, -RNP, -scleroderma70 and -thyroid peroxidase (TPO) were negative in all patients and remained unchanged during the study. Cessation of treatment with infliximab was found to be associated with the appearance of ANA. The authors concluded that an increased titer or a new appearance of ANA was observed in 12 out of 26 patients. The main autoantibodies found were anti dsDNA, ACA-IgM and -IgG and anti-histone. The authors noted that in their cohort, the appearance of some autoantibodies seemed to predict late cessation of treatment.
The FDA-approved product labeling for Remicade includes a black box warning that patients treated with infliximab are at increased risk for infections, including progression to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections. The black box warning states that patients should be educated about the symptoms of infection, closely monitored for signs and symptoms of infection during and after treatment with infliximab, and should have access to appropriate medical care. The warning states that patients who develop an infection should be evaluated for appropriate antimicrobial therapy and for serious infections infliximab should be discontinued. The labeling states that tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving infliximab. The black box warning states that patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating infliximab and during therapy. The labeling recommends that treatment of latent tuberculosis infection should be initiated prior to therapy with infliximab. Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation in patients receiving infliximab. The labeling notes that some patients who tested negative for latent tuberculosis prior to receiving infliximab have developed active tuberculosis. The black box warning states that physicians should monitor patients receiving infliximab for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.
The black box also warns that rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. All of these hepatosplenic T-cell lymphomas with infliximab have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine.
The labeling for Remicade states that infliximab has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. The labeling states that there have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. The labeling recommends that, if a decision is made to administer infliximab to patients with heart failure, they should be closely monitored during therapy, and infliximab should be discontinued if new or worsening symptoms of heart failure appear.
In a Cochrane review, Doherty et al (2009) examined the use of medical therapies for the prevention of post-operative recurrence of Crohn’s disease. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify relevant studies. References from selected papers and abstracts from Digestive Disease Week were also searched. Randomized controlled trials that compared medical therapy to placebo or other medical agents for the prevention of recurrence of intestinal Crohn’s disease were selected for inclusion. Two authors reviewed all abstracts containing search terms, and those meeting inclusion criteria were selected for full data abstraction. Dichotomous data were summarized using relative risk and 95 % confidence intervals (CI). A fixed-effects model was used, and sensitivity analysis performed. A total of 23 studies were identified for inclusion. Probiotics were not superior to placebo for any outcome measured. The use of nitroimidazole antibiotics appeared to reduce the risk of clinical (RR 0.23; 95 % CI 0.09 to 0.57, number needed to treat [NNT] = 4) and endoscopic (RR 0.44; 95 %CI 0.26 to 0.74, NNT = 4) recurrence relative to placebo. However, these agents were associated with higher risk of serious adverse events (RR 2.39, 95 % CI 1.5 to 3.7). Mesalamine therapy was associated with a significantly reduced risk of clinical recurrence (RR 0.76; 95 % CI 0.62 to 0.94, NNT = 12), and severe endoscopic recurrence (RR 0.50; 95 % CI 0.29 to 0.84, NNT = 8) when compared to placebo. Azathioprine/6MP was also associated with a significantly reduced risk of clinical recurrence (RR 0.59; 95 % CI 0.38 to 0.92, NNT = 7), and severe endoscopic recurrence (RR 0.64; 95 % CI 0.44 to 0.92, NNT = 4), when compared to placebo. Neither agent had a higher risk than placebo of serious adverse events. When compared to azathioprine/6MP, mesalamine was associated with a higher risk of any endoscopic recurrence (RR 1.45, 95 % CI 1.03 to 2.06), but a lower risk of serious adverse events (RR 0.51; 95 % CI 0.30 to 0.89). There was no significant difference between mesalamine and azathioprine/6MP for any other outcome. The authors concluded that there are insufficient randomized controlled trials of infliximab, budesonide, tenovil and interleukin-10 to draw conclusions. Nitro-imidazole antibiotics, mesalamine and immunosuppressive therapy with azathioprine/6-MP or infliximab all appear to be superior to placebo for the prevention of post-operative recurrence of Crohn’s disease. The cost, toxicity and tolerability of these approaches require careful consideration to determine the optimal approach for post-operative prophylaxis.
In a review on standard and novel treatments to Behçet’s disease, Gul (2007) stated that multi-center, multi-disciplinary and long-term trials aiming to assess the effectiveness of interventions (including infliximab) in both the treatment of acute inflammatory attacks and the prevention of relapses are needed in order to provide more generalizable results that can lead to better management plans. Kobayashi et al (2007) stated that 5-aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçet’s disease. Moreover, infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy.
Moravan and Segal (2009) described the effects of infliximab, and the anti-proliferative immunosuppressant, mycophenolate mofetil, in refractory neurosarcoidosis. These researchers treated patients with biopsy-proven sarcoidosis and central nervous system (CNS) involvement, who had failed treatment with steroids, with infliximab (5 mg/kg on weeks 0, 2, and 6, and then every 6 to 8 weeks thereafter). Six out of seven patients were co-treated with mycophenolate mofetil (1,000 mg PO BID). Patients underwent a review of symptoms and complete neurological examination every 3 months and MRI scanning before and after 3 to 4 infusions of infliximab. All patients reported significant symptomatic improvement by the 4th infusion of infliximab, including relief of headache and neuropathic pain, reversal of motor, sensory, or coordination deficits, and control of seizure activity. Furthermore, infliximab therapy was universally associated with a decrease in lesion size or suppression of gadolinium enhancement as documented by MRI. A positive treatment response was attained irrespective of location or distribution of CNS involvement by sarcoidosis (dural/leptomeningeal based versus intra-parenchymal; cord versus brain; single lesion versus multi-focal). There were no serious adverse effects in a follow-up period spanning 6 to18 months. The authors concluded that combination treatment with mycophenolate mofetil and infliximab is a promising therapeutic approach for neurosarcoidosis.
Sodhi and colleagues (2009) stated that CNS involvement is a severe manifestation of sarcoidosis that often requires aggressive immunosuppressive therapy. The most effective approach for refractory disease is unknown. These investigators reviewed the cases of 4 subjects who demonstrated active progression of neurosarcoidosis while under treatment with cyclophosphamide, and who were subsequently treated with infliximab. All 4 subjects demonstrated rapid and substantial reversal of their clinical course. Radiological findings were concordant with the clinical responses. There were no notable toxicities. Infliximab may be more effective than cyclophosphamide for refractory CNS sarcoidosis. The authors noted that a larger, prospective study is warranted.
In a Cochrane review, Jessop et al (2009) assessed the effects of drugs for discoid lupus erythematosus. These investigators updated their searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2009), MEDLINE, EMBASE, LILACS, and online ongoing trials registers. The reference lists of relevant reviews were searched. Index Medicus (1956 to 1966) was handsearched and we approached authors for information about unpublished trials. They included all randomized trials of drugs to treat people with discoid lupus erythematosus. Drugs included in the search were azathioprine, chloroquine, clofazimine, corticosteroids, (oral and topical), dapsone, gold, interferon alpha-2a, methotrexate, phenytoin, retinoids, sulphasalazine, thalidomide, topical calcineurin blockers (pimecrolimus and tacrolimus), and biological agents (etanercept, efalizimab, infliximab, and rituximab). Two reviewers independently examined each retrieved study for eligibility. Two trials involving 136 participants were included. No new trials were included in this update. In a cross-over study of 12 weeks duration, fluocinonide 0.0 5% cream (a potent topical corticosteroid), appeared to be better than hydrocortisone 1 % cream (a mild corticosteroid) when the first arm of the trial involving 78 subjects was analyzed at 6 weeks. Clearing or excellent improvement was seen in 27 % of individuals using fluocinonide and in 10 % of those using hydrocortisone, giving a 17 % absolute benefit in favor of fluocinonide (95 % CI 0.0 to 0.34, NNT = 6). In the second trial, acitretin (50 mg/day) was compared with hydroxychloroquine (400 mg/day) in 58 people in a parallel trial of 8 weeks duration. There was marked improvement or clearing in 46 % of people using acitretin and in 50 % of those on hydroxychloroquine, but there was no significant difference between the 2 interventions. The adverse effects were more frequent and more severe in the acitretin group. In this trial clearing of erythema was measured and found to be better in the hydroxychloroquine group (RR 0.61, 95 % CI 0.36 to 1.06). The authors concluded that fluocinonide cream may be more effective than hydrocortisone in treating people with discoid lupus erythematosus. Hydroxychloroquine and acitretin appear to be of equal efficacy, although adverse effects are more frequent and more severe with acitretin. There is not enough reliable evidence about other drugs used to treat discoid lupus erythematosus.