| Medical Policy |
| Subject: | Tumor Necrosis Factor Antagonists | ||
| Policy #: | DRUG.00002 | Current Effective Date: | 11/21/2011 |
| Status: | Revised | Last Review Date: | 11/17/2011 |
| Description/Scope |
Tumor necrosis factor alpha (TNFα) is a naturally occurring cytokine that is involved in a variety of inflammatory and immune responses. This document addresses the indications for a class of biologic disease-modifying antirheumatic drugs (DMARDs) known as tumor necrosis factor (TNF) antagonists (inhibitors), that target specific pathways of the immune system and either enhance or inhibit immune response.
The U.S. Food and Drug Administration (FDA) has approved the following TNF antagonists for use in specific indications:
Note: Please see the following documents for information concerning other drugs that may be used for the treatment of either moderate to severe plaque psoriasis, moderately to severely active rheumatoid arthritis, or moderately to severely active polyarticular or systemic juvenile idiopathic arthritis:
| Position Statement |
I. Infliximab
Medically Necessary:
Infliximab is considered medically necessary when criteria are met for any of the following indications:
Not Medically Necessary:
Infliximab is considered not medically necessary for an individual with any of the following:
Note: The clinician should consider the status of an individual with moderate or severe heart failure - New York Heart Association (NYHA) Functional Class III-IV before initiating treatment with infliximab at doses greater than 5mg/kg.
Investigational and Not Medically Necessary:
Infliximab is considered investigational and not medically necessary for all other indications, including, but not limited to treatment of asthma, Behcet's syndrome, chronic obstructive pulmonary disease, disc-herniation-induced sciatica, hairy cell leukemia, graft-versus-host disease (GVHD), hidradenitis suppurativa (HS), juvenile idiopathic arthritis, sarcoidosis, Still's disease, Sjögren's syndrome, Takayasu arteritis, uveitis, and Wegener's granulomatosis.
II. Etanercept
Medically Necessary:
Etanercept is considered medically necessary when criteria are met for any of the following indications:
Not Medically Necessary:
Etanercept is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Etanercept is considered investigational and not medically necessary for all other indications, including, but not limited to treatment of asthma, disc-herniation-induced radiculopathy or sciatica, GVHD, inclusion-body myositis, inflammatory bowel disease, HS, sarcoidosis, septic shock, Sjögren's syndrome, and Wegener's granulomatosis.
III. Adalimumab
Medically Necessary:
Adalimumab is considered medically necessary when criteria are met for any of the following indications:
Not Medically Necessary:
Adalimumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Adalimumab is considered investigational and not medically necessary for all other indications, including, but not limited to the treatment of hidradenitis suppurativa.
IV. Certolizumab pegol
Medically Necessary:
Certolizumab pegol is considered medically necessary when criteria are met for either of the following indications:
Not Medically Necessary:
Certolizumab pegol is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Certolizumab pegol is considered investigational and not medically necessary for all other indications.
V. Golimumab
Medically Necessary:
Golimumab is considered medically necessary for individuals when criteria are met for any of the following indications:
Not Medically Necessary:
Golimumab is considered not medically necessary for an individual with any of the following:
Golimumab is considered investigational and not medically necessary for all other indications.
| Rationale |
Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab) belong to a class of drugs known as tumor necrosis factor (TNF or TNF-α) antagonists (e.g. inhibitors). TNF antagonists are designed to neutralize inflammatory cytokines that mediate joint damage and destruction due to its activities on many cells in the joints as well as effects on other organs and body systems. TNF antagonists are biologic DMARDs approved by the U.S. Food and Drug Administration (FDA) for use in specific indications. These indications, along with the clinical study data, are included on the current FDA-approved product information label for each agent. There is currently no evidence available in the peer-reviewed literature to support the use of one of these TNF agents (adalimumab, etanercept, golimumab, or infliximab) over the other for the specific indications of ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis. In addition, this applies to the use of certolizumab pegol over the other TNF products for the specific indication of rheumatoid arthritis. Current evidence indicates in adults with RA, use of methotrexate plus a TNF antagonist as combination therapy, is more efficacious than monotherapy with any of the TNF antagonists. Remicade and Simponi are only approved by the FDA when given in combination with methotrexate in adult RA.
Infliximab (Remicade)
Remicade has been approved by the FDA for the treatment of adults with moderately to severely active RA (in combination with methotrexate) (Lipsky, 2000; Maini, 1999), active AS (van der Heijde, 2005), active PsA (Antoni, 2005; Kavanaugh, 2006), chronic moderate to severe plaque psoriasis (Gottlieb, 2004; Reich, 2005), UC (Rutgeerts, 2005), and adult and pediatric CD and fistulizing CD (Baldassano, 2003; Borrelli, 2004; de Ridder, 2004; Hanauer, 2002; Kugathasan, 2000; Sands, 2004).
On September 23, 2011 the FDA approved infliximab to treat moderately to severely active UC in children older than six years of age who have had inadequate response to conventional therapy. The safety and efficacy of infliximab was supported by a multi-center, randomized, open-label study (Study C0168T72) in 60 children ages 6 years to 17 years with moderately to severely active UC. Subjects had to be receiving or have failed to respond to 5-ASA compounds, immunomodulators, or oral or intravenous corticosteroids at screening. Infliximab was administered at 5 mg/kg at Weeks 0, 2, and 6 and then every 8 (q8wk) or 12 (q12wk) weeks. Infliximab induced clinical response at Week 8 in 73.3% (44/60) of the children with UC. At Week 8, 45 subjects were randomized as responders (22 and 23 in the q8wk and q12wk maintenance treatment groups, respectively) and the remaining 15 discontinued the study agent. Of the 45 randomized subjects, 23 increased their dose or dosing frequency (i.e., stepped-up); more subjects stepped up in the q12wk group than in the q8wk group (60.9% vs. 40.9%). The results demonstrated that the q8w maintenance treatment regimen was more effective than the q12w maintenance treatment regimen in maintaining remission at Week 54. A substantial reduction in median corticosteroid use by Week 8 was maintained through Week 54 in the q8w maintenance treatment group, with 38.5% of subjects in remission and off steroids at Week 54. Infliximab was generally well tolerated in this population, with a safety profile consistent with that reported in other studies of infliximab. There were no reports of deaths, malignancies, opportunistic infections, serious neurologic events, or TB and the safety profiles observed in the q8w and q12w maintenance treatment groups were similar.
Off-Label and Other Proposed Indications
Pediatric Crohn's Disease
The majority of children and adolescents with refractory CD appear to respond to infliximab therapy, whether the drug is used to treat inflammatory or fistulizing disease. The limiting factors appear similar to the adult experience: lack of a maintained response, potential allergic reaction, and the fact that long-term side effects (if any) from this drug have not yet been established. The FDA has mandated that the safety and effectiveness of infliximab and other TNF-α agents be monitored in children and adolescents (CCFA, 2009; FDA, June 2008). Hyams and colleagues (2007) performed the first pediatric trial (REACH trial) aimed at evaluating the efficacy of infliximab as maintenance therapy in children (n=112) with moderate to severe CD. In this multicenter, randomized, open-label cohort study, the use of infliximab as scheduled maintenance therapy was compared to two different schedules: repeat infliximab infusions of 5 mg/kg at two versus three-month intervals. At the endpoint visit of 54 weeks, 29 of 52 subjects (56%) of the two-month (8 weeks) interval group were in clinical remission compared to 12 of 51 children (23.5%) in the three-month (12 weeks) interval group. The results of this study were the basis for the FDA approval of infliximab for pediatric CD. In the crossover arm of this study, children who lost clinical response to infliximab were eligible to receive treatment more frequently, at higher doses, or both. Of the 32 of 35 evaluable children who crossed over to the higher dose of 10 mg/kg every 8 weeks, 24 (75%) regained response after crossing over, including five of nine children (55.6%) who initially received infliximab 5 mg/kg every eight weeks and subsequently crossed over to infliximab 10 mg/kg every eight weeks, and 19 of 23 children (82.6%) who initially received infliximab 5 mg/kg every 12 weeks and subsequently crossed over to receive either infliximab 10 mg/kg (12/13, 92.3%) or 5 mg/kg (7/10, 70.0%) every eight weeks. However, the small number of subjects in the crossover arm of the study was not sufficiently powered to allow FDA approval of dose escalation for children with CD who initially responded but lost clinical response to infliximab (Hyams, 2007).
A subsequent prospective, multicenter, inception cohort study assessed the long-term outcome of infliximab maintenance therapy in a subgroup of children with CD enrolled in the Pediatric Inflammatory Bowel Disease Registry (Hyams, 2009). Children eligible to participate were under the age of 16 and newly diagnosed with IBD at a pediatric gastroenterology center in the U.S. and Canada collectively (n=21). During the entire first, second, and third years of maintenance therapy, 64% (78/121), 70% (50/71), and 83% (30/36), respectively, achieved sustained clinical response; sustained remission was achieved in 26%, 44%, and 33%, respectively. These findings, however, should be considered in the context of the following limitations. This study was observational and not a formal clinical trial. Dose escalation or decreased dosing intervals at any time during follow-up were required in 63 of 128 (49%) of children in the outcome cohort. Sixty-five percent of these children had their dose increased from 5 mg/kg to 10 mg/kg and the remainder had their interval reduced from every eight weeks to at least every six weeks. Fifteen of these 63 children (24%) eventually required both a dose increase and interval decrease during follow-up. It was noted that the occurrence of adverse events was not related to dose escalation.
Given the aggressive nature of pediatric onset CD, individualized treatment takes numerous factors into account: the specific disease manifestations such as location of inflammation in the intestines, duration, and prior response to therapy, and the child's age and weight. Because the incidence of pediatric onset CD is increasing and recent reports confirm that the disease has a more aggressive presentation and poorer prognosis than adult onset CD (Van Limbergen, 2008), pediatric gastroenterologists recognize the importance of achieving a sustained remission in these children to prevent rapid progression from uncomplicated to complicated CD. An additional benefit of the use of infliximab has been demonstrated on pediatric growth failure which affects 15% to 40% of children presenting with CD (Newby, 2005). Despite the suggestion that longitudinal observational studies beyond three years in larger sample populations of children with CD are necessary to determine the long-term safety of infliximab therapy (Hyams, 2009), pediatric gastroenterologists agree that the benefits of a sustained clinical response and remission outweigh the risks associated with the use of infliximab, and, that there does not appear to be an increased risk of adverse events associated with dose escalation. Therefore, if the child with CD responds and then loses response, consideration may be given to increase infliximab dosing to 10 mg/kg or increase the frequency of administration from every eight weeks to every six weeks thereafter. This dose escalation of infliximab for children with CD from 5 mg/kg to 10 mg/kg, and the frequency of administration at every six weeks are more frequent than the current FDA label indication of every eight weeks.
Behcet's Syndrome
The American Hospital Formulary Service® (AHFS®, 2011) notes that infliximab has been used in a limited number of individuals with Behcet's syndrome; however, further study is needed to evaluate the safety and efficacy of the drug in this disease. The peer-reviewed literature consists of case series and case reports that suggest improvement in orogenital ulceration, skin lesions, ocular, and neurological symptoms with the use of infliximab in treatment-resistant Behcet's disease. In addition, infliximab has been used in combination with prednisone, methotrexate, or azathioprine in a number of small, open-label prospective and retrospective studies of subjects with sight-threatening, relapsing uveitis in Behcet's disease, refractory to immunosuppressive regimens (Niccoli, 2007; Tognon, 2007; Tugal-Tutkun, 2005). In these studies, the investigators report a lack of serious adverse events and suggest that infliximab was effective in suppressing the occurrence of uveitis attacks during the treatment period, had a corticosteroid-sparing effect, and favorable implications for the visual prognosis of subjects with resistant Behcet's uveitis. However, ocular and systemic manifestations tended to recur after infliximab withdrawal or when the interval between infliximab courses was longer than eight weeks (Tognon, 2007). In a prospective, open-label phase II clinical trial (n=23) to assess the effectiveness of infliximab in treating refractory autoimmune uveitis, Suhler and colleagues (2005) suggested that infliximab was an effective short-term immunosuppressive agent in most of the subjects, with 18 of 23 meeting criteria for clinical success at week ten and in subjects (7 of 14) able to complete 50 weeks of therapy. Although some subjects achieved benefit, the rate of serious adverse events was unexpectedly high (n=7), including thromboses (n=3), malignancy (n=1), new onset CHF (n=1), and drug-induced lupus (n=2). The investigators concluded that further long-term studies were warranted to determine the safety and efficacy of infliximab in treating intraocular inflammation.
In a phase II, non-randomized, uncontrolled, prospective clinical trial, Suhler and colleagues (2009) reported on the two-year follow-up data of individuals from the one-year follow-up of the trial published in 2005. Of subjects who received at least three injections, 75 % also developed elevated antinuclear antibody (ANA) titers, although the significance of this is unknown. Longer-term follow-up data were also collected for subjects who continued with infliximab therapy after study completion. Of these 31 subjects, approximately 75 % had an initial favorable response, and the drug was effective in select subjects for two to four years. Three subjects developed a drug-related lupus-like illness. Two developed fatal solid malignancies, which the authors considered as having an unclear relationship to the drug. There were no further cases of CHF or venous thrombosis. However, subjects were lost to follow-up including two who completed the one-year protocol and two of seven who completed the two-year protocol. The authors concluded that the risk of long-term adverse effects may be even higher than reported in this article.
Further trials are required in the form of randomized, double-blind, controlled studies with long-term follow-up to evaluate the safety and efficacy of infliximab in individuals with Behcet's syndrome and its complications, Behcet's-related uveitis, and autoimmune uveitis/intraocular inflammation.
Juvenile Idiopathic Arthritis and JIA-associated Uveitis
Although infliximab has been used with some success in a limited number of adults and children with juvenile idiopathic arthritis (JIA), the safety and efficacy has not been established for this usage (AHFS, 2011). A multicenter, randomized, double-blind, placebo-controlled study (n=117), failed to establish the efficacy of infliximab in children with JIA; the study yielded high placebo response rates and a higher rate of immunogenicity compared to that observed in adults. Although the study did not demonstrate a statistically significant difference between infliximab and placebo (p=0.12), it appears that this was in part due to the low dosing of infliximab (3 mg/kg) and the exclusion of 45 children from the efficacy analysis. This high withdrawal rate, due to data collection irregularities at one investigator site, may have resulted in a loss of the ability to detect the difference in efficacy of infliximab between the groups (Ruperto, 2007; Remicade Product Information, 2011). In an open-label extension (weeks 52-204) study, 78 of 122 (64%) of children received infliximab 3-6 mg/kg every eight weeks plus methotrexate. Forty-two of the children discontinued infliximab, most commonly due to consent withdrawal (n=11), lack of efficacy (n=8) or subject/physician/sponsor requirement (n=8). Infliximab was generally well tolerated. Infusion reactions occurred in 32% (25 of 78) of the children, with a higher incidence in children positive for antibodies to infliximab (58%, 15 of 26). At week 204, the proportions of children achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. The authors concluded that in this limited population of children with JIA remaining in the study at four years, infliximab was safe and effective but associated with a high discontinuation rate (Ruperto, 2010).Long-term safety concerns of infliximab, including development of malignancies, have not been determined in this population. Infliximab has been studied as an adjunct to second-line agents for the treatment of JIA-associated uveitis in small, retrospective case series and uncontrolled trials (Ardoin, 2007; Gallagher, 2007; Kahn, 2006; Saurenmann, 2007; Sharma, 2007; Sobrin, 2007; Tynjälä, 2007) and a cross-sectional multinational cohort survey (Foeldvari, 2007). Overall, the study investigators report that infliximab (higher doses in some individuals) is an effective, well-tolerated therapeutic agent that resulted in a reduction in symptoms or control of ocular inflammation in individuals with chronic, medically refractory, JIA-associated uveitis. In addition to infliximab-induced remission, some individuals were able to reduce or discontinue corticosteroid and other immunosuppressive therapy. Some individuals with active uveitis who had previously failed other treatments, responded to infliximab better than etanercept in controlling inflammation (Tynjälä, 2007) and improving visual acuity, glaucoma and complication rates (Saurenmann, 2007). Tynjälä and colleagues also reported findings during the two-year follow-up where "the frequency of long-term complications of uveitis seemed to increase despite decreased ocular inflammatory activity." Studies of infliximab for pediatric JIA-related uveitis have been hampered by variables including small numbers, the uncontrolled, retrospective nature of most reports, differential follow-up times, lack of standardization of disease activity and disease outcome measures, reports on children with a variety of underlying diagnoses, and the concomitant use of other drug therapies. In a prospective, comparative case series of children with JIA-related refractory uveitis, during the first year of treatment, 13 of 15 children achieved a complete remission on infliximab over a median period of 10 weeks (range 6-16 weeks) after starting therapy. No relapse of uveitis occurred in these 13 children during the first year, while before starting infliximab, the median number of relapses was four per year (range 2-6). However, all 13 responder children relapsed after the first year of infliximab infusions. At first relapse of uveitis, median follow-up on treatment was 15 months (range 12-23) and the median number of infusions was 12 (range 10-18). The investigators concluded that even if limited to a small cohort, their data showed that infliximab appeared to be an effective treatment for uveitis in the short term, "but its efficacy seems to wane over time" (Simonini, 2008). Kahn and colleagues (2006) concluded that larger, randomized, controlled studies may provide a better understanding of the dose, interval, and duration of treatment needed and data on long-term safety of the use of infliximab for JIA-associated uveitis. To date, no prospective, placebo-controlled data exists regarding the efficacy of infliximab for the treatment of JIA-associated uveitis (Foeldvari, 2007).
In 2011, the ACR issued recommendations for the treatment of JIA which includes initiation and safety monitoring of therapeutic agents for the treatment of systemic features. A TNFα inhibitor was recommended for individuals who have received methotrexate or leflunomide for three months at the maximum tolerated typical dose and have moderate or high disease activity, irrespective of poor prognostic features (Level of Evidence: B). A TNFα inhibitor was also recommended for initiation in individuals who have received methotrexate or leflunomide for six months and have low disease activity, irrespective of poor prognostic features (Level of Evidence: B) (Beukelman, 2011).
Wegener's Granulomatosis
The use of infliximab has been studied as an adjunct to immunosuppressive therapy in a small case series (n=6) (Lamprecht, 2002) of individuals with Wegener's granulomatosis and in an open-label pilot study (n=10) (Bartolucci, 2002) of individuals with active systemic vasculitides, including Wegener's granulomatosis. Treatment led to remission in five of six subjects in the case series and symptomatic improvement in the subjects in the open-label pilot study. However, further randomized controlled trials of larger sample populations are needed to determine the efficacy and safety of infliximab for this condition.
Heart Failure
Because of evidence that tumor necrosis factor may play a role in progression of heart failure, infliximab has been investigated for the management of individuals with moderate to severe CHF (AHFS, 2011). A phase II, double-blind, placebo-controlled, pilot study of subjects with stable NYHA class III or IV CHF (left ventricular ejection fraction equal to or less than 35%) reported that short-term use of infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of individuals with this chronic condition (Chung, 2003).
Other Proposed Indications
Infliximab has been investigated as a single agent or in combination therapy as a treatment for other conditions including advanced renal cell carcinoma (Larkin, 2010), asthma (Erin, 2006), chronic obstructive pulmonary disease (Rennard, 2007; van der Vaart, 2005), chronic recurrent gonarthritis (van der Bijl, 2009), cutaneous systemic sclerosis (Denton, 2009), disc herniation-induced sciatica (Korhonen, 2006), discoid lupus erythematosus (Jessop, 2009), erythrodermic psoriasis (Rosenbach, 2010), graft-versus-host disease (GVHD) (Couriel, 2009; Hamadani, 2008), hidradenitis suppurativa (HS) (Grant, 2010; Kaufman, 2005; Mekkes, 2008), JIA (Ruperto, 2007), Kawasaki syndrome (Burns, 2005), neurosarcoidosis (Moravan, 2009), orbital/ocular-related uveitis or scleritis (Prendiville, 2008), pelvic pain associated with endometriosis (Lu, 2010), pityriasis rubra pilaris (Gemmeke, 2010), polymyalgia rheumatica (Hernández-Rodríguez, 2009), post-intestinal resection of CD (Doherty, 2009), pyoderma gangrenosum (Brooklyn, 2006), refractory diabetic macular edema (Sfikakis, 2010; Wu, 2011), refractory ulcerative proctitis (UP) (Bouguen, 2010), Still's disease, Sjogren syndrome (Mariette, 2004), systemic lupus erythematosus (Aringer, 2009), Takayasu arteritis (Hoffman, 2004), and treatment-resistant, chronic sarcoidosis (Baughman, 2006; Rossman, 2006). The available medical literature for these conditions consists of case reports, uncontrolled case series, small, open-label prospective pilot studies and randomized controlled trials reporting short-term treatment outcomes. While some of these reports present a positive effect on the clinical manifestations of these diseases, there is a lack of larger scale, randomized controlled trials evaluating the long-term effects of infliximab compared to placebo (Suhler, 2005; Theodossiadis, 2007).
Etanercept (Enbrel)
Enbrel has been approved by the FDA for the treatment of adults with moderately to severely active RA (Genovese, 2002; Johnsen, 2006; Keystone, 2004; Klareskog, 2006), active PsA (Mease, 2000), chronic moderate to severe plaque psoriasis (Leonardi, 2003), active AS (van der Heijde, 2006a), and children two years of age or older with moderately to severely active polyarticular JIA (Lovell, 2000).
Off-Label and Other Proposed Indications
Graft Versus Host Disease (GVHD)
In a small non-randomized trial (n=21), Busca and colleagues (2007) reported that etanercept was well tolerated and induced a high response rate in individuals with steroid-refractory aGVHD (acute) and cGVHD (chronic), particularly in the setting of GI involvement, following allogeneic hematopoietic stem cell transplant. These results are similar to those reported by Chiang and colleagues in an earlier study (2002), where etanercept was given without adverse side effects in an eight-week treatment course to ten individuals with cGVHD post allogeneic hematopoietic stem cell transplant. The authors concluded, however, that these results were preliminary and warranted further investigation in larger, prospective trials. A subsequent randomized four-arm, phase II trial by Alousi and colleagues (2009) designed to identify the most promising agent(s) for initial therapy for aGVHD identified a 26% complete response rate with etanercept at Day 28, with a nine-month overall survival rate of 47%. The response rates with etanercept were lower when compared to the other agents, with the authors suggesting that combinations of other agents offered a more promising regimen for treatment of aGVHD.
Wegener's Granulomatosis
Enbrel has been investigated for the management of Wegener's granulomatosis and is designated as an orphan drug by the FDA for this use (AHFS, 2011). According to the AHFS, "clinical benefit is unclear; use with standard immunosuppressive agents has been associated with an increased incidence of solid malignant tumors. Use to induce or maintain remission currently is not justified. Use in individuals with Wegener's granulomatosis receiving immunosuppressive therapy is not recommended." In an open-label study in a limited number of subjects with Wegener's granulomatosis who had not responded adequately to standard therapy (i.e., prednisone, cyclophosphamide, methotrexate, azathioprine, cyclosporine), addition of etanercept (25 mg subcutaneously twice weekly) for a mean of 21 weeks resulted in a positive clinical response in most subjects, although limited flares and persistent minor features of active disease occurred frequently (Stone, 2001). However, in a randomized placebo controlled study of subjects with Wegener's granulomatosis (n=180), the rates of sustained remission, sustained periods of low level disease activity, and time needed to achieve these measures in subjects receiving etanercept in combination with standard therapy (glucocorticoids plus cyclophosphamide or methotrexate) were similar to those who received standard therapy alone. Additionally, disease flares did not differ significantly between the groups. In addition, solid malignant tumors developed in a significant group (p=0.01) of these etanercept-treated subjects, (n=6 of 89) versus placebo group (n=0) (Stone, 2006; Wegener's Granulomatosis Etanercept Trial (WGET) Research Group, 2005).
Heart Failure
Etanercept has been investigated for the treatment of heart failure (AHFS, 2011) in two clinical studies, the RECOVER and RENAISSANCE trials, both terminated early because of a lack of efficacy of the drug (Louis, 2001; Enbrel Product Information, 2011). In a subsequent publication, The Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL), Mann and colleagues (2004) reported that etanercept had no effect on clinical status in RENAISSANCE (p=0.17) or RECOVER (p=0.34) and had no effect on the death or chronic heart failure hospitalization end point (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, p=0.33). Mann and colleagues concluded that the results of the RENEWAL report rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.
Hidradenitis Suppurativa
Two small phase II clinical trials evaluated the safety and effectiveness of etanercept for the treatment of HS. The results of these studies were conflicting; one study reported improvement in disease activity without adverse events at week 12 and week 24 (Giamarellos-Bourboulis, 2008) whereas the other study failed to show statistically significant improvement in Physician Global Assessment (PGA) scores when baseline scores were compared with week-12 scores (Lee, 2009). The authors suggested there is a need for a double-blind, placebo-controlled trial to fully evaluate the safety and efficacy of etanercept for the treatment of HS. "Future studies using higher doses of etanercept are indicated; however, patients need to be carefully monitored for infection and other adverse events, in order to demonstrate the risk-to-benefit ratio of TNF-a inhibitors in the treatment of hidradenitis" (Lee, 2009). A follow-up single-center, randomized, prospective, double-blind, placebo-controlled trial (n=20) evaluated the use of etanercept (50 mg) or placebo subcutaneously (SC) twice weekly for 12 weeks. After 12 weeks, all subjects received open-label etanercept (50 mg) SC twice weekly for 12 more weeks. The primary endpoints reported no statistically significant difference among measurements of PGA and Dermatology Life Quality Index (DLQI) at 12 or 24 weeks between the treatment and placebo groups (p>.05 for all comparisons). The authors concluded that etanercept (50 mg) SC administered twice weekly did not have significant efficacy in the improvement of HS. "In light of our negative results, as well as those of previous studies, we suggest that future studies focus on other agents for the treatment of HS" (Adams, 2010). This conclusion was confirmed in a recent small, prospective open-label phase II study of ten individuals with HS treated with etanercept. Only three participants achieved a long-term treatment effect (weeks 24-144) of 50% improvement in the PGA score at week 12 of treatment. The remaining seven subjects presented with reoccurrence of symptoms within 14 and 68 weeks after withdrawal of etanercept (Pelekanou, 2010).
Other Proposed Indications
Etanercept has been investigated as a treatment for acute Kawasaki disease (KD) (Choueiter, 2010), asthma (mild to moderate disease; corticosteroid-refractory) (Berry, 2006; Morjaria, 2008), disc-herniation-induced radiculopathy or sciatica (Cohen, 2007; Cohen, 2009; Okoro, 2010), discoid lupus erythematosus (Jessop, 2009), inclusion-body myositis (Barohn, 2006), myelodysplastic syndromes (MDS) (Scott, 2010), pemphigus vulgaris (Fiorentino, 2011), polymyalgia rheumatica (Kreiner, 2010), septic shock (Fisher, 1996), and Sjögrens syndrome (Mavragani, 2007; Sankar, 2004; Zandbelt, 2004). While some of these studies report positive outcomes on the clinical manifestations of these diseases, there is a lack of large scale, randomized controlled trials evaluating the long-term effects of etanercept compared to placebo.
Adalimumab (Humira)
Humira has been approved by the FDA for the treatment of adults with moderately to severely active RA (Rau, 2002; Weinblatt, 2003; Weinblatt, 2006), active PsA (Gladman, 2007; Mease, 2005), chronic moderate to severe plaque psoriasis (Gordon, 2006a, 2006b; Menter, 2008), active AS (van der Heijde, 2006b), moderately to severely active CD (Hanauer, 2006; Sandborn, 2004; Sandborn, 2007a; Sandborn, 2007b), and children four years of age or older with moderately to severely active polyarticular JIA (Lovell, 2008).
Hidradenitis Suppurativa
The long term efficacy and safety of adalimumab has been studied in a small number of individuals (n=6) with refractory HS (Blanco, 2009). The authors reported significant improvements after one month of treatment as measured by the DLQI; in the number of affected regions, nodules, and fistulas; and in basic laboratory findings. Improvements were maintained for a mean follow-up of 21.5 (range, 13-29) months; adalimumab was well tolerated. As these results are preliminary, the authors suggested further investigation is indicated in the form of larger, prospective trials. In a small, prospective, open-label phase II study (Amano, 2010), the efficacy of adalimumab for HS was not demonstrated in six of ten participants who completed a 12-week treatment period. Statistically significant difference in HS Severity Index (HSSI) score was found between baseline and week eight (p<0.05) only, but no significant differences were identified between weeks two, four, and 12. Comparison of baseline with week 12 Visual Analogue Scale (VAS) and DLQI scores failed to show statistically significant improvements. The authors suggested that further studies using higher doses of adalimumab are warranted. Arenbergerova and colleagues (2010) reported results of a small study of individuals with severe, recalcitrant HS (n=8) treated with adalimumab in a standard regimen and subsequently followed for one year. All participants demonstrated improvement, with decreased drainage from all affected sites within four to six weeks during treatment. At four to six months, significant improvement was evident with a concomitant stable clinical picture. Affected areas were reduced by a mean of 13.8% after 12 months of therapy. However, after one year of therapy, participants were switched to a follow-up regimen that only included topical treatment with no systemic adalimumab. Only three participants remained recurrence-free, with an average time to reoccurrence at 9.5 months; five participants showed recurrences several months after discontinuation of the therapy. Further study of larger populations is needed to determine the long-term efficacy of adalimumab in the treatment of HS.
Other Proposed Indications
Adalimumab has been investigated as a treatment for other conditions including acute and severe sciatica due to lumbar disc degeneration (Genevay, 2010), ANCA-associated systemic vasculitis (AASV) (Laurino, 2010), ocular Behcet's disease (Bawazeer, 2010), pediatric CD unresponsive to infliximab (Rosh, 2009), focal segmental glomerulosclerosis (FSGS) (Joy, 2010; Peyser, 2010) and UC unresponsive or intolerant to infliximab (Afif, 2009; Oussalah, 2008). The available medical literature for these conditions consists of case reports, uncontrolled case series, a retrospective uncontrolled chart review, small, open-label or uncontrolled phase I and II studies, and a small, randomized, double-blind, controlled trial that are insufficiently powered and measure short-term treatment outcomes. A recent small, interventional, retrospective, multi-center study by Wu and colleagues (2011) failed to demonstrate a treatment benefit of intravitreal injections of adalimumab in 39 eyes with refractory diabetic macular edema. The central macular thickness remained unchanged from baseline at three months follow-up (p=0.125). Larger, prospective trials are needed to assess the safety and efficacy of adalimumab therapy for these conditions.
Certolizumab pegol (Cimzia)
Cimzia has been approved by the FDA for the treatment of adults with moderately to severely active CD (Sandborn, 2007; Schreiber, 2007) and for adults with moderately to severely active RA (Fleischmann, 2009; Keystone, 2008; Smolen, 2009).
Golimumab (Simponi)
Simponi, in combination with methotrexate, has been approved by the FDA for the treatment of adults with moderately to severely active RA and active PsA. In addition, for adults with RA (Keystone, 2009), PsA (Kavanaugh, 2009), or AS (Inman, 2008), corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with Simponi.
Other Proposed Indications
The safety and efficacy of Simponi was evaluated in a multi-center, double-blind, placebo-controlled trial in adults with moderately to severely active PsA, despite NSAID or nonbiologic DMARD therapy (Kavanaugh, 2009). Study subjects reported improvement in enthesitis and skin manifestations, however, the safety and efficacy of Simponi in the treatment of individuals with plaque psoriasis has not been established (Simponi Product Information, 2011.
Severe Persistent Asthma
The treatment effect of golimumab was assessed in a large population of subjects (n=309) with uncontrolled, severe persistent asthma despite high-dose inhaled corticosteroids and long-acting beta-2 agonists (Wenzel, 2009). Subjects were randomized to receive monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through week 52. Co-primary endpoints were the change from baseline through week 24 in prebronchodilator percent-predicted FEV1 and the number of severe asthma exacerbations through week 24. The results showed no significant differences were observed for the change in percent-predicted FEV1 or severe exacerbations through week 24; in addition, 2.6% of subjects treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the week-24 database lock. Through week 76, 20.5% of subjects treated with placebo and 30.3% of subjects treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated subjects. One death and all eight malignancies occurred in the active groups. The investigators concluded that treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of subjects with severe persistent asthma.
| Background/Overview |
Tumor necrosis factor (TNF or TNF-α) is a member in a family of proteins which induce necrosis (death) of tumor cells and have a wide range of proinflammatory actions. They are a multifunctional cytokine or a small protein released by cells which has a specific effect on the interaction of the cell, on the communication between the cells or on the behavior of the cells. TNF antagonists (inhibitors) belong to a class of drugs called biologic DMARDs that target specific pathways of the immune system and either enhance or inhibit immune response.
The American College of Rheumatology's Task Force Panel (TFP) (ACR, 2008) and the American Academy of Dermatology expert workgroup (AAD, 2008) have developed treatment recommendations concerning the therapeutic contraindications to the use of biologic agents based on data derived from the observational studies, and to a lesser degree from evidence in randomized controlled trials, expert consensus/opinion, and case studies. The AAD has made the following statement:
Patients with both rheumatoid arthritis and inflammatory bowel disease are often treated with the combination of TNF inhibitors and an immunosuppressive agent (methotrexate or azathioprine), whereas patients with psoriasis are most often treated with the TNF inhibitors as monotherapy. It, therefore, seems possible that extrapolations regarding the safety of TNF inhibitors derived from this combination therapy data may overestimate the potential risk of these agents when used as monotherapy in psoriasis. In addition, patients with psoriasis may have distinctive comorbidities that distinguish them from patients with either rheumatoid arthritis or Crohn's disease (AAD, 2008).
The ACR and AAD state that consideration should be given to the FDA-approved product information (contraindications and boxed warnings) for each biologic DMARD and the underlying risks and benefits of therapy for the individual. For example, in the presence of acute hepatitis B or C and chronic hepatitis B or C, treatment with a biologic agent is recommended as a contraindication by the ACR's TFP. The severity of compromised liver function and the presence of significant liver injury, as defined as chronic Child-Pugh classes B or C is considered a key factor in this therapeutic recommendation for both chronic hepatitis B and C (treated and untreated). For oncologic considerations, the TFP recommends that the TNF antagonists are contraindicated in individuals with prior lymphoproliferative disease that has been diagnosed and/or treated within the last five years. Because the available clinical trials are underpowered to evaluate the risk of rare events such as cancer, the AAD consensus panel of experts concludes that the overall risk of malignancies, including lymphoma, was not increased over baseline levels in individuals with rheumatoid arthritis being treated with TNF antagonists (AAD, 2008). Therefore, because individuals with psoriasis may have an increased risk of lymphoma (particularly Hodgkin lymphoma and cutaneous T-cell lymphoma), the AAD panel cautions the physician to "carefully consider the decision to use TNF antagonists in patients with a history of malignancy, particularly lymphoma."
In 2010, a joint working group from the ACR and the European League Against Rheumatism (EULAR) (Aletaha, 2010) developed a new approach to classifying RA. The focus of the workgroup was to identify, among individuals newly presented with undifferentiated inflammatory synovitis, the factors that best discriminated between individuals who were not at high risk for persistent and/or erosive disease. The new ACR/EULAR criteria set, classified as "definite RA," is "based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of six or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1)." From this new classification criteria for RA, the ACR/EULAR hopes that early identification of those individuals with a short duration of symptoms may benefit from "early institution of DMARD therapy or entry into clinical trials of promising new agents that may halt the development of disease that currently fulfills the 1987 ACR criteria."
FDA Boxed Warnings
The Product Information (PI) for each TNF antagonist includes the following boxed warning (Note: Cimzia, Enbrel, Humira, Remicade, and Simponi are referred to collectively as [TNF antagonists]):
Warning: Risk of Serious Infections (Full Prescribing Information)
Warning: Malignancy (Full Prescribing Information)
The PI for Humira and Remicade includes an additional boxed warning (Humira and Remicade Product Information, 2011):
Warning: Malignancy (Full Prescribing Information)
The PI for Enbrel includes an additional warning and precaution for subcutaneous injection (Enbrel Product Information, 2011):
Warnings and Precautions, Malignancies: Melanoma and Non-Melanoma Malignancies (Full Prescribing Information)
PI Precautions and Warnings with the Use of TNF Antagonists
The following are drug interactions and contraindications/warnings/precautions for specific [TNF antagonists] from the PI (2011):
Drug Interactions
Contraindications/Precautions/Warnings
Screening Recommendations
The American Academy of Dermatology (AAD, 2008) recommends monitoring individuals receiving treatment with Enbrel, Humira, or Remicade for active psoriatic arthritis or chronic moderate to severe psoriasis:
FDA Alerts and Communications
The FDA has issued a number of alerts and early communications reporting adverse events and the safety of the TNF antagonist agents. On June 4, 2008, the FDA posted an Early Communication About an Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia). The FDA investigated approximately 30 reports submitted to the Adverse Event Reporting System over a ten-year interval involving the possible association between the use of TNF antagonists and the development of lymphoma and other cancers in children and young adults. As a result, the FDA added a boxed warning to the prescribing information of the four drugs to inform healthcare providers, parents, and caregivers about the possible risk of lymphoma and other cancers in children and young adults (FDA, June 2008). On September 4, 2008, an alert was posted notifying healthcare professionals that histoplasmosis and other invasive fungal infections are not consistently recognized in individuals taking the TNF antagonists, resulting in delays in appropriate treatment and death in some individuals who developed pulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis and other opportunistic infections. The FDA alert encouraged individuals taking TNF antagonists to promptly seek medical attention when experiencing signs and symptoms of possible systemic fungal infection, such as fever, malaise, weight loss, sweats, cough, and/or dyspnea. Healthcare professionals were encouraged to ascertain if individuals who present with these symptoms live in or have traveled to areas of endemic mycoses, giving consideration to initiating empiric antifungal treatment until the pathogen(s) are identified if the individual presents with any of these symptoms (including pulmonary infiltrates or other serious systemic illness with or without concomitant shock) (FDA, September 2008). On August 4, 2009, the FDA posted a follow-up to the June 2008 early communications requiring stronger warnings in the prescribing information for the TNF antagonists. The warnings required an updated boxed warning, highlighting the increased risk of cancer in children and adolescents who receive these drugs to treat JIA, CD, and other inflammatory diseases. An analysis of U.S. reports of cancer in children and adolescents treated with TNF antagonists showed an increased risk of cancer, occurring, on average, after 30 months of treatment. About half of the cancers were lymphomas; some of the reported cancers were fatal. Additional required updates to the prescribing information include incorporation of reports of psoriasis associated with the use of TNF antagonists.
On April 14, 2011, a drug safety communication/update was posted by the FDA in response to ongoing reports of the occurrence of hepatosplenic T-cell lymphoma (HSTCL), primarily in adolescents and young adults being treated for CD and UC with the TNF antagonist drugs, as well as with azathioprine and/or mercaptopurine. The FDA recommends ongoing education to individuals and caregivers about the signs and symptoms of malignancies such as HSTCL, so they can be recognized and reported to the prescribing practitioner for evaluation and treatment.
On September 7, 2011 the FDA notified healthcare professionals that the boxed warning for the entire class of TNFα blockers was updated to include the risk of infection from two bacterial pathogens, Legionella and Listeria. In addition, the boxed warning and warnings and precautions sections of the product labels for all of the TNFα blockers were revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens. Individuals treated with TNFα blockers are at increased risk for developing serious infections involving multiple organ systems and sites that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens (FDA, 2011).
Description of Conditions
Ankylosing Spondylitis
Ankylosing spondylitis (AS), the most familiar and severe form of spondyloarthritis (SpA), is classified with a group of spondyloarthritides comprised of Reiter's syndrome, reactive arthritis, and PsA. AS is characterized not by the inflammation of the synovium, as seen in RA, but inflammation of the enthesis, the site where ligaments, tendons, and joint capsules insert into bone. Inflammation around the spine/vertebrae, joints and feet can lead to fibrosis, ossification, deformity, and ankylosis. It can also cause inflammation in or injury to other organs, such as the eyes, heart, lungs, and kidneys. The incidence of AS may be underestimated due to unreported cases, with the estimated prevalence in almost one million individuals in the United States. The usual age of onset is between 17 and 35 years. Conventional therapy for AS consists primarily of NSAIDs, corticosteroids, and non-biologic DMARDs, including methotrexate and sulfasalazine.
Crohn's Disease
Crohn's disease (CD) is an inflammatory bowel disease (IBD) generally accepted as an autoimmune disease that occurs in genetically predisposed individuals; clinical presentation is primarily determined by the anatomic location of the disease. The most common presenting symptoms are fever, abdominal pain, and diarrhea with or without blood. Fistula formation, fissuring, discontinuous intestinal and transmural involvement with bowel-wall thickening and extraintestinal manifestations such as arthritis, skin and eye manifestations, metabolic deficiencies, hypercoagulation, and hepatobiliary disease are frequent complications. The clinical course of CD is chronic and intermittent and there is no known cure. Medical therapy includes the use of 5-ASA products such as mesalamine, sulfasalazine, or olsalazine, glucocorticoids such as prednisone or budesonide, antibiotics, immunosuppressive drugs (6-MP/AZA), methotrexate and other anti-inflammatory agents.
The clinical practice guideline, Management of Crohn's Disease in Adults, was updated in 2009 under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. This guideline offers general management and therapeutic recommendations for CD in adults, citing that "significant advances have been made focusing on therapeutic alternatives for patient care. As a consequence of the varied presentations of patients with CD, and the heterogeneity among patients, a comprehensive evidence-based approach for each clinical scenario is not plausible" (Lichtenstein, 2009).
Juvenile Idiopathic Arthritis
Juvenile idiopathic arthritis (JIA) is a condition that describes arthritic inflammation of the synovium (lining of the joints) with an onset, typically before 16 years of age. Previously called juvenile rheumatoid arthritis, the name has been changed to reflect the difference between the juvenile (childhood) forms of arthritis and adult forms of arthritis. Although JIA is idiopathic (the cause is unknown), it is likely the result of a combination of genetic, infectious, and environmental factors. Because arthritis in children may resemble the joint pain associated with infections, cancer, bone disorders, and other inflammatory disorders, these potential causes should be excluded before the diagnosis of JIA can be made. JIA is categorized into five main types based on the number of joints involved during the first six months of disease and the involvement of other organs. These types include oligoarthritis, polyarthritis, systemic arthritis, enthesitis-related arthritis, and PsA. Treatment depends on the category of JIA and the extent of joint involvement. Medications are available to decrease the symptoms of joint pain and stiffness and alter the disease process, preventing permanent damage to the joint or joints (Ringold, 2005). Uveitis is the most common extra-articular manifestation of childhood JIA and can be acute anterior, recurrent anterior, chronic anterior, or anterior uveitis with vitritis. The chronic form of anterior uveitis, usually seen in JIA, is asymptomatic, typically occurs in females greater than four years of age, and is strongly associated with a positive antinuclear antibody titer (Wright, 2007). The most important complication is visual loss with significant visual impairment in 3% to 66% of children with JIA who develop uveitis (Sabri, 2008). Without early detection and aggressive therapy, the uveitis and topical steroid therapy used to treat it may result in cataracts, glaucoma, and even blindness. A variety of systemically administered anti-inflammatory agents have been found useful for the treatment of JIA-associated uveitis. Methotrexate is often the first line disease modifying systemic agent used to help wean topical corticosteroids, but when ineffective, a variety of other systemic agents have shown promising results in refractory JIA-associated uveitis (Wright, 2007).
Plaque Psoriasis and Psoriatic Arthritis
Psoriasis is a multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. The major manifestation of psoriasis is chronic inflammation of the skin, characterized by "disfiguring, scaling, and erythematous plaques that may be painful or often severely pruritis and may cause significant quality of life issues" (AAD, 2008). For individuals with chronic plaque psoriasis, key metrics for outcome assessment include improvement in the Psoriasis Area and Severity Index (PASI) as well as objective assessment of disease via the PGA. The PASI is a measure of overall psoriasis severity and coverage that assesses body surface area (BSA) and erythema, induration, and scaling. PASI is the metric commonly used in the clinical trials for psoriasis treatments, but is rarely used in clinical practice. Therefore, the AAD states that the physician generally uses subjective qualitative assessment of the severity of an individual's psoriasis by combining objective assessment of the BSA involvement, disease location, thickness, and symptoms, presence or absence of psoriatic arthritis with the subjective assessment of the physical, financial, and emotional impact of the diseases on the individual's life. Treatments available to help manage the symptoms of psoriasis include topical therapy, phototherapy, systemic therapy, and biologic DMARDs.
Psoriatic arthritis (PsA) is an inflammatory seronegative spondyloarthropathy associated with psoriasis. PsA is characterized by stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments and tendons (dactylitis and enthesitis). Symptoms of PsA can range from mild to very severe. According to the American College of Rheumatology (ACR, 2008), PsA usually appears in individuals between the ages of 30 to 50, but can begin as early as childhood. Men and women are equally at risk. Approximately 15% of people with psoriasis develop psoriatic arthritis. In about 15% of individuals with PsA, the joint disease precedes the psoriasis skin symptoms (NPF, 2009). The AAD guidelines, Psoriatic Arthritis: Overview and Guidelines of Care for Treatment with an Emphasis on the Biologics (AAD, 2008), estimates the prevalence of PsA in the general population of the United States as between 0.1% to 0.25%. In a large clinical trial with more than 1000 subjects, 84% had cutaneous manifestations for an average of 12 years before the onset of PsA.
The classification of PsA is an area of ongoing, international discussion. The CASPER (classification criteria for PsA) criteria consists of established inflammatory arthritis, defined by the presence of tender and swollen joints and prolonged morning or immobility-induced stiffness, and a total of at least three other features. The criteria for selection of appropriate candidates for the use of biologic agents in the treatment of PsA have typically considered the disease severity inclusion criteria cited in the clinical trials that accompanied the FDA approval of each agent. Based on current standards of practice and expert opinion, psoriatic arthritis disease severity includes the definition of active arthritis in an individual with three or more swollen joints and three tender joints. This is consistent with the general AAD recommendations for treatment of mild to moderate psoriatic arthritis, including "nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of DMARDs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis" (AAD, 2008).
The American Academy of Dermatology has approved a set of evidence-based guidelines, Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis (AAD, 2008), intended to assist physicians in managing the complexities of the treatment of individuals with psoriasis and PsA. The two published guidelines include: Section 1: Overview of Psoriasis and Guidelines of Care for the Treatment of Psoriasis with Biologics, and Section 2: Psoriatic Arthritis: Overview and Guidelines of Care for Treatment with an Emphasis on the Biologics (AAD, 2008). According to the AAD, the first set of guidelines provides an overview of psoriasis classification, co-morbidities, assessment tools, and the use of biologics to treat psoriasis. The work group states that approximately 80% of individuals affected with psoriasis have mild to moderate disease, with 20% having moderate to severe psoriasis, defining the extent of BSA involvement as "affecting more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals." "The areas of involvement and types of psoriasis should be considered in evaluating severity of disease because the impact of these types of psoriasis may be quite substantial." Treatment planning for use of an FDA-approved biologic agent for moderate to severe plaque psoriasis considers this definition of BSA involvement with plaque psoriasis. In addition, for individuals with plaque psoriasis involving sensitive areas or areas that would significantly impact daily function (e.g. palms, soles of feet, head/neck, or genitalia), less than or equal to 5% of BSA involvement is considered as moderate to severe disease. The second set of guidelines is intended to assist dermatologists in arriving at an early diagnosis of PsA. It states, "Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis" (AAD, 2008). Subsequent sections of the guidelines have been published, including Section 4: Guidelines of Care for the Management and Treatment of Psoriasis with Traditional Systemic Agents (Menter, 2009). This section reiterates that treatment planning should consider BSA criteria as recommended in the earlier guidelines. In addition, this section discusses in detail the "efficacy and safety, and offers recommendations for the use of the three most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin."
Rheumatoid Arthritis
Rheumatoid arthritis (RA) affects 2.1 million Americans, usually between the ages of 20 and 60. Adults in their mid to late fifties are especially vulnerable. RA is three times as prevalent in women as in men. Arthritis and related musculoskeletal conditions such as RA cost the U.S. economy nearly $125 billion per year in medical care and indirect expenses such as lost wages and production. The pharmacologic approach to treatment of RA consists of NSAIDs to reduce pain, swelling, and inflammation, plus a nonbiologic DMARD, such as methotrexate, hydroxychloroquine (an antimalarial), sulfasalazine, gold salts, d-penicillamine, azathioprine, or cyclosporine, to slow the course of the disease and prevent joint and cartilage destruction.
The American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis focuses on "the nonbiologic and biologic therapies for the treatment of RA on the background of optimal and appropriate use on nonmedical therapies as well as anti-inflammatory pharmacologic interventions. The recommendations developed focus on the initiation of drug therapies or indications to resume drug therapy in RA." Included with these recommendations are therapeutic contraindications derived "primarily from observational studies, and to a lesser degree from evidence from randomized controlled trials." Safety monitoring, risk surveillance, and recommendations for vaccinations in individuals with RA receiving nonbiologic and biologic DMARDs are also addressed in this document (ACR, 2008).
Ulcerative Colitis
The American College of Gastroenterology (ACG), Practice Parameters Committee released the Ulcerative Colitis Practice Guidelines: Adults (Kornbluth, 2010). According to the ACG, UC is a chronic disease characterized by diffuse mucosal inflammation limited to the colon, affecting approximately 500,000 individuals in the U.S. with an incidence of 8-12/100,000 population per year. "It involves the rectum in about 95% of cases and may extend proximally in a symmetrical, circumferential, and uninterrupted pattern to involve parts or all of the large intestine." Besides the primary clinical symptom of bloody diarrhea, UC is often accompanied with symptoms of rectal urgency and tenesmus. The clinical course is marked by exacerbations and remissions, "which may occur spontaneously or in response to treatment changes or intercurrrent illness." Besides recommendations for diagnosis and assessment, the guidelines include recommendations for management of mild-moderate distal colitis, maintenance of remission in distal disease, and management of mild-moderate extensive colitis (active disease) with infliximab as "an effective treatment for patients who are steroid refractory or steroid dependent despite adequate doses of thiopurine, or who are intolerant of these medications (Evidence A)." For the maintenance of remission in mild-moderate extensive colitis, "infliximab is effective in maintaining improvement and remission in the patients responding to the infliximab induction regimen (Evidence A)." For the management of severe colitis, "infliximab may also be effective in avoiding colectomy in patients failing intravenous steroids but its long-term efficacy is unknown in this setting (Evidence A)."
| Definitions |
5-Aminosalicylic acid (5-ASA) products: A class of anti-inflammatory drugs used to treat bowel inflammation, diarrhea, rectal bleeding, and abdominal pain in Crohn's disease and ulcerative colitis; includes mesalamine or mesalamine converting products such as balsalazide, olsalazine, and sulfasalazine.
Ankylosing spondylitis: A disease that causes inflammation of the joints between the spinal bones, and the joints between the spine and pelvis.
Arthritis: Inflammation of one or more joints, which results in pain, swelling, stiffness, and limited movement.
Biologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing Il-12 and IL-23, or by directly suppressing lymphocytes. Includes the following:
Conventional therapy: Treatments that are widely accepted and practiced by the medical community.
Corticosteroids (systemic): A class of drugs, also referred to as glucocorticoids, that reduce inflammation and are synthetic derivatives of the natural steroid, cortisol, which is produced by the adrenal glands; includes prednisone, methylprednisone, and hydrocortisone.
Crohn's disease (CD): An idiopathic, inflammatory bowel disease (IBD), also referred to as regional enteritis, characterized by discontinuous, transmural inflammation located anywhere in the gastrointestinal tract from the mouth to the anus.
Disease modifying anti-rheumatic drugs (DMARDs): A variety of drugs that work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.
Fistulizing: The formation of an abnormal passage from one epithelialized surface to another.
Immunosuppressive drugs: A class of immunomodulatory drugs that reduce inflammation by affecting the immune system; includes 6-mercaptopurine (6-MP), azathioprine, cyclophosphamide, cyclosporine, methotrexate, and tacrolimus.
Induction: Treatment designed as a first step toward treatment of a given condition.
Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include:
Juvenile idiopathic arthritis (JIA): A form of rheumatoid arthritis in children that generally occurs prior to the age of 16, favors one or more large joints and can interfere with normal bone growth.
Monoclonal antibody: Monoclonal antibodies are produced by a single clone of cells and are of exceptional purity and specificity.
Nonbiologic disease modifying antirheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown; includes azathioprine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds, penicillamine, and sulfasalazine.
Nonsteroidal anti-inflammatory drugs (NSAIDs): A class of drugs used to treat pain, redness, swelling, and inflammation from conditions including different types of arthritis; includes over-the-counter (OTC) and prescription medicines, such as celecoxib, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen, sulindac, tolmetin, and valdecoxib.
Psoriasis: A chronic autoimmune skin disease that is characterized by circumscribed red patches covered with white scales.
Psoriatic arthritis (PsA): A form of arthritis that can affect any joint within the body, either in a single joint or in the same joint on both sides of the body.
Refractory disease: Illness or disease that is unresponsive to conventional treatment.
Rheumatoid arthritis (RA): A chronic inflammatory disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints.
Spondyloarthropathy: The spondyloarthropathies (SpA) are a heterogeneous set of disorders which include ankylosing spondylitis (AS) and psoriatic arthritis (PsA), characterized by axial skeletal involvement and frequent association with the HLA B27 antigen.
Tumor necrosis factor (TNF or TNF-α): A protein manufactured by white blood cells to stimulate and activate the immune system in response to infection or cancer; also referred to as tumor necrosis factor alpha. Overproduction of this protein can lead to diseases, such as arthritis or psoriasis, where the immune system acts against healthy tissues.
Ulcerative colitis: An idiopathic IBD that presents as inflammation and ulcers in the lining of the rectum and colon.
| Coding |
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
| HCPCS | |
| J0135 | Injection, adalimumab, 20 mg (Humira) |
| J0718 | Injection, certolizumab pegol, 1 mg (Cimzia) |
| J1438 | Injection, etanercept; 25 mg (when drug administered under the direct supervision of a physician, not for use when drug is self administered) (Enbrel) |
| J1745 | Injection, infliximab; 10 mg (Remicade) |
| J3590 | Unclassified biologics [no specific code for golimumab (Simponi)] |
| S9359 | Home infusion therapy, antitumor necrosis factor intravenous therapy; (e.g., Infliximab); per diem |
| ICD-9 Diagnosis | |
| 555.0-555.2 | Regional enteritis (Crohn's disease) – (Remicade, Humira, Cimzia ) |
| 555.9 | Regional enteritis, unspecified site – (Remicade, Humira, Cimzia ) |
| 556.0-556.9 | Ulcerative colitis - (Enbrel, Remicade) |
| 569.81 | Fistula of intestine, excluding rectum and anus – (Remicade) |
| 619.1 | Digestive-genital tract fistula, female (rectovaginal fistula) – (Remicade) |
| 696.0 | Psoriatic arthropathy – (Enbrel, Remicade, Humira, Simponi) |
| 696.1 | Psoriasis – (Enbrel, Remicade, Humira) |
| 714.0-714.2 | Rheumatoid arthritis (Enbrel, Remicade, Humira, Cimzia, Simponi) |
| 714.30-714.31 | Polyarticular juvenile rheumatoid arthritis – (Enbrel, Humira) |
| 720.0-720.9 | Ankylosing spondylitis and other inflammatory spondylopathies – (Enbrel, Remicade, Humira, Simponi) |
When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above, in situations described in the Position Statement section as not medically necessary.
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above, when criteria are not met, for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding
| References |
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
| Web Sites for Additional Information |
| Index |
Adalimumab
Ankylosing Spondylitis
Behcet's Syndrome
Certolizumab Pegol
Cimzia
Crohn's Disease
Enbrel
Enteritis
Etanercept
Golimumab
Humira
Ileitis
Inflammatory Bowel Disease
Infliximab
Juvenile Idiopathic Arthritis
Multiple Sclerosis
Plaque Psoriasis
Psoriatic Arthritis
QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
Regional Enteritis
Remicade
Rheumatoid Arthritis
Sarcoidosis
Simponi
T-SPOT.TB Test (T-Spot)
Tuberculin Skin Test (TST)
Tumor Necrosis Factor Antagonist
Ulcerative Colitis
Uveitis
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
| Document History |
| Status | Date | Action |
| Revised | 11/17/2011 | Medical Policy & Technology Assessment Committee (MPTAC) review. Revised medically necessary age criterion for infliximab (Remicade) for UC: FDA approval for use in children 6 years of age and older (that otherwise meet criteria). Clarified not medically necessary statements for evaluating TB status and for clinically significant/serious infections. Updated Background with FDA black box warnings for Legionella and Listeria infections and other PI warnings and precautions. Updated Rationale, References, Web Sites for Additional Information. |
| Revised | 08/18/2011 | MPTAC review. Revised not medically necessary criterion based on updated FDA labels, adding additional drugs that are not recommended for use in combination therapy with the TNF antagonists. Updated Rationale, Background, Definitions, References, Web Sites for Additional Information, and Index. |
| Reviewed | 08/19/2010 | MPTAC review. Clarified not medically necessary Position Statement for each TNF antagonist drug in combination with other agents, without revision to criteria. Updated Rationale, Discussion, Definitions, and References. |
| Reviewed | 02/25/2010 | MPTAC review. Clarified Position Statements. Updated Description, Background (including FDA Boxed Warnings, Alerts and Communications; Medical Management Information), Definitions, and References. |
| 01/01/2010 | Updated Coding section with 01/01/2010 HCPCS changes; removed HCPCS C9249 deleted 12/31/2009. | |
| Revised | 08/27/2009 | MPTAC review. Merged contents of CG-DRUG-12 including indications for TNF antagonists for psoriasis and psoriatic arthritis into document. Removed Dosing Information table. Reworded/reordered and clarified Position Statements. Revised medically necessary statements for psoriatic arthritis, removing specific criteria for number of involved joints, qualifying target lesion, and arthritis distributions. Revised not medically necessary statements for each drug, retaining specific contraindications per product information and FDA boxed warning criteria. Updated Rationale, categorizing off-label uses and adding Proposed Off Label Indications sections. Added sections for FDA Boxed Warnings, Medical Management Information, Screening Recommendations, and FDA Alerts and Communications to the discussion. Updated Definitions with descriptions of medical conditions and specific agents by drug category. Updated References. |
| Revised | 05/21/2009 | MPTAC review. Revised document, adding medically necessary, not medically necessary, and investigational and not medically necessary Position Statements for golimumab (Simponi), an FDA-approved (April 2009) TNF antagonist for active PsA, RA, and AS. Added an additional Cimzia medically necessary statement for adults with moderately to severely active RA. Clarified medically necessary criterion for Humira for JIA, adding that the individual "have had an inadequate response to one or more DMARDs" before initiating Humira. Revised Dosing sections based on updated FDA labels. Updated Description, Rationale, Discussion, References, Coding and Index. |
| 04/01/2009 | Updated Coding section with 04/01/2009 HCPCS changes. | |
| Revised | 02/26/2009 | MPTAC review. Revised dose escalation and maintenance dose information for Remicade for pediatric CD (more frequent than the FDA label indication). Updated Rationale, Discussion and References to address: 1) off-FDA label indication of Remicade for JIA-related uveitis; 2) updated Enbrel and Cimzia labels. |
| Revised | 11/20/2008 | MPTAC review. Aligned not medically necessary statements to CG-DRUG-12 for the TNF antagonists. Clarified language for use of TNF antagonists as not medically necessary if the individual is not tested with a TST or a CDC-recommended equivalent to rule out latent Tb. Defined conventional therapies in the ulcerative colitis medically necessary statement. Updated Background/Overview re: 1) use of TNF antagonists during pregnancy and lactation; 2) FDA Alert and Boxed Warnings for the increased risk of potentially life-threatening, opportunistic fungal infections while on TNF antagonists; and, 3) recommendation for updating vaccination status of children with CD and JIA prior to initiation of TNF antagonists, and, not medically necessary indication of concurrent administration of live vaccines with TNF antagonists. Updated Definitions and References. |
| Revised | 08/28/2008 | MPTAC review. Revised investigational and not medically necessary indications for Remicade and Enbrel to address specific off-label conditions. Reformatted Humira medically necessary criteria. Revised Dosing Information based on FDA labels for Enbrel for adult RA, ankylosing spondylitis, and psoriatic arthritis (50 mg dose can be given as two 25 mg SC injections in one day or 3 or 4 days apart) and added combination therapy statement. Addition of Enbrel induction dosing information for adult plaque psoriasis. Revised maintenance dosing information to include administration every 6 (more frequent than the FDA label) to 8 weeks for Remicade for adult psoriatic arthritis and plaque psoriasis. Expanded Rationale to include investigational and not medically necessary off-label conditions. Addition of an FDA boxed warning (June 4, 2008) concerning the development of lymphomas and other cancers in children and young adults. Addition of Professional Organization Guidelines and recommendations for use of TNF antagonists. Updated References. |
| Revised | 05/15/2008 | MPTAC review. Addition of medically necessary criteria to include the FDA-approved use of Cimzia for the treatment of CD in adults with moderately to severely active disease who have had an inadequate response to conventional therapies. Addition of not medically necessary and investigational and not medically necessary criteria for Cimzia. For Enbrel, revised juvenile idiopathic arthritis (JIA) medically necessary criteria for children with moderately to severely active polyarticular disease to expand age to 2 years and older. Black box warning discussion added to Enbrel regarding the risk of infections and tuberculosis. For Remicade and Enbrel, removed/deleted the medically necessary off label uses for reactive arthritis (adults) and arthritis associated with inflammatory bowel disease (adults). Addition of not medically necessary statement to all TNF antagonists for concurrent administration of live vaccines. Updated examples of conventional therapies for CD for consistency with CG-DRUG-17. Updated Rationale, Background, Dosing Information, Definitions, Coding and References. |
| Revised | 02/29/2008 | MPTAC review. Revised medically necessary criteria to include new FDA-approved use of Humira for the treatment of moderately to severely active polyarticular juvenile idiopathic arthritis in individuals four years of age and older. |
| Revised | 02/21/2008 | MPTAC review. Revised medically necessary criteria to include new FDA-approved use of adalimumab for the treatment of individuals 18 and older with moderate to severe chronic plaque psoriasis. Modified language in medically necessary indication for Remicade and Enbrel for psoriatic arthritis and plaque psoriasis to more closely match language in CG-DRUG-12. Updated Dosing Information, Rationale, Coding, and References. |
| Revised | 11/29/2007 | MPTAC review. Changed dosing frequency for Remicade for adults with GI disorders from every 8 weeks to every 6 weeks if there is drug failure when being given every 8 weeks. Noted that dosing change is more frequent that FDA labeled use. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." Updated Coding section. |
| Revised | 03/08/2007 | MPTAC review. Addition of Humira for treatment of CD as approved by the FDA. |
| Revised | 12/07/2006 | MPTAC review. Addition of Remicade for treatment of chronic extensive or disabling plaque psoriasis as approved by the FDA. Addition of Remicade for treatment of ulcerative colitis including as maintenance therapy as approved by the FDA. Addition of Humira for inhibiting the progression of structural damage and improving physical function in individuals with psoriatic arthritis as approved by the FDA. Addition of usage of another immunosuppressive instead of methotrexate with Remicade for rheumatoid arthritis with methotrexate intolerance. |
| Revised | 09/14/2006 | MPTAC review. Addition of Humira for treatment of ankylosing spondylitis as approved by FDA. Review and update safety indications. Addition of dosage chart per product information. Extensive literature review. |
| Revised | 06/08/2006 | MPTAC review. Change to title. Removal of Biologic Response Modifiers and placement of Kineret (anakinra) into Pharmacology Toolkit. Updated References. Inclusion of black box warning for Remicade to include Hepatosplenic T-Cell Lymphoma in adolescent and young adults. Change to labeled indication for Remicade for CD to include children greater than or equal to 6 years of age. |
| Revised | 12/01/2005 | MPTAC review. Addition of FDA approval of Humira. |
| Revised | 09/22/2005 | MPTAC review. Position Statement: Removed indication of Enbrel as first-line treatment for psoriatic arthritis before use of Remicade. Provided clarification of off-label use of Remicade for arthritis associated with inflammatory bowel disease. Noted that additional specific selection criteria for use for psoriatic arthritis and plaque psoriasis may apply for Remicade and Enbrel. |
| Revised | 04/28/2005 | MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization. Updated coding: Added HCPCS code J0135; added ICD-9 Diagnoses codes 714.0-714.2, 714.30, 720.0-720.9 |
| Pre-Merger Organizations | Last Review Date | Document Number | Title |
| Anthem, Inc. | 04/28/2004 | DRUG.00002 | Tumor Necrosis Factors and Biologic Response Modifiers |
| WellPoint Health Networks, Inc. | 12/02/2004 | Pharmacology Toolkit | Infliximab (Remicade) |