Ankylosing Spondylitis and Other Spondyloarthropathies:
Members with active ankylosing spondylitis or other active spondyloarthropathy with evidence of inflammatory disease who have an inadequate response to 2 or more non-steroidal anti-inflammatory drugs (NSAIDS) (e.g., celecoxib, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen, sulindac, and valdecoxib).
Reactive Arthritis and Inflammatory Bowel Disease Arthritis:
Members with refractory reactive arthritis (e.g., Reiter's syndrome) or inflammatory bowel disease arthritis (enteropathic arthritis) who have failed or are intolerant to NSAIDs, methotrexate, and sulfasalazine.
Members with active ulcerative colitis in persons who meet either of the following criteria:
Member is hospitalized with fulminant ulcerative colitis (i.e., persons severe ulcerative colitis who have more than 10 stools per day, continuous bleeding, abdominal pain, and distension, and acute, severe toxic symptoms including fever and anoxia); or
Member has moderate to severe active ulcerative colitis and meets all of the following criteria:
Member is refractory to or requires continuous immunosuppression with corticosteroids (e.g., methylprednisolone, prednisone) at a dose of prednisone 40 to 60 mg/day (or equivalent) for 30 days for oral therapy or 7 to 10 days for IV therapy); and
Member is refractory to or has a contraindication to 5-aminosalicylic acid agents (e.g., balsalazide, mesalamine, sulfasalazine); and
Member is refractory to or has a contraindication to immunosuppressants (6-mercaptopurine or azathioprine).
Chronic Pulmonary Sarcoidosis:
Members with chronic pulmonary sarcoidosis who remain symptomatic despite treatment for 3 or more months with steroids (10 mg per day or more) and immunosuppressants (such as azathioprine, cyclophosphamide, or methotrexate).
Persons with refractory pyoderma gangrenosum.
Persons with refractory Behçet's uveitis.
Persons with severe disease refractory to systemic antibiotics.
Aetna considers measurements of serum levels of infliximab and antibodies to infliximab (human anti-chimeric antibodies [HACA]) (e.g., the Anser IFX test [Prometheus Lab]) experimental and investigational because the clinical value of these measurements for individuals receiving infliximab therapy has not been established.
Aetna considers measurements of anti-histone antibodies for monitoring infliximab therapy experimental and investigational because the clinical value of these measurements for individuals receiving infliximab therapy has not been established.
Aetna considers infliximab experimental and investigational for all other indications (not an all-inclusive list) because its effectiveness for these indications has not been established:
Central nervous system amyloidosis
Chronic immune-mediated myelitis
Chronic obstructive pulmonary disease
Cranial nerve palsy
Cystoid macular degeneration
Disc herniation-induced sciatica
Discoid lupus erythematosus
Hepatitis C genotype 1
Prevention of post-operative recurrence of Crohn's disease
Rejection following small bowel transplantation
Systemic lupus erythematosus
Tubulo-interstitial nephritis with uveitis (TINU) syndrome
Infliximab is a monoclonal antibody that binds to and inhibits tumor necrosis factor (TNF)-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 (RA) 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 RA, 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 Food and Drug Administration (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 3 months duration. Initial therapy consists of three doses of infliximab (5 mg/kg) given at 0, 2 and 6 weeks. Re-treatment 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 (5 mg/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. Re-treatment 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 RA in patients who have had an inadequate response to methotrexate monotherapy. The safety and efficacy of infliximab for RA was demonstrated in a 30-week-long, multi-center, randomized, controlled clinical study involving RA patients who had failed to adequately respond to 6 or more months of methotrexate monotherapy. When used for treatment of RA, infliximab is administered intravenously in 3 mg/kg doses at 0, 2 and 6 weeks and then every 8 weeks thereafter. Infliximab may be administered as frequently as every 4 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 3 biological response modifiers for RA currently on the market: infliximab (Remicade) and etanercept (Enbrel) act by inhibiting TNF, 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 3 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 RA 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 1 clinical trial involving 364 subjects with moderate-to-severe ulcerative colitis (Sandborn et al, 2005), 62 % of subjects in the 10-mg group and 69 % of subjects in the 5-mg group had a clinical response at 8 weeks, compared to 37 % of subjects in the placebo group (p < 0.001 for both). At that time, 32 % of subjects in the 10 mg group and 39 % of subjects in the 5 mg group were in clinical remission, versus 15 % of subjects in the placebo group (p = 0.002 and p < 0.001, respectively). By 30 weeks, 51 % of the 10-mg group and 52 % of the 5-mg group achieved clinical response versus 30 % of placebo-treated subjects (p = 0.002 and p < 0.001). At that time, 37 % of the 10-mg group and 34 % of the 5-mg group were in clinical remission, versus 16 % of the placebo group (p < 0.001 and p = 0.001).
In a 2nd clinical trial involving 364 subjects with moderate-to-severe ulcerative colitis (Sandborn et al, 2005), 69 % of subjects in the 10-mg group and 65 % of subjects in the 5-mg group had a clinical response at 8 weeks, compared to 29 % of subjects in the placebo group (p < 0.001 for both). At that time, 28 % of subject in the 10-mg group and 34 % of subjects in the 5-mg group were in clinical remission, versus 6 % of subjects in the placebo group (p < 0.001 for both). By 30 weeks, 60 % of subjects in the 10-mg group and 47 % of subjects in the 5-mg group had a clinical response, compared to 26 % of subjects receiving placebo (p < 0.001 for both). At that time, 36 % of subjects in the 10-mg group and 26 % of subjects in the 5-mg group were in clinical remission, compared to 11 % in the placebo group (p < 0.001 and p = 0.003).
On September 23, 2011, the FDA approved infliximab to treat moderately to severely active ulcerative colitis in children older than 6 years who have had inadequate response to conventional therapy.
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 colitis 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's 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 2 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 1 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 5 mg/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 3 (9 %) of 35 on placebo (difference 44 % (95 % confidence interval [CI]: 23 to 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 3 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 1 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 2 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 2 of 11 patients assigned to placebo. In initial studies, remissions seemed to be durable, with many patients improving for 6 months or longer.
Based on the evidence of efficacy of infliximab in a variety of spondyloarthropathies where TNF 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 non-significant trend in favor of infliximab in polyarticular juvenile idiopathic arthritis (Ruperto et al, 2007). In this multi-center, 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 methotrexate 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 4 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 2 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 greater than 50 % to less than 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 TNF 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 comparison group, and substantial loss to followup.
In an accompanying editorial of the afore-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 2 weeks later and, during the open label portion of the study, non-responders were offered open labeled infliximab, and were re-assessed 4 weeks later. At week 2, significantly more patients in the infliximab group had improved (46 % (6/13) compared with the placebo group (6 % (1/17) (p = 0.025). Overall, 29 patients received infliximab with 69 % (20/29) demonstrating a clinical beneficial response. Remission rate at week 6 was 21 % (6/29). There was no response in 31 % (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 1 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) noted 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 erythrocyte sedimentation rate (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 cytoplasmic (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.
Afif, et al. (2010) evaluated the clinical utility of measuring human anti-chimeric antibodies (HACA) and infliximab concentrations. The investigators reviewed the medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured to determine whether the result affected clinical management. The investigators reported that 155 patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49 percent), partial response after initiation of infliximab (22 percent), and possible autoimmune / delayed hypersensitivity reaction (10 percent). HACAs were identified in 35 patients (23 percent) and therapeutic infliximab concentrations in 51 patients (33 percent). The investigators found, of 177 tests assessed, the results impacted treatment decisions in 73 percent. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92 percent of patients, whereas dose escalation had a response of 17 percent. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86 percent of patients, whereas changing to another anti-TNF agent had a response of 33 percent. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76 percent of the time and had no evidence of active inflammation by endoscopic / radiographic assessment 62 percent of the time. The investigators concluded that these results indicate that measurement of HACA and infliximab concentration impacts management and is clinically useful. The investigators stated that increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent. An accompanying editorial by D'Haens (2010) noted limitations of the study by Afif, et al., which were acknowledged in the discussion of the paper. The editorialist stated that the retrospective nature of the study by Afif, et al., without standard measurements of disease activity and the random selection of patients included in the analysis (based on the investigators’ individual practice) warrant cautious interpretation of the results.
Pariente, et al. (2012) reported that trough levels and antibodies to infliximab did not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. The investigators sought to assess the clinical value of measuring infliximab trough levels and antibodies to infliximab concentrations in IBD patients who lost response to infliximab therapy. The investigators retrospectively studied records of IBD patients who lost response to infliximab therapy. The investigators first assessed clinical responses of different therapeutic strategies that were applied when patients lost response to infliximab and then we looked at the correlation between clinical response and infliximab trough levels and infliximab antibody concentrations. The investigators reported that 76 IBD patients were included.; 31 patients (41%) continued infliximab therapy without any modification, 39 patients (51%) had an intensification of infliximab therapy, five patients (7%) had switched to adalimumab therapy, and one patient (1%) underwent surgery. Clinical response was observed in 27 patients (69%) with an intensification of infliximab therapy. The investigators found no significant difference in mean infliximab trough level at inclusion in patients who responded to intensification of infliximab therapy (3.3 + 4.1 mcg/mL) as compared with patients who did not respond (2.3 + 2.2 mcg/mL, p = 0.85). In all, 16/76 patients (22.4%) presented detectable infliximab antibodies in the serum. Ten antibody-positive patients had an intensification of infliximab therapy and six (60%) demonstrated a clinical response. After intensification of infliximab therapy the infliximab antibody concentration decreased in five patients. The investigators concluded that, in patients with IBD who lose response to infliximab, clinical improvement may occur upon intensification of infliximab therapy, irrespective of infliximab serum concentration or presence of infliximab antibodies.
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 % 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 7 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, efalizumab, 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.
Kraetsch and colleagues (2001) examined the efficacy of infliximab in the treatment of patients with severe and active adult onset Still's syndrome (AOSD) despite conventional immunosuppressive therapy. A total of 6 patients with the diagnosis of AOSD according to the Yamagushi criteria of 1992 were treated with infliximab. All patients had severe disease with high clinical and serological activity. Patients were treated initially with high dose steroids or more intensive immunosuppressive therapy. Two patients had a history of multiple disease modifying antirheumatic drug (DMARD) treatments. One patient had a history of 3 years of AOSD with fever, chills, pleural and pericardial effusions, and hepatosplenomegaly. Despite these treatments, the patient developed increasing serological signs of inflammation and arthritis of both hips and peripheral joints. Another patient had a history of 5 years of AOSD with oligoarthritis, myalgias, and recurrent fever despite multiple DMARD treatment, including cyclophosphamide pulse therapy. These patients with AOSD presented with massive polyarthralgias, polyarthritis, splenomegaly or hepatomegaly, the typical rash, sore throat, weight loss, serositis, continuing fever, leucocytosis, and raised C reactive protein (CRP), ESR, and ferritin levels. Four patients with early onset of the disease, fulfilling the diagnostic criteria for AOSD and a clinical and serological high disease activity, were included in this pilot study without any further DMARD treatment apart from the initial steroid treatment. Reduction of established treatment, mainly with steroids, caused a relapse of the disease in all these patients. Patients then received 3 to 5 mg/kg infliximab on weeks 0, 2, and 6, continuing with intervals of 6 to 8 weeks depending on the patient's individual disease activity. In all patients, fever, arthralgias, myalgias, hepatosplenomegaly, and the rash resolved after the first courses of treatment with infliximab. All serological variables (CRP, ESR, hyperferritinaemia) returned to normal. After 3 courses of infliximab infusions, splenomegaly could not be detected in any of these patients. After 3 courses of treatment with infliximab, splenomegaly could not be detected in any of the patients. Up to now, these patients have received infliximab infusion treatment for between 5 and 28 months. Throughout this period, all patients have continued to benefit from this treatment, with improvement in their clinical symptoms, joint counts, and serological disease activity. One of the patients had a moderate infusion reaction during the second treatment. The infusion was discontinued for 1 hour and then was resumed with no further problems. The authors concluded that the disease improved remarkably in all 6 patients with AOSD after treatment with infliximab, also in the early stage of AOSD. These preliminary data suggested the potential therapeutic benefit of anti-TNF-alpha treatment in AOSD.
In a prospective, non-comparative case-series study, Kokkinos et al (2004) examined the effects of infliximab on refractory AOSD. A total of 4 patients with severe and highly active AOSD, refractory to high doses of corticosteroids (which had been combined with methotrexate in 3 of them) and methotrexate were treated with infliximab (initial dose 3 to 5 mg/kg, continuing at intervals depending on the patient's individual disease activity). Resolution of their symptoms, which was evident within few days after the first infusion, and a parallel rapid improvement of the acute inflammatory response indices were observed in all. Concomitant corticosteroid treatment was reduced after the first courses of treatment with infliximab, which was well-tolerated, and complete disease remission was sustained during a 5 to18 months follow-up period. The authors noted that although further studies are needed to confirm long-term efficacy and safety in larger numbers of patients, they suggested that administration of infliximab with observation for objective improvement is the treatment of choice in cases of AOSD refractory to conventional treatment.
Schmitt et al (2007) noted that systemic immunosuppressive agents are recommended for patients with atopic eczema in whom disease activity can not be controlled adequately with topical treatments. Guidelines do not give clear advice which agents to prefer. These investigators systematically reviewed clinical trials on systemic treatment for severe atopic eczema to provide evidence-based treatment recommendations. Standardized literature search, independent standardized assessment of eligibility and data abstraction was performed by 2 reviewers. A total of 27 studies totaling 979 patients were included. Eleven studies consistently showed effectiveness of cyclosporine. Cyclosporine is recommended as first option for patients with atopic eczema refractory to conventional treatment. Evidence from randomized controlled trials also exists for gamma interferon and azathioprine. Although frequently used in clinical practice, systemic glucocorticosteroids have not been assessed adequately in studies. Mycophenolate mofetile showed effectiveness in 2 small uncontrolled studies. Intravenous immunoglobulins and infliximab are not recommended based on published data.
Belloni et al (2008) stated that atopic eczema is a common inflammatory skin disease showing chronically relapsing eczema and high association with elevated serum IgE levels. A subgroup of atopic eczema patients requires systemic immunomodulatory treatment for long time periods. However, beyond cyclosporine A and azathioprine, only limited consent exists on systemic treatment options. Timely published systemic treatment modalities include studies on efalizumab, infliximab, adalimumab, and etanercept, omalizumab, rituximab, specific immunotherapy, leflunomide, and leukotriene receptor antagonists with varying clinical results and with particular safety profiles. The authors concluded that although there is not yet a treatment modality reaching clinical efficacy of cyclosporine A as gold standard of systemic therapy, limitation in its application duration as in its side effect profile as well as the search for alternatives has set a focus on the new alternatives of which especially B-cell-directed therapies might be promising candidates.
In a retrospective study, Molloy and co-workers (2008) assessed the efficacy of anti-TNF therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies. Patients (n = 25) were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months; range of 2 to 84) and 9 with ETA (median 28 months; range of 4 to 82); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60 %) and successfully tapered below 10 mg/day in an additional 7 patients (28 %). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50 %) could taper or discontinue the additional agent. Major relapses occurred in 4 patients that initially achieved stable remission. Four patients suffered adverse events, including 1 with opportunistic infections and 1 with breast cancer. The authors concluded that in this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomized controlled trial of anti-TNF therapy in TAK.
Filocamo et al (2008) noted that 4 children with TAK were treated with TNF antagonists because of disease relapse during conventional therapy or as a first-line agent. Two patients went into remission; in the other 2, the response was partial. The authors concluded that anti-TNF agents can have a role in the treatment of TAK; however, further controlled studies are needed.
Haslund and associates (2009) noted that hidradenitis suppurativa (HS) is a common inflammatory skin disease. Medical treatment is often disappointing and in severe disease surgery remains the therapy of choice. Extensive surgery may be effective but also mutilating. Patients experience a significant reduction in quality of life and the need for new treatment modalities are urgent. In recent years, patients with HS have been treated off-label with TNF-alpha inhibitors with a varying degrees of effect. These researchers performed a systematic review of papers retrieved from 2 databases (PubMed and Web of Science) using the following keywords: hidradenitis suppurativa, acne inversa, infliximab, etanercept, and adalimumab. A total of 34 publications were retrieved, describing treatment of 105 patients. Most cases reported treatment with infliximab (52/105). A positive treatment outcome was reported in 90/105 cases, with only 7/105 non-responders and 8/105 patients experiencing side-effects. The side-effects were comparable to those seen in other TNF-alpha inhibitor studies. In the majority of cases, the treatment was effective when given as a suppressive therapy, but 15/105 cases were described with long-term remission (greater than or equal to 3 months) after the end of therapy. In most publications follow-up was, however, insufficient to allow a systematic exploration of this. The authors concluded that TNF-alpha inhibitors seem to be effective in the treatment of HS. However, several questions remain to be answered through specific studies. This review has also identified a need for more standardized reporting of the outcomes as well as randomized controlled trials in this disease.
Rambhatla, et al. (2012) conducted a systematic review of the effectiveness of various modalities to treat hidradenitis suppurativa (HS). The authors reported that treatments of HS shown to be effective were a clindamycin-rifampin combination regimen, a course of infliximab, monthly Nd:YAG laser sessions, and surgical excision and primary closure with a gentamicin sulfate-collagen sponge. The authors stated that most therapies used to treat HS were supported by limited or weak scientific evidence. The authors emphasized the need for large randomized controlled trials to evaluate treatment options for HS.
Randomized controlled clinical trials of tumor necrosis factor inhibitors for hydradenitis suppurativa have shown inconsistent results (Jemec, 2012). Grant, et al. (2011) reported positive results with infliximab therapy for patients with moderate to severe hidradenitis suppurativa in a randomized, double-blind, placebo-controlled crossover trial. Study subjects received infliximab or placebo during an eight-week double-blind treatment phase, followed by an open-label phase where subjects taking placebo were given the opportunity to cross over to infliximab, and an observational phase. Primary treatment efficacy was based on HS Severity Index. Secondary endpoints included Dermatology Life Quality Index, visual analog scale, and Physician Global Assessment scores. Inflammatory markers erythrocyte sedimentation rate and C-reactive protein were also assessed. The investigators found that more patients in the infliximab than in the placebo group showed a 50 percent or greater decrease from baseline HS Severity Index score. In addition, statistically and clinically significant improvement from baseline was observed at week 8 in Dermatology Life Quality Index score, visual analog scale score, erythrocyte sedimentation rate, and C-reactive protein compared with placebo. The investigators reported that patients in the placebo group treated with infliximab after week 8 (crossover) responded similarly to the original infliximab group. The investigators noted that many patients withdrew during the observational phase to continue anti-tumor necrosis factor-alfa therapy. No unexpected serious adverse events were observed. The investigators noted limitations of this study, including that patients were treated by a single physician at a single center, and some patients did not return after their last infusion, and the HS Severity Index requires validation. The investigators reported that infliximab was well tolerated, no unexpected safety issues were identified, and improvements in pain intensity, disease severity, and quality of life were demonstrated with concomitant reduction in clinical markers of inflammation.
However, another randomized, double-blind, placebo-controlled trial failed to show a significant benefit of the tumor necrosis factor inhibitor etanercept with the use of a physician's global assessment scale (Adams, et al., 2010). In a third randomized, controlled trial, the tumor necrosis factor inhibitor adalimumab resulted in significant improvement on the basis of a score that reflected the extent and severity of disease at 6 weeks, but this benefit was not maintained at 12 weeks (the primary outcome of the trial).
In a comparative study, Rappard, et al. (2012) compared the outcomes of the tumor necrosis factors infliximab and adalimumab HS, and found that infliximab was more effective than adalimumab. The authors performed a retrospective study to compare two cohorts of 10 adult patients suffering from severe, recalcitrant HS. Ten patients were treated with intravenous infliximab, and subsequently 10 other patients were treated in the same hospital with subcutaneous adalimumab. Both cohorts were followed up for one year using identical evaluation methods [Sartorius score, quality of life index, reduction of erythrocyte sedimentation rate and C-reactive protein, patient and doctor global assessment, and duration of efficacy]. The authors reported that 19 patients completed the study. In both groups, the severity of the HS diminished. The investigators found that infliximab performed better than adalimumab in all aspects. The average Sartorius score was reduced to 54 percent of baseline for the infliximab group and 66 percent of baseline for the adalimumab group. The authors concluded that subcutaneous adalimumab is less effective than intravenous infliximab.
Shuja et al (2010) noted that there are various treatment options for HS, but none is wholly satisfactory or effective. There have been many reports on the efficacy of biologic drugs for the treatment of HS; this article was an in-depth review of the published evidence on this topic. Because the current evidence is limited, randomized, double-blinded, placebo-controlled trials are needed to better elucidate the future of these drugs for the treatment of HS.
In a retrospective descriptive case series, Eleftheriou and colleagues (2009) reported the safety and effectiveness of biologic therapies in a multi-center series of children with primary systemic vasculitis (PSV). Primary retrospective outcome assessment measures were: daily corticosteroid dose; Birmingham Vasculitis Activity Score (BVAS); and adverse events (including infection rate). A total of 25 patients median age 8.8 (range of 2.4 to 16) years; 11 males with active PSV (n = 6 with anti-neutrophil cytoplasmic antibody associated vasculitides, n = 11 with polyarteritis nodosa, n = 7 with unclassified vasculitis and n = 1 with Behçet's disease) were treated with biologic agents including infliximab (n = 7), rituximab (n = 6), etanercept (n = 4), adalimumab (n = 1) or multiple biologics sequentially (n = 7). Overall, there was a significant reduction in BVAS from a median of 8.5 (range of 5 to 32) at start of therapy to 4 (range of 0 to 19) at median 32 months follow-up (p = 0.003) accompanied by significant reduction in median daily prednisolone requirement from 1 (range of 0.2 to 2) to 0.25 (range of 0 to 1) mg/kg/day, p = 0.000. For those receiving multiple biologic agents sequentially, a similar clinical improvement was observed with corticosteroid sparing. Infections occurred in 24 %, the most severe in those receiving infliximab. The authors concluded that these findings provided retrospective evidence of efficacy of these agents, and high-lighted the associated infectious complications. They stated that further multi-center standardization of treatment protocols and data collection of biologic therapy in systemic vasculitis of the young is needed.
Lateef and Petri (2010) stated that the pathogenesis of systemic lupus erythematosus (SLE) involves aberrations in multiple components of the immune system including B cells, T cells, cytokines and growth factors. Therapeutic agents targeting these mediators selectively have been tested for the treatment of SLE. This review summarized the recent advances in these biological therapies. The 2 large phase II/III randomized placebo-controlled trials of B-cell depletion, using rituximab, in SLE, reported unexpected negative results. On the contrary, 2 large phase III trials of belimumab, the monoclonal antibody against B-lymphocyte stimulator (BLyS), showed significant clinical benefit. Response rates were 57.6 and 43.2 % for 10 mg/kg belimumab, compared with 43.6 and 33.8 % for placebo in BLISS-52 and BLISS-76, respectively. Studies of a co-stimulation blocker (abatacept), TNF inhibitor (infliximab), and interleukin-6 inhibitor (tocilizumab) were either negative (abatacept) or were associated with high rates of adverse events. Studies of T cell and interferon inhibition remain in the early development phase. The authors concluded that despite the enthusiasm in the field of biologic therapies, the majority of these new modalities have fallen short of expectations for various reasons. Only belimumab has recently met its primary outcome in 2 phase III trials.
In a phase III clinical trial, Couriel et al (2009) examined if the addition of infliximab to steroids could improve results for patients with newly diagnosed grade II to IV acute graft-versus-host-disease (aGVHD). A total of 63 patients were randomized either to 2 mg/kg/day methylprednisolone (MP) or infliximab + MP. Average age was 47 years (range of 20 to 70 years); 64 % were male. Fifty-three percent and 51 % of patients received a matched-sibling and/or bone marrow (BM) graft. Sixty-seven percent had grade II, 33 % grade III to IV aGVHD; 62 % had skin, 53 % gastrointestinal (GI), and 7 % had liver involvement. At days 7 and 28, the response rate for infliximab + MP versus MP was 52 % versus 78 %, p = 0.03 and 62 % versus 58 %, p = 0.7, respectively. Cumulative incidences of GVHD-related mortality, non-relapse mortality (NRM), and overall survival (OS) were not significantly different between the 2 groups (GVHD-related mortality: 38 % versus 32 %, p = 0.6; NRM: 52 % versus 36 %, p = 0.3; OS: 17 % and 28 %, p = 0.4 for infliximab + MP versus MP, respectively). Patients with newly diagnosed aGVHD derive no benefit from the addition of anti-TNF-alpha therapy with infliximab when compared to corticosteroids alone.
Pidala et al (2009) examined the effectiveness of infliximab as a salvage therapy for steroid-refractory aGVHD. In a series of 52 patients, 71 % of whom had grade III to IV aGVHD, only 15 % achieved complete remission (CR) with the use of infliximab alone as salvage therapy. Complete remission of aGVHD differed according to overall aGVHD grade at salvage (grade II, 5/15; grade III, 2/17; grade IV, 1/20; p = 0.03). Median OS was only 1.7 months (95 % CI: 0.99 to 2.3 months). Complete remission of aGVHD was significantly associated with OS, with a hazard ratio of 8.4 for death in those without CR (95 % CI: 3.6 to 19.6; p < 0.0001). The authors concluded that this series demonstrated the limited activity of infliximab in patients with high-grade aGVHD. They stated that further work is needed to identify effective therapy for aGVHD.
In a retrospective analysis, Motllo et al (2011) evaluated the activity and toxicity of infliximab in 9 patients with acute or chronic steroid-resistant GVHD. Six patients had acute GVHD and 3 chronic GVHD. The source of progenitors was peripheral blood in all patients except 1. Six received matched-related stem cell transplant and 3 unrelated stem cell transplant. Patients received between 2 and 7 doses of infliximab, and 5 achieved a partial response. All patients presented infections: 4 developed pseudomonas aeruginosa septicemia and 5 probable or confirmed infection by aspergillus fumigatus. The authors concluded that infliximab provides transient response in steroid-resistant GVHD. However, it is associated with a high rate of infections. The authors stated that earlier administration of infliximab should be explored to reduce the frequency of infections.
Rager et al (2011) noted that treatment options for steroid-refractory GVHD are unsatisfactory and prognosis is poor. Inflammatory cytokines IL-2 and TNF-α are important mediators of GVHD and may be critical targets for therapy. These researchers retrospectively reviewed their experience using combination anti-cytokine therapy of daclizumab and infliximab. A total of 17 evaluable patients had a median age of 47 years (range of 35 to 63). The conditioning regimen was myeloablative in 13 and non-myeloablative in 4 cases. Graft-versus-host-disease occurred at a median of 49 days after transplant in 12 patients (range of 21 to 231 days) and at a median of 46 days (range of 25 to 119 days) after donor lymphocyte infusion in 5 patients. All patients had persistent or progressive GVHD despite 1 to 2 mg/kg/day of corticosteroids for a median of 7 days (range of 2 to 26 days). They received a combination of daclizumab and infliximab for acute GVHD Center for International Blood and Marrow Transplant Research (CIBMTR)severity index B (3), C (10) or D (4). Of the 17 patients analyzed, 47 % responded to treatment, 24 % had complete resolution of symptoms and 24 % had partial responses. Survival was limited and all the patients died a median of 6.7 months (range of 1.6 to 26) from transplant and 35 days from initiation of daclizumab/infliximab. The findings of this retrospective analysis suggested that combination anti-cytokine therapy with daclizumab/infliximab has significant activity in steroid-refractory GVHD, but outcomes remain poor. New methods to prevent and treat GVHD are urgently needed. The authors do no recommend combination of daclizumab and infliximab for advanced steroid-refractory GVHD.
Hengstman et al (2008) examined the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis (DM) and polymyositis (PM) . A multi-center, open-label, controlled trial was conducted. Disease activity was assessed using patient's and physician's disease activity assessment, manual muscle testing (MMT), handheld dynamometry, and serum CK. The primary objective was to assess the efficacy using MMT after a period of 26 weeks. The study was terminated prematurely because of a low inclusion rate and a high drop-out rate due to disease progression and the occurrence of an infusion reaction. The few patients who did reach the primary endpoint showed improvement in all aspects studied. The authors concluded that infliximab combined with weekly methotrexate might be safe and well-tolerated in a small subgroup of patients with drug-naive recent-onset myositis. At present, the authors do not advocate the use of this treatment because treatment response can not be predicted beforehand.
Dastmalchi et al (2008) investigated the effect of the TNF blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. A total of 13 patients with refractory PM, DM, or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1alpha, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon gamma (IFNgamma), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analyzed in sera. Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by greater than or equal to 20 % in 3 or more variables of the disease activity core set, 4 were unchanged and 2 worsened greater than or equal to 30 %. No patient improved in muscle strength by manual muscle test. At baseline, 2 completers had signs of muscle inflammation by MRI, and 5 at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. The authors concluded that infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.
Also, an UpToDate review on "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults" (Miller and Rudnicki, 2012) states that "[d]ata related to the efficacy of tumor necrosis factor inhibition in DM and PM are mixed. Only small studies of etanercept and infliximab have been reported, and further studies will be required to further define their role".
Dry eye affects many individuals worldwide. Significant proportion of patients with dry eye has underlying Sjogren's syndrome (SS), a progressive autoimmune condition. Akpek et al (2011) reported treatment options for patients with dry eye secondary to SS. A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by 4 or more review authors. The searches identified 3,559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review. In the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. The review noted that prospective trials using infliximab and etanercept failed to demonstrate any objective improvement in the sicca component of SS syndrome.
In a retrospective case series, Artornsombudh et al (2013) reported the outcomes of infliximab treatment of birdshot retinochoroidopathy (BSRC) refractory to conventional immunomodulatory therapy. A total of 22 BSRC patients (44 eyes) who received infliximab between July 2005 and June 2012 were identified by retrospective chart review. All patients received 4 to 5 mg/kg infliximab at 4- to 8-week intervals. Data regarding patient demographics, use of immunosuppressive drugs, biologic agents, and reason for conventional therapy discontinuation were gathered. Disease activity markers, including signs of ocular inflammation, fluorescein angiography evidence of retinal vasculitis or papillitis, indocyanine green angiography evidence of active choroiditis, electroretinography parameters indicative of stable or worsening of retinal functions, and optical coherence tomography findings indicative of static or worsening macular edema were recorded. Main outcome measures included abolition of all evidence of active inflammation, visual acuity (VA), presence of cystoid macular edema at 6 months and 1 year, and adverse responses to infliximab. Mean duration of disease before starting infliximab was 58.6 months. Before infliximab therapy, all patients received and failed conventional immunosuppressive therapy; 10 patients had received another biologic agent. After initiating infliximab, control of inflammation was achieved in 81.8 % at 6 months and in 88.9 % at the 1-year follow-up. Three patients had active inflammation during therapy. The rate of cystoid macular edema decreased from 22.7 % at baseline to 13.9 % at 6 months and 6.7 % at 1 year after receiving the drug. Initial VA of 20/40 or better was found in 34 eyes (84.1 %). At 6 months and 1 year, 91.7 % and 94.4 % of eyes, respectively, had VA of 20/40 or better. Six patients had adverse events; infliximab therapy was discontinued in these patients because of neuropathy, drug-induced lupus, allergic reaction, or fungal infection. The authors concluded that these data suggested that infliximab is effective for controlling inflammation in otherwise treatment-refractory cases of BSRC. The main drawbacks of this study were its retrospective design, small sample size, and the lack of a control group. The authors stated that further prospective randomized controlled studies in larger populations are needed to ascertain the potential role of infliximab in the treatment of BSRC.
Uhlving et al (2012) stated that bronchiolitis obliterans following allogeneic hematopoietic SCT is a serious complication affecting 1.7 to 26.0 % of the patients, with a reported mortality rate of 21 to 100 %. It is considered a manifestation of chronic graft-versus-host disease, but the knowledge of etiology and pathogenesis is still limited. The authors noted that there is only limited evidence of infliximab on bronchiolitis obliterans (case study and case-series studies).
Mirshahi et al (2012) stated that TNF-α plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. Tumor necrosis factor-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in non-infectious uveitis. Preliminary studies suggested a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intra-vitreal use of TNF-α inhibitors, in particular, intra-ocular inflammatory responses have been reported after intra-vitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g., adalimumab) are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.
An UpToDate review on “Age-related macular degeneration: Treatment and prevention” (Arroyo, 2013) states that “Several investigational clinical trials are underway to evaluate treatment options for dry AMD. Potential new treatments include topical antioxidant eye drops, implantation of encapsulated human NTC cells, and fetal cell transplantation. The first report of transplantation of cells derived from human embryonic stem cells (hESCs) into human beings involved subretinal transplantation of cells differentiated to retinal pigment epithelium in a patient with dry AMD. At four months there was no evidence of rejection, tumorigenicity, or ectopic tissue; there was minimal visual improvement although the patient had advanced disease at baseline. Ongoing trials for patients with neovascular AMD include evaluation of the angiogenesis inhibitor pazopanib given as topical eye drops, subconjunctival injection of an antiproliferative polyamine analog (CGC-11047), and various combination treatment protocols that combine photodynamic therapy with intravitreal anti-VEGF agents. A topical kinase inhibitor with multiple growth factor targets, including VEGF, suppressed choroidal neovascularization in a mouse model. Genetic defects in various loci in the complement factor H gene can be found in over 50 percent of cases of macular degeneration. Gene-environment interactions compound the genetic risk for AMD and have been demonstrated for smokers and for antibodies to C pneumonia. Rapid and affordable genetic screening is being developed commercially, with the intent to identify high risk patients who could modify some risk factors or benefit from targeted therapy. Some genetic mutations associated with AMD are thought to result in increased complement activation and inflammation. The effects of anti-inflammatory drugs or vaccines on the progression of AMD are under investigation. Research trials include study of an intravitreal complement inhibitor (POT-4), vaccination with the immunomodulator copaxone, and treatment with anti-inflammatory agents (infliximab, sirolimus, and daclizumab). Whenever possible, patients should be encouraged to enroll in clinical trials of treatments for AMD”.
Rovensky and Sedlackova (2012) noted that relapsing polychondritis (RP) is an unusually rare disease involving multiple organs. It has an episodic course, occasionally also progressing. Typically, inflammation of cartilaginous tissues and tissues rich in glycosaminoglycans is present. Clinical symptoms are concentrated in auricula, nose, larynx, upper respiratory tract, joints, heart, blood vessels, inner ear, cornea and sclera. Manifestations include: (i) chondritis of auricular, nasal, laryngo-tracheal, costal and joint cartilages, (ii) inflammation of the eyes and inner ear, (iii) collapse of laryngo-tracheal structures and structures in the subglottic area resulting in increased susceptibility to upper respiratory tract infections, and (iv) diversity of clinical manifestations, of the disease course and also of the treatment response. Concurrent systemic vasculitis or glomerulonephritis may contribute to higher morbidity and premature mortality. In about 30 % of cases the RP is secondary, accompanied by other systemic connective tissue disorders as RA, SLE, Sjogren's syndrome, thyroiditis, ulcerative colitis, psoriasis and Behcet's syndrome. Diagnosis is based on 1986 diagnostic criteria from Minnesota and RP has to be suspected when the inflammatory bouts involve at least 2 of the typical sites -- auricular, nasal, laryngo-tracheal or 1 of the typical sites and 2 other -- ocular, stato-acoustic disturbances (hearing loss and/or vertigo) and arthritis. Conventional treatments entail corticoids and non-steroidal anti-inflammatory drugs, corticoids combined with immunosuppressive therapy (cyclophosphamide, azathioprine, chlorambucil, cyclosporine). More recently, also biologic therapy is used in RP (infliximab, adalimumab, etanercept, tocilizumab, rituximab). It is necessary to underscore that biologic therapy for RP is only a research modality used in very severe refractory forms of RP. Preliminary results suggested that biologic therapy will have its place in severe refractory relapsing forms of RP.
Also, an UpToDate review on "Treatment of relapsing polychondritis" (Michet, 2013) states that "[t]he major second-line drugs in RPC include cyclophosphamide, azathioprine, cyclosporine, pulse methylprednisolone, methotrexate, and other newer therapies. Response to antiinflammatory/immunomodulatory compounds with potential efficacy, such as leflunomide, soluble tumor necrosis factor alpha receptor (etanercept) or anti-tumor necrosis factor antibody (infliximab, adalimumab), and anti-interleukin 1 receptor (anakinra), have been largely limited to individual case reports .... Successful treatments with infliximab (5 mg/kg by intravenous infusion at two, four, then eight-week intervals) and etanercept (50 mg weekly) have been reported. Potential efficacy has been shown in refractory RPC associated laryngo-tracheal disease, necrotizing vasculitis, episcleritis/scleritis, aortic valve disease, synovitis, and auricular and nasal cartilage inflammation. These promising uncontrolled results warrant further investigation to assess the role of anti-TNF alpha therapies".
An UpToDate review on "Cerebral amyloid angiopathy" (Greenberg, 2013) does not mention infliximab as a therapeutic option.
UpToDate reviews on “Treatment of idiopathic membranous nephropathy” (Cattran, 2013) and “Alternative agents in the treatment of idiopathic membranous nephropathy” (Wetzels and Apppel, 2013) do not mention the use of infliximab as a therapeutic option.
An UpToDate review on "Tubulointerstitial nephritis and uveitis (TINU syndrome)" (Lee and Ashfaq, 2013) does not mention the use of infliximab as a therapeutic option.
Cordero-Coma et al (2013) established evidence-based recommendations regarding the use TNF-α agents for managing uveitis patients. Medline was searched via OVID (1950 - October Week 3, 2011) using a Cochrane highly sensitive search (phases 1 and 2). Additional literature searches were also conducted including the following databases: the Cochrane, LILACS and the TRIP Database. A total of 54 studies met all of the inclusion criteria and were included in this review. A different level of recommendation and evidence is assigned to each anti-TNF-α agent. The overall rate of reported side effects with anti-TNF-α agents for the treatment of uveitis that required discontinuation of therapy was 2.2 % (26/1,147 patients). The authors concluded that based on the evidence gathered, infliximab and adalimumab seem to be effective in the management of immune-mediated uveitis. Moreover, they stated that further randomized studies evaluating the efficacy of these agents are warranted. It is the most common cause of inflammatory eye disease, with an estimated prevalence of 115 cases per 100,000 persons. Endogenous or associated with a systemic disease, non-infectious uveitis accounts for approximately 75 % of total cases comprising of a heterogeneous group of inflammatory conditions responsible for about 10 % of legal blindness in developed nations. Endogenous uveitides are thought to have an autoimmune component mediated by T lymphocytes specific to intraocular antigens that have failed to successfully pass basic processes designed to maintain self-tolerance.
Also, an UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2013) states that “The role of tumor necrosis factor-alpha (TNF) inhibitors such as infliximab, adalimumab, or etanercept in the management of patients with uveitis is uncertain. Further data from controlled trials are needed to clarify the indications and risks of TNF inhibition in the treatment of ocular inflammatory disease”.
The Anser IFX (Prometheus, Inc., San Diego, CA) is a test that simultaneously measure and monitor serum infliximab and antibodies to infliximab concentrations to clarify factors that may be contributing to a patient's loss of response and help guide treatment decisions. However, there is a lack of evidence regarding the clinical value of this test.
Lee and colleagues (2012) stated that IFX is a chimeric monoclonal antibody directed against TNF-alpha. When used in IBD, primary non-response is found in at least 10 % of patients, with secondary loss of response occurring in a further 10 to 15 % per year. It has been suggested that this may in part be a result of the development of anti-IFX antibodies (ATIs). These researchers determined in patients receiving IFX the prevalence of ATIs, the effect of immunosuppressants on the prevalence of ATI, the effect of ATIs on the prevalence of infusion reactions and the effect of ATIs on the rates of remission. MEDLINE and EMBASE databases were searched from 1948 and 1980, respectively, to October 2011. A total of 18 studies involving 3,326 patients were included. The prevalence of ATIs was 45.8 % when episodic infusions of IFX were given and 12.4 % when maintenance IFX was given. The rates of infusion reactions were significantly higher in patients with ATIs (relative risk: 2.07; 95 % CI: 1.61 to 2.67). Immunosuppressants resulted in a 50 % reduction in the risk of developing ATIs (p < 0.00001). However, the presence or absence of ATIs did not affect the rates of clinical remission. The prevalence of ATIs depends on the regimen of IFX administration and the use of immunosuppressants. Patients who tested positive for ATIs were at an increased risk of infusion reactions, but had similar rates of remission compared with patients who tested negative for ATIs. The authors noted that further analysis is needed to determine whether loss of response is dependent on the titer of ATIs.
Steenholdt (2013) examined the clinical utility of measuring IFX and anti-IFX Ab by novel radioimmunoassay (RIA) techniques. Specifically, the aim was to investigate if these measurements could aid in evaluating and optimizing safety and effectiveness of IFX therapy in patients with Crohn's disease. An experimental study for comparison of analytical properties of assays for measuring IFX and anti-IFX Ab was applied. In addition, 3 observational, retrospective, single-center cohort studies of all patients with Crohn's disease treated with IFX were carried out. Serum levels of IFX and anti-IFX Ab measured by RIA strongly associated with clinical response types to IFX maintenance therapy. Cut-off values providing optimal discrimination of patients with loss of response or maintained remission were established. An algorithm for evaluating and optimizing therapy in individual patients with loss of treatment response based on IFX and anti-IFX Ab levels was proposed. Acute severe infusion reactions appeared not to be true IgE-mediated anaphylactic reactions, but rather associated with development of anti-IFX IgG Ab. Risk was increased during episodic therapy, but absence of anti-IFX Ab prior to a re-initiation series did not exclude reactions and assessments hereof could not be used for risk stratification. Several factors may potentially interfere with associations of IFX and anti-IFX Ab with clinical outcome including use of different analytical techniques, different cut-off values for reporting of positive test results, differences in timing of measurements, and transiency of anti-IFX Ab. The author concluded that monitoring serum levels of IFX and anti-IFX Ab by novel RIA techniques appears promising for evaluating and optimizing the safety and effectiveness of IFX therapy in Crohn's disease. Moreover, the author noted that previous conflicting reports on the importance of tests are potentially biased by use of different types of assays, different cut-off values for binary classification of test results, and inconsistent timing of measurements; prospective validation of proposed treatment algorithms in larger cohorts is needed.
Hernandez et al (2014) determined the sensitivity and specificity of an available commercial ELISA assay; considering cut-off of DAS28 for IFX levels and HACA in RA patients. These researchers assessed 60 serum samples from patients diagnosed with RA treated with IFX (1st line of biological treatment) taken prior to infusion. Patients were classified as responders, based on low disease activity (DAS28 less than 3.2; greater than 6 months) or non-responders, based on DAS28greater than 3.2 with more than 1 swollen joint and/or elevated CRP/ESR. Infliximab levels and anti-IFX HACA were measured using a commercial ELISA kit (Progenika™) following manufacturer's recommendations. The sample size was previously calculated to ensure a sensitivity of 0.8 and specificity of 0.6, with a CI of 95 %, related to the clinical activity index DAS28. Statistical analysis to establish the appropriate values for the cut-off was performed using median (percentiles 25 to 75), U test Mann-Whitney and ROC curves (Receiver operating characteristic). Median IFX levels in non-responder RA patients (n = 24) was lower compared with responder patients (n = 36). These investigators identified the optimal cut-off with ROC analysis for DAS28 less than 5.1 and IFX levels less than 0.046 ug/ml, with a sensitivity and specificity of 100 % and 79 %, respectively. Receiver operating characteristic analysis could not be calculated because of the low percentages of positivity for anti-IFX HACA in the selected patient group (n = 8/60, 13.33 %). The authors concluded that the cut-off values for IFX levels, rather than anti-IFX HACA determination, may be useful in evaluating clinical response measured by DAS28 in RA. However, they stated that there is a priority in standardizing laboratory techniques (variability inter-/intra-assay and inter-/intra-laboratory) to validate this information and its possible clinical application.
Also, an UpToDate review on “Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases” (Stone, 2014) states that “The development of HACA has potentially important clinical effects. However, the full clinical impact of HACA is not clear. Solid data have linked HACA to the development of infusion reactions, but it is less clear that HACA is responsible for the blunting of clinical responses to infliximab that occur with regular administration over time. In addition, testing for HACA is not widely available, and there is no consensus about the optimal use of such assays. More than half of patients with RA receiving infliximab require increases in their regular dose over time or shortening of the interval at which the medication is administered. Although this “dose creep” may be related to the formation of HACA, there is no evidence to confirm this theory. An alternative theory is that the need to increase infliximab doses over time simply reflects underdosing at the start of therapy. Thus, some patients with RA or Crohn’s disease may benefit from infliximab given at doses higher than the recommended 3 mg/kg or more frequently than every eight weeks. The usual approach to lessening clinical efficacy of infliximab is either to increase the dose or to increase the frequency with which the medication is administered”.
In a retrospective, interventional, non-comparative cohort study, Kruh and colleagues (2014) examined the safety and effectiveness of IFX for the treatment of refractory non-infectious uveitis. A total of 88 patients from a single-center private practice were included in this study. Patients with chronic, recalcitrant uveitis treated with IFX were identified through an electronic medical record database. All charts were reviewed for sex, diagnosis, location of inflammation, presence of vasculitis, prior immunomodulatory treatments, duration of IFX treatment, dose received, secondary side effects, and other medications continued while receiving treatment with IFX. The primary outcome measures were the rate of remission, time to remission, relapse rate, failure rate, and patient tolerance. Additional analysis aimed to identity risk factors that would predict a higher success rate of IFX to treat various types of non-infectious uveitis. Of the 72 patients (81.8 %) who achieved clinical remission while being treated with IFX, 42 (58.3 %) required additional immunomodulatory medications. At 7, 18.1, and 44.7 weeks, 25 %, 50 %, and 75 % of patients, respectively, achieved clinical remission off all corticosteroids. Moreover, 32 patients (36.4 %) experienced at least 1 side effect while on IFX therapy, and 17 patients (19.3 %) discontinued treatment secondary to 1 or more intolerable side effects. The most common adverse effects were skin rash (9.1 %) and fatigue (8 %). Factors associated with a higher chance to achieve clinical remission were non-idiopathic uveitis (p < 0.001), intermediate or panuveitis (p < 0.001), absence of vasculitis (p < 0.001), and a starting dose greater than or equal to 5 mg/kg (p < 0.011). The authors concluded that IFX induces a high rate of complete clinical remission in recalcitrant uveitis and is well-tolerated by most patients. Moreover, they stated that "Although our study is limited by the follow-up period and the retrospective design without a control group, we have shown that our infliximab protocol is highly effective in inducing clinical remission in refractory uveitis, with a relatively low rate of treatment-ending adverse events. Few patients achieved durable remission off infliximab during our follow-up period, but extended maintenance therapy may well be a necessary component in the treatment of recalcitrant uveitis. Continued follow-up of our cohort will be required to fully determine the long-term effects of infliximab, and our results will need to be confirmed by a larger multicenter study".
Cooper and associates (2014) noted that serum TNF-alpha levels correlate negatively with hepatitis C virus (HCV) anti-viral response. In a phase IIIB, randomized, prospective, open-label pilot trial conducted at 8 Canadian sites, these researchers tested the hypothesis that a single IFX induction dose would positively influence on-treatment virological response and sustained virological response (SVR). Treatment-naive HCV genotype 1-infected patients 18 to 65 years of age with high serum TNF-alpha values (greater than 300 pg⁄ml) were randomly assigned to receive a single pre-treatment induction IFX infusion (5 mg⁄kg) 7 days before anti-viral therapy (arm A) or no pre-treatment (arm B). All patients received pegylated interferon alpha 2b (1.5 μg⁄kg⁄week) plus weight-based ribavirin (800 mg⁄day to 1,400 mg⁄day) for up to 48 weeks. A total of 85 patients (arm A [n = 41], arm B [n = 44]; 70 % male) received pegylated interferon alpha 2b. The mean age (48.1 years), race (81 % white) and METAVIR fibrosis stage (F0-2 = 79 %, F3-4 = 21 %) were similar between groups. Infliximab was well-tolerated without attributable severe adverse events; 56.5 % completed the study (arm A [n = 21], arm B [n = 27]). Most discontinuations were due to virological failure at weeks 12 (n = 20 [23.5 %]) and 24 (n = 7 [8.2 %]) and did not differ according to group. Numerically lower proportions of IFX recipients achieved rapid virological response (19.5 % versus 36.4 %), complete early virological response (43.9 % versus 59.1 %) and SVR (34.1 % versus 52.3 %). However, between-group differences did not reach statistical significance. No differences in adverse event profile or laboratory measures were noted. The authors concluded that a single IFX dose before pegylated-interferon alpha 2b and ribavirin therapy did not result in greater viral decline during the first 12 weeks of HCV therapy or improved SVR.
An UpToDate review on “Treatment of scleritis” (Stone and Dana, 2014) states that “Case reports and small, uncontrolled case series suggest that the tumor necrosis factor (TNF) alpha inhibitor infliximab may be partially effective in the treatment of scleritis that is resistant to treatment with other agents. Doses in the range of 3 to 5 mg/kg administered every four to eight weeks have been employed for this purpose. Additional investigation of infliximab for this indication is required”.
Microscopic colitis may be defined as a clinical syndrome, of unknown etiology, consisting of chronic watery diarrhea, with no alterations in the large bowel at the endoscopic and radiologic evaluation (Ianiro, et al., 2012). Therefore, a definitive diagnosis is only possible by histological analysis. Microscopic colitis includes two histological subtypes [collagenous colitis (CC) and lymphocytic colitis (LC)] with no differences in clinical presentation and management. Collagenous colitis is characterized by a thickening of the subepithelial collagen layer that is absent in LC. The main feature of LC is an increase of the density of intra-epithelial lymphocytes in the surface epithelium. Microscopic colitis typically presents as chronic or intermittent watery diarrhea, that may be accompanied by symptoms such as abdominal pain, weight loss and incontinence.
Evidence supporting the use of infliximab for microscopic colitis is limited to case reports and small case series (Pola, et al., 2013; Esteve, et al., 2011). In a review on the management of microscopic colitis, Ianiro, et al. (2012) concluded that the use of anti-tumor necrosis factor-α agents, infliximab and adalimumab, constitutes a new, interesting tool for the treatment of microscopic colitis, but larger, adequately designed studies are needed to confirm existing data.
Table 1: Infliximab Dosing
Induction: 5 mg/kg IV at weeks 0, 2, and 6
Maintenance: 5 mg/kg IV every 6 weeks
Crohn's disease, fistulizing
Induction: 5 mg/kg IV at weeks 0, 2, and 6
Maintenance: 5 mg/kg IV every 8 weeks
For persons who respond and then lose their response, consideration may be given to treatment with 10 mg/kg IV every 8 weeks.
Crohn's disease, moderate-to-severe
Induction: 5 mg/kg IV at weeks 0, 2, and 6
Maintenance: 5 mg/kg IV every 8 weeks
For persons who respond and then lose their response, consideration may be given to treatment with 10 mg/kg IV every 8 weeks.
Plaque psoriasis, chronic (severe)
Induction: 5 mg/kg IV at weeks 0, 2, and 6
Maintenance: 5 mg/kg IV every 8 weeks
Psoriasis with arthropathy
Induction: 5 mg/kg at weeks 0, 2, and 6
Maintenance: 5 mg/kg IV every 8 weeks
Rheumatoid arthritis, moderate-to-severe
Induction: 3 mg/kg IV at weeks 0, 2 and 6
Maintenance: 3 mg/kg IV every 8 weeks
Incomplete response: 10 mg/kg IV every 8 weeks; or 3 mg/kg IV every 4 weeks
Induction: 5 mg/kg IV at weeks 0, 2 and 6
Maintenance: 5 mg/kg IV every 8 weeks
Pediatric Crohn's disease
Induction: 5 mg/kg IV at weeks 0, 2 and 6
Maintenance: 5 mg/kg IV every 8 weeks
Pediatric ulcerative colitis
Induction: 5 mg/kg IV at weeks 0, 2 and 6
Maintenance: 5 mg/kg IV every 8 weeks
Chronic pulmonary sarcoidosis
Induction: 3 mg/kg IV at weeks 0, 2, and 6
Maintenance: 3 mg/kg IV every 6 weeks
5 mg/kg IV every 6 to 8 weeks
Sources: Remicade prescribing information; Baughman et al (2006); Brooklyn et al (2006).
Table 2: Grading of Severity of Rheumatoid Arthritis
Joint pain Inflammation of at least 3 joints No inflammation in tissues other than the joints Usually, a negative result on a rheumatoid factor test An elevated erythrocyte sedimentation rate (ESR) or C reactive protein (CRP) level No evidence of bone or cartilage damage on x-rays
Between 6 and 20 inflamed joints Usually no inflammation in tissues other than the joints An elevated ESR or CRP levels A positive rheumatoid factor test or anti-cyclic citrullinated peptide (anti-CCP) antibodies Evidence of inflammation but no evidence of bone damage on x-rays
More than 20 persistently inflamed joints or a rapid loss of functional abilities Elevated ESR or CRP levels Anemia related to chronic illness Low blood albumin level A positive rheumatoid factor test, often with a high level Evidence of bone and cartilage damage on x-ray Inflammation in tissues other than joints
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes not covered for indications listed in the CPB:
Other CPT codes related to the CPB:
96910 - 96913
96360 - 96361
96365 - 96368
99601 - 99602
HCPCS codes covered if selection criteria are met:
Injection, infliximab, 10 mg
Home infusion therapy, anti-tumor necrosis factor intravenous therapy; (e.g., Infliximab); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
Other HCPCS codes related to the CPB (examples of other drug therapies):
Injection, abatacept, 10 mg (code may be used for medicare when drug administered under the direct supervision of a physician, not for use when drug is self administered)
Injection, adalimumab, 20 mg
Injection, methylprednisolone acetate, 20 mg
Injection, methylprednisolone acetate, 40 mg
Injection, methylprednisolone acetate, 80 mg
Injection, dexamethasone acetate, 1 mg
Injection, etanercept, 25 mg
Injection, gold sodium thiomalate, up to 50 mg
Injection, methylprednisolone sodium succinate, up to 40 mg [Solu-Medrol]
Injection, methylprednisolone sodium succinate, up to 125 mg [Solu-Medrol]
Azathioprine, oral, 50 mg
Azathioprine, parenteral, 100 mg
Cyclosporine, oral, 100 mg
Prednisone, oral, per 5 mg
Methylprednisolone, oral, per 4 mg
Prednisolone, oral, per 5 mg
Cyclosporine, oral, 25 mg
Cyclosporine, parenteral, 250 mg
Cyclophosphamide, oral, 25 mg
Dexamethasone, oral, 0. 25 mg
Methotrexate, oral, 2.5 mg
Cyclophosphamide, 100 mg
Methotrexate sodium, 5 mg
Methotrexate sodium, 50 mg
Mercaptopurine, oral, 50 mg
Home infusion therapy, immunotherapy, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem
ICD-9 codes covered if selection criteria are met:
Other chronic bronchitis [bronchiolitis obliterans]
493.00 - 493.92
Chronic airway obstruction, not elsewhere classified
Other and unspecified noninfectious gastroenteritis and colitis [microscopic colitis]
Sclerosing mesenteritis [mesenteric panniculitis]
Nephrotic syndrome with lesion of membranous glomerulonephritis [membranous glomerulopathy]
Nephrotic syndrome with lesion of membranoproliferative glomerulonephritis [membranous glomerulopathy]
Chronic glomerulonephritis with lesion of membranous glomerulonephritis [membranous glomerulopathy]
Chronic glomerulonephritis with lesion of membranoproliferative glomerulonephritis [membranous glomerulopathy]
Nephritis and nephropathy, not specified as acute or chronic, with lesion of membranous glomerulonephritis [membranous glomerulopathy]
Nephritis and nephropathy, not specified as acute or chronic, lesion of membranoproliferative glomerulonephritis [membranous glomerulopathy]
Nephritis and nephropathy, not specified as acute or chronic, lesion of membranoproliferative glomerulonephritis [membranous glomerulopathy]
Inflammatory disease of breast [granulomatous mastitis]
Lupus erythematosus [discoid]
Other specified erythematous conditions [granuloma annulare]
Circumscribed scleroderma [scleroderma, circumscribed or localized]
Systemic sclerosis [scleroderma]
Sicca syndrome (Sjogren's syndrome)
Displacement of lumbar intervertebral disc without myelopathy [disc-herniation-induced sciatica]
Panniculitis specified as affecting neck
Other symptoms referable to back [panniculitis affecting the back]
Other disorders of muscle, ligament, and fascia [eosinophilic fasciitis]
729.30 - 729.39
730.00 - 730.99
Other disorders of bone and cartilage [relapsing polychondritis]
Complications of transplanted intestine [rejection]
The above policy is based on the following references:
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