Aetna Infliximab Form
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Background for this Policy
U.S. Food and Drug Administration (FDA)-Approved Indications
Compendial Uses
Infliximab products include Avsola (infliximab-axxq), Inflectra (infliximab-dyyb), Remicade (inflximab), and Renflexis (infliximab-abda) brands, which are considered tumor necrosis factor (TNF) blockers. Infliximab neutralizes the biological activity of tumor necrosis factor-alpha (TNF‐α) by binding to the soluble and transmembrane forms of TNF‐α therefore effectively inhibiting the binding of TNF‐α with its receptors. Infliximab does not neutralize TNF‐β (lymphotoxin α), a related cytokine that utilizes the same receptors as TNF‐α. TNF‐α is a cytokine that plays an important role in various inflammatory processes including: induction of pro‐inflammatory cytokines such as interleukins 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or 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.
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. 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. 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. Some patients who tested negative for latent tuberculosis prior to receiving infliximab have developed active tuberculosis. 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 warning states that lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab. Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers including infliximab. Almost all had received azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of infliximab cases were reported in patients with Crohn’s disease or ulcerative colitis, most of whom were adolescent or young adult males (Janssen Biotech, 2021).
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 post-marketing reports of new onset and worsening 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 (Janssen Biotech, 2021).
In addition to risk of serious infections, malignancies and heart failure, other labeled warnings and precautions include the following:
Most common adverse reactions (greater than 10%) – infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain (Janssen Biotech, 2021).
The product labeling for Remicade recommends against use with other biologics. The prescribing information states: "The combination of Remicade with other biological therapeutics used to treat the same conditions as Remicade is not recommended."
Inflectra (infliximab-dyyb) (Pfizer, Inc.) is a biosimilar to Remicade (infliximab) (Janssen Biotech, Inc), which was originally licensed in 1998. Inflectra was approved by the FDA in April 2016 for the treatment of the following indications, for which Remicade has the same approval. The indication and usage to include pediatric ulcerative colitis was later FDA-approved in June 2019. In 2017, the U.S. Food and Drug Administration (FDA) approved infliximab-abda (Renflexis), a biosimilar referencing infliximab (Remicade), across all eligible indications. Infliximab-abda has labeled indications for reducing signs and symptoms in patients with adult and pediatric Crohn’s disease, adult ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, and for the treatment of adult plaque psoriasis. The indication and usage to include pediatric ulcerative colitis was later FDA-approved in June 2019. Renflexis is manufactured by Samsung Bioepis of Incheon, Korea. Renflexis is marketed and distributed in the United States by Merck.In December 2019, the U.S. Food and Drug Administration (FDA) approved the biosimilar, Avsola (infliximab-axxq), for all approved indications of the reference product, Remicade (infliximab). Thus, Avsola is FDA approved for the treatment of moderate-to-severe rheumatoid arthritis (RA), moderate-to-severe Crohn's Disease (CD) in the adult and pediatric population, moderate-to-severe ulcerative colitis (UC) in the adult and pediatric population, chronic severe plaque psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Avsola, an anti-tumor necrosis factor alpha (anti-TNF) monoclonal antibody, was found to be highly similar to Remicade with no clinically meaningful differences based on a totality of evidence which included comparative analytical, nonclinical and clinical data (Amgen, 2019b).
FDA approval was based on a randomized, double-blind comparative clinical study which evaluated the efficacy and safety of infliximab-axxq (ABP710; Avsola) compared to infliximab (Remicade) in 558 patients with moderate-to-severe RA. The patients were randomized (1:1) to receive either Avsola or Remicade at a dose of 3 mg/kg administered as an infusion on day 1, at weeks 2 and 6, and every 8 weeks thereafter. The primary endpoint was the response difference (RD) of 20% improvement in American College of Rheumatology core set measurements (ACR20) at week 22. Key secondary endpoints included DAS28-CRP change from baseline, RD of ACR20, ACR50 and ACR70 at weeks 2, 6, 14, 22, 30, 34, 38, 46 and 50. The study also incorporated the evaluation of a single transition in 119 subjects from Remicade to Avsola at week 22, which demonstrated similar safety and immunogenicity in patients who were previously on Remicade (Amgen 2019b, 2019c).
Avsola has the same pharmaceutical dosage form and strength as Remicade.
Acne Fulminans
Iqbal and Kolodney (2005) stated that acne fulminans is a syndrome of sudden onset hemorrhagic and ulcerative acne involving the back, chest, and face combined with systemic symptoms. It can be the dermatologic manifestation of the synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. Current therapy for acne fulminans consists of wound care, topical and systemic corticosteroids, isotretinoin, and non-steroidal anti-inflammatory drugs (NSAIDs). Infliximab has shown efficacy in the treatment of psoriatic arthritis and ankylosing spondylitis both of which share clinical similarities to the SAPHO syndrome. These investigators reported the case of a patient with the SAPHO syndrome and acne fulminans who was treated with infliximab; 10 months after initiating therapy with infliximab, the area of the patient's ulcerative lesions was reduced by 70 %. The authors concluded that infliximab might be considered as a treatment option for patients with acne fulminans unresponsive to conventional therapies.
Furthermore, an UpToDate review on “Treatment of acne vulgaris” (Graber, 2019) states that “Oral glucocorticoids (typically, prednisone 0.5 to 1 mg/kg per day) and oral isotretinoin are the mainstays of treatment for acne fulminans. There is a paucity of high-quality data to guide the approach to treatment”.
Currently, there is insufficient evidence to support the use of infliximab for the treatment of acne fulminans.
Age-Related Macular Degeneration
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”.
Ankylosing Spondylitis and Spondyloarthropathies
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 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.
Atopic Eczema
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.
Autoimmune Cholangiopathy
Rojas-Feria et al (2013) noted that abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extra-intestinal manifestations for both Crohn's disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90 %. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 months after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 months after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy did not seem to promote reactivation of hepatitis C, and hepatitis C anti-viral treatment did not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events (AEs) is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the 1st month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.
Furthermore, an UpToDate review on “Autoimmune hepatitis variants: Definitions and treatment” (Heneghan, 2018) does not mention infliximab as a therapeutic option.
Behçet's disease
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.
In the 2018 update of the European League Against Rheumatism (EULAR) recommendations for the management of Behcet's syndrome (BS), Hatemi and colleagues (2018) noted that several new therapeutic modalities with different mechanisms of action have been studied in patients with BS. These researchers updated the recommendations in the light of these new data under the auspices of EULAR Standing Committee for Clinical Affairs. The recommendations on the medical management of muco-cutaneous, joint, eye, vascular, neurological and GI involvement of BS were modified; 5 overarching principles and a new recommendation about the surgical management of vascular involvement were added. For BS with eye involvement, among the monoclonal anti-TNF antibodies, although there is more accumulated experience with IFX, ADA also appeared to be an effective alternative. Switching between these agents appeared to be possible in patients with primary or secondary unresponsiveness or AEs. Patients presenting with an initial or recurrent episode of acute sight-threatening uveitis should be treated with high-dose glucocorticoids, IFX or IFN-alpha. Intravitreal glucocorticoid injection is an option in patients with unilateral exacerbation as an adjunct to systemic treatment (Level of evidence: IIA; strength of recommendation: B).
Birdshot Retinochoroidopathy
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.
Cerebral Amyloid Angiopathy
An UpToDate review on "Cerebral amyloid angiopathy" (Greenberg, 2022) does not mention infliximab as a therapeutic option.
Chronic Cutaneous Sarcoidosis
Doherty and colleagues (2008) stated that although healthcare providers have arrived at a relatively comfortable zone of accepted clinical practice in the management of cutaneous sarcoidosis, virtually every treatment is based on minimal evidence-based data and relies almost exclusively on anecdotal information. Although it would be convenient to blame this state of affairs on the lack of certainty about disease etiology, the unavoidable fact is that little has been executed, even in the realm of well-designed comparative trials. Nonetheless, worldwide accepted standard therapies for sarcoidosis include the administration of corticosteroids, anti-malarials and methotrexate. A step-wise approach to patient care is appropriate, and potent topical corticosteroids (e.g., clobetasol) or repeated intralesional injections of triamcinolone (3 to 10 mg/ml) may be all that is needed in mild skin-limited disease. In patients requiring systemic therapy for recalcitrant or deforming skin lesions (or for widespread disease), corticosteroids (e.g., prednisone 40 to 80 mg/day, tapered accordingly) used alone or in combination with anti-malarials or methotrexate may be indicated. Anti-malarials and methotrexate are considered 2nd-line interventions and may be used as monotherapy for steroid-resistant sarcoidosis or in patients unable to tolerate steroids. Given the concern regarding ocular toxicity, the maximum dosages of chloroquine and hydroxychloroquine should not exceed 3.5 and 6.5 mg/kg/day, respectively. Methotrexate is given in weekly doses of 10 to 30 mg, with the caveat that hematological, gastro-intestinal (GI), pulmonary and hepatic toxicities are possible. Despite universal acceptance as standard care, the afore-mentioned treatments often result in an incomplete clinical response or unacceptable AEs. In such situations, more innovative treatment options may be used. Treatments that may well gain widespread future use include the TNF-alpha inhibitors infliximab and adalimumab. Experience was limited, but early reports are promising. Infliximab was administered via intravenous infusion at doses of 3 to 10 mg/kg at 0, 2 and 6 weeks and as indicated thereafter, whereas adalimumab was injected subcutaneously at doses of 40 mg either weekly or every 2 weeks. Because adalimumab is not approved for the management of sarcoidosis, the optimum dose administration interval is uncertain. However, it has been given in both weekly and every other week regimens. Isotretinoin, 0.5 to 2 mg/kg/day, has been used successfully in a handful of reported cases. However, the teratogenic potential of isotretinoin is often prohibitive considering that the primary demographic group likely to develop sarcoidosis is women of child-bearing potential. Thalidomide at dosages of 50 to greater than 400 mg/day has limited, albeit promising, supporting data. However, access is restricted in many countries because of a deserved pregnancy category X rating. Melatonin (20 mg/day) and allopurinol (100 to 300 mg/day) are not well studied in cutaneous sarcoidosis, and the clinical experience with tetracycline derivatives has been mixed. That said, there are compelling reports of therapeutic benefit with both doxycycline and minocycline. Because neither of these agents is associated with the severe toxicity of cytotoxic drugs, they may serve as effective therapy in some patients. Pentoxifylline (400 mg, 3 times daily) has been of use in a small number of reported cases of pulmonary sarcoidosis, but there are no reports on its use in patients with primarily cutaneous disease. Both cyclosporine and chlorambucil have been largely abandoned given their associated toxicity and disappointingly unreliable efficacy. Finally, laser therapy is a newer modality that may provide patients with a quick and non-invasive treatment option for cutaneous sarcoidosis.
Toussirot and Pertuiset (2010) noted that increased production of TNF-α by alveolar macrophages and involvement of TNF-α in granuloma formation suggested that this cytokine is involved in the pathophysiology of sarcoidosis. The 3 available TNF-α blocking agents have been tested in sarcoidosis refractory to corticosteroids or immunosuppressive drugs. Data were available from isolated case reports or limited series of patients treated in open-label trials with favorable issue with anti-TNF-α monoclonal antibodies; 2 randomized, placebo-controlled studies evaluated the efficacy of infliximab in pulmonary and extra-pulmonary sarcoidosis, showing that infliximab improved significantly extra-pulmonary disease. There was no significant difference between infliximab and placebo in the treatment of pulmonary manifestations. Etanercept showed no efficacy for treating ocular sarcoidosis in a controlled trial and for pulmonary disease in an open-label trial. Paradoxical cases of proven sarcoidosis have been reported in patients receiving anti-TNF-α agents for chronic inflammatory rheumatic diseases. A literature review identified 28 cases, including 16 with etanercept, 8 with infliximab and 4 with adalimumab. Although these cases were mainly reported with etanercept, paradoxical sarcoidosis has been reported with the 3 available anti-TNF-α agents, suggesting a class effect. Changes in the cytokine balance may be involved in these cases of induced sarcoidosis, which must be known by the clinician.
Drent et al (2014) stated that in severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment, the 3rd-line TNF-α inhibitors infliximab and adalimumab might be an alternative. However, appropriate studies to guide the clinician are lacking. These researchers established practical recommendations for the use of TNF-α inhibitors in the management of refractory sarcoidosis patients. Based on a literature search and the opinion of sarcoidosis experts worldwide, the recommendations were established. Studies conducted in sarcoidosis were supplemented with data obtained from relevant studies in other inflammatory diseases. A Delphi method of polling, using an online survey addressing 12 clinical questions, was performed amongst 20 of the world's leading sarcoidologists to investigate consensus in case of inadequate data to determine an objective answer. Of the 256 papers found, 101 were included. Randomized controlled trials (RCTs) about the use of TNF-α inhibitors in sarcoidosis were limited; 95 % (19 of 20) of the sarcoidologists contacted, completed the questionnaire (Europe 68 %, North America 32 %); 9 recommendations were formulated concerning general aspects of TNF-α inhibitor use. The authors concluded that based on earlier studies and consensus among world's leading sarcoidologists, practical recommendations for the use of TNF-α inhibitors in sarcoidosis were established. These recommendations, with emphasis on indications, dosage and discontinuation regimens, have been developed to support the clinician in the management of refractory sarcoidosis patients.
In a large, observational study, Heidelberger et al (2017) determined the safety and efficacy of anti-TNF in treating cutaneous sarcoidosis. STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multi-center observational database that received data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments . Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. These researchers extracted data for patients with skin involvement at anti-TNF initiation. Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop greater than or equal to 2 points from baseline but greater than 1 at last follow-up). Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46 %]) and nodules (n = 20 [43 %]). The median cutaneous severity score was 5 and/or 6 at baseline; 21 patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93 %). Most patients received infliximab (n = 40 [87 %]), with systemic steroids in 28 cases (61 %) and immunosuppressants in 32 cases (69.5 %). The median (range) follow-up was 45 (3 to 103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14 to 78) years, and 33 patients (72 %) were women. The OCRR was 24 % after 3 months, 46 % after 6 months, and 79 % after 12 months. Steroid sparing was significant. Treatment was discontinued because of AEs in 11 patients (24 %), and 21 infectious events occurred in 14 patients (30 %). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48 %] versus n = 2 of 21 [9.5 %], respectively; p = 0.02). The relapse rate was 44 % 18 months after discontinuation of treatment. Relapses during treatment occurred in 35 % of cases, mostly during anti-TNF or concomitant treatment tapering. The authors concluded that anti-TNF agents were effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered.
Furthermore, an UpToDate review on “Management of cutaneous sarcoidosis” (Prystowsky and Sanchez, 2019) states that “For patients who fail to improve with 1st- and 2nd-line therapies for cutaneous sarcoidosis, we suggest a trial of anti-TNF therapy (Grade 2C). Therapeutic options include infliximab, adalimumab, and thalidomide. Additional study is necessary to confirm the efficacy of these therapies”.
Chronic Pulmonary Sarcoidosis
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.
Chronic Recurrent Multifocal Osteomyelitis (CRMO)
Deutschmann et al (2005) described the case of an 18-year old girl with chronic recurrent multifocal osteomyelitis (CRMO) over a period of 10 years. She had suffered predominantly from very painful recurrent swelling of her cheeks. Various therapeutic regimens including non-steroidal anti-inflammatory drugs (NSAIDs) and steroids had shown only a partial or temporary response. Because tumor necrosis factor-alpha-blocking agents have been successfully applied in Crohn's-associated CRMO and the related SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome, tumor necrosis factor-alpha-blocking therapy with infliximab was initiated. Thereafter, apart from 1 mild episode, no additional recurrences were observed during 21 months of follow-up. Infliximab was well-tolerated, and steroids were tapered off. The authors concluded that their observation indicated that infliximab may be an effective therapeutic option in CRMO.
Crohn's Disease
Infliximab is 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.
: Requires Precertification:
Precertification of infliximab products (Avsola, Inflectra, Remicade, and Renflexis) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Avsola, Inflectra, Remicade, and Renflexis
,call (866) 752-7021 (commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see
Specialty Pharmacy Precertification.
For Medicare Part B plans, call (866) 503-0857 or fax (844) 268-7263.
Note:For commercial plans, Site of Care Utilization Management Policy applies. For information on site of service for infliximab products (Avsola, Inflectra, Remicade, and Renflexis), see
Utilization Management Policy on Site of Care for Specialty Drug Infusions.
Prescriber Specialties
This medication must be prescribed by or in consultation with
oneof the following:
Criteria for Initial Approval
Aetna considers infliximab (Remicade), infliximab-abda (Renflexis), infliximab-axxq (Avsola), and inflixmab-dyyb (Inflectra) medically necessary for members with any of the following indications, where the member has had a documented negative tuberculosis (TB) test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)
Footnotes *within 6 months of initiating therapy for persons who are naïve to biologic drugs or targeted synthetic drugs associated with an increased risk of TB:
Crohn’s disease (CD)
For treatment of moderately to severely active CD in members 6 years of age or older.
Ulcerative colitis (UC)
For treatment of moderately to severely active UC in members 6 years of age or older.
Rheumatoid arthritis (RA)
Member meets
eitherof the following criteria:
Member has been tested for
eitherof the following biomarkers and the test was positive:
Member has been tested for
allof the following biomarkers:
Ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)
Psoriatic arthritis (PsA)
Member has mild to moderate disease and meets
oneof the following criteria:
Member has severe disease;
Plaque psoriasis (PsO)
Behçet’s disease
Hidradenitis suppurativa
Pyoderma gangrenosum
Sarcoidosis
For treatment of sarcoidosis in members when
anyof the following criteria is met:
Takayasu’s arteritis
For treatment of refractory Takayasu’s arteritis when
anyof the follow criteria is met:
Uveitis
Reactive arthritis
Member has experienced an inadequate response to at least a 3-month trial of
oneof the following despite adequate dosing or maximally tolerated dose:
Member has an intolerance or contraindication to methotrexate (see
Appendix) and sulfasalazine (e.g., porphyria, intestinal or urinary obstruction);
Immune Checkpoint Inhibitor Toxicity
For treatment of immune checkpoint inhibitor toxicity when
eitherof the following is met:
For treatment of immune checkpoint inhibitor toxicity when the member has severe inflammatory arthritis and has experienced an inadequate response, intolerance, or contraindication to corticosteroids;
Acute graft verus host disease (GVHD)
For treatment of acute graft versus host disease when
eitherof the following criteria is met:
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy
Crohn’s disease (CD)
Ulcerative colitis (UC)
Rheumatoid arthritis (RA)
For all adult members (including new members) who are using the requested medication for moderately to severely active rheumatoid arthritis and who achieve or maintain a positive clinical response as evidenced by disease activity improvement of at least 20% from baseline in tender joint count, swollen joint count, pain, or disability;
Ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)
For all adult members (including new members) who are using the requested medication for active ankylosing spondylitis or active non-radiographic axial spondyloarthritis and who achieve or maintain a positive clinical response with the requested medication as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in
anyof the following from baseline:
Psoriatic arthritis (PsA)
For all adult members (including new members) who are using the requested medication for psoriatic arthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in
anyof the following from baseline:
Plaque psoriasis (PsO)
For all adult members (including new members) who are using the requested medication for moderate to severe plaque psoriasis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when
anyof the following is met:
Hidradenitis suppurativa
For all members (including new members) who are using the requested medication for severe, refractory hidradenitis suppurativa and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when
anyof the following is met:
Uveitis
For all members (including new members) who are using the requested medication for uveitis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when the patient meets
anyof the following:
Reactive arthritis
For all members (including new members) who are using the requested medication for reactive arthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition (e.g., tender joint count, swollen joint count, or pain);
Immune checkpoint inhibitor toxicity and acute graft verus host disease
For all members (including new members) requesting authorization for continuation of therapy must meet all initial authorization criteria;
All other indications
For all members (including new members) who are using the requested medication for an indication outlined in Section II and who achieve or maintain positive clinical response with the requested medication as evidenced by low disease activity or improvement in signs and symptoms of the condition.
Footnotes* If the screening test for TB is positive, there must be further testing to confirm there is no active disease. Do not administer the requested medication to members with active TB infection. If there is latent disease, TB treatment must be started before initiation of the requested medication.