Results Interpretation

Please click below to display the details for each drug

Adalimumab

Adalimumab Level	Detectable Antibody	Clinical Evidence
Not detected or ADA<6 µg/ml	Not detected	In patients with IBD, higher trough levels of adalimumab (ADA) are associated with better patient outcomes, including remission and mucosal healing. ^1,2 Multiple studies have associated an ADA trough level of 4.9 – 6.5 µg/ml with improved outcomes in patients with IBD. ^2,3,4 One study proposed that ADA trough levels of 8 – 12 µg/ml are required to achieve mucosal healing. ¹¹ Low trough levels of ADA in serum without antibodies to adalimumab (ATA) is predictive of a favorable clinical response after ADA dose and/or frequency optimization in patients with IBD. ⁴
Interpretation/Action**
A higher dose of adalimumab or shortening the dosing interval may be appropriate.

Adalimumab Level	Detectable Antibody	Low ADA trough serum concentration is observed more frequently in patients who develop ATA. ⁵ Presence of ATA predicts a lack of mucosal healing in patients with IBD. ² Patients with high titers of ATA and poor response have been shown to have longer duration of response when anti-TNF agents have been switched compared with patients whose dosage was increased. ⁶ Some patients on anti-TNF therapy may develop antibodies that resolve over time. ^{6, 7, 8}
Not detected or ADA<6 µg/ml	Detected
Interpretation/Action**
In good responders, repeat test to see if antibodies resolve. In poor responders, a change to another anti-TNF drug and/or addition of concomitant immunosuppressant may be appropriate.

Adalimumab Level	Detectable Antibody	In patients with IBD with loss of response to ADA, one study showed high trough levels (>4.9µg/ml) of ADA were associated with failure of two anti-TNF agents (ADA and infliximab) in 90% of cases. Switching these patients to another therapeutic class should be considered. ⁴ In patients with CD that fail to respond to anti-TNF therapy but have a therapeutic drug concentration and low or undetectable antibody levels, clinical guidelines suggest a switch to another drug class. ⁹ In patients with UC that fail to respond to anti TNF therapy but have a therapeutic drug concentration, clinical guidelines suggest a switch to another drug class. ¹⁰
ADA>6 µg/ml	Not Detected
Interpretation/Action**
In patients who do not have antibodies that do not respond or lose response, a change to another therapeutic class (not targeting TNFα) may be appropriate.

Adalimumab Level	Detectable Antibody	Data are limited One study demonstrated that exceeding an ADA trough level of 12 µg/ml produces only a negligible gain in proportion of patients with mucosal healing. ¹¹ In patients with IBD with good response to other biologic therapies, supra therapeutic doses have been reduced without disease flares, resulting in significant cost saving. ¹²
ADA>12 µg/ml	Not Detected
Interpretation/Action**
In good responders, consider a reduction in dose to reduce potential AEs.

** These findings are not diagnostic. They should be independently evaluated by the treating physician and used to supplement clinical findings in accordance with the treating physician’s independent medical judgment.

Certolizumab

Certolizumab Level	Detectable Antibody	Literature Findings**
Week 6: Not detected or CZP </= 43 µg/ml Week 12: Not detected or CZP </= 18 µg/ml	Not detected	Endoscopic response and remission are associated with higher plasma concentrations of certolizumab pegol (CZP). ¹ A significant inverse relationship has been found between plasma concentration of CZP and C-reactive protein. ¹ In a study of CZP dose optimization in patients with CD, remission rates were higher in patients whose CZP levels were greater than 27.5 µg/ml using an in-house ELISA assay. ² Inform Tx drug levels were validated with drug levels measured by the UCB in-house ELISA assay. The tests had good correlation, although Inform Tx tended to consistently measure 19% higher than the in-house test. ³ The association between CZP levels and achievement of several definitions of clinical response has been studied in a large pooled dataset of pivotal trials. ⁴ The CZP levels measured by InformTx have been extrapolated to be: Week 6 CZP >/= 43 µg/ml associated with CDAI < 150 and FC </= 250 µg/ml; Week 12, CZP levels >/= 18 µg/ml associated with CDAI < 150 and FC </= 250 µg/ml at week 26. ^4,5
Interpretation/Action**
Check patient compliance to treatment. A higher dose of certolizumab or shortening the dosing interval may be appropriate.

Certolizumab Level	Detectable Antibody	Data are limited Clinical trials exploring CZP immunogenicity have not found a relationship between development of antibodies to certolizumab (ATC) and clinical response.^6,7,8,9,10 Some patients on anti-TNF therapy may develop antibodies that resolve over time. ^11,12,13 The presence of antibodies to certolizumab has been associated with decreased serum CZP levels and decreased clinical efficacy in rheumatoid arthritis trials. ¹⁴
Week 6: Not detected or CZP </= 43 µg/ml Week 12: Not detected or CZP </= 18 µg/ml	Detected
Interpretation/Action**
In good responders, repeat test to see if antibodies resolve. In poor responders, a change to another anti TNF drug and/or addition of concomitant immunosuppressant may be appropriate.

Certolizumab Level	Detectable Antibody	Data are limited. In patients with CD that fail to respond to anti-TNF therapy but have a therapeutic drug concentration and low or undetectable antibody levels, clinical guidelines suggest a switch to another drug class.¹⁵
Week 6: Not detected or CZP > 43 µg/ml Week 12: Not detected or CZP > 18 µg/ml	Not Detected
Interpretation/Action**
In poor responders who do not have antibodies, a change to another therapeutic class (not targeting TNFα) may be appropriate.

Certolizumab Level	Detectable Antibody	Data are limited. In patients with IBD with good response to other biologic therapies, supra therapeutic doses have been reduced without disease flares, resulting in significant cost saving. ¹⁶
Upper range trough level	Not Detected
Interpretation/Action**
In good responders, consider a reduction in dose to reduce potential AEs.

Infliximab

Infliximab Level	Detectable Antibody	Clinical Evidence
Not detected or IFX<3.5 µg/ml	Not detected	In patients with IBD, trough levels of infliximab (IFX) are correlated with clinical response, clinical remission, and mucosal healing. ^1,2,3 Multiple studies have associated an IFX trough level of 3.5 µg/ml or higher with improved outcomes in patients with IBD. ^1,4,5,17 IFX trough levels > 3-4 µg/ml at week 8–14 may predict long term response to maintenance therapy. ^1,2 One study showed that levels of IFX above 5 µg/ml identified patients with mucosal healing with 85% specificity and proposed that IFX trough levels of 6 – 10 µg/ml are required to achieve mucosal healing. ¹⁷ Patients with loss of response to IFX with no antibodies to infliximab (ATIs) and sub therapeutic drug concentrations have benefited from dose escalation. ^6,7
Interpretation/Action**
A higher dose of infliximab or shortening the dosing interval may be appropriate.

Infliximab Level	Detectable Antibody	Multiple studies have established that antibodies to infliximab (ATI) have negative effects on clinical outcomes of patients with IBD and the presence of ATI has been consistently associated with lower IFX levels. ⁸ Observations from randomized, controlled trials have shown that concomitant use of immunosuppressants increases anti-TNF levels^4,8 and decreases the number of patients with ATI. ⁹ Patients with high titers of ATI have been shown to have longer duration of response⁹ and greater likelihood of response⁶ when anti-TNF agents have been switched than patients whose dosage was increased. However, some patients on IFX therapy may develop antibodies that resolve over time. ^9,10,11
Not detected or IFX<3.5 µg/ml	Detected
Interpretation/Action**
In good responders, repeat test to see if antibodies resolve. In poor responders, a change to another anti-TNF drug and/or addition of concomitant immunosuppressant may be appropriate.

Infliximab Level	Detectable Antibody	In patients with adequate trough levels who do not respond or who lose response, but are ATI negative, inflammation may be driven by processes that are not TNF dependent. A switch to an out of class agent might be optimal. ¹² In patients with CD that fail to respond to anti-TNF therapy but have a therapeutic drug concentration and low or undetectable antibody levels, clinical guidelines suggest a switch to another drug class. ¹³ In patients with UC that fail to respond to anti-TNF therapy but have a therapeutic drug concentration, clinical guidelines suggest a switch to another drug class. ¹⁴
IFX>3.5 µg/ml	Not Detected
Interpretation/Action**
In patients who do not have antibodies that do not respond or lose response, a change to another therapeutic class (not targeting TNFα) may be appropriate.

Infliximab Level	Detectable Antibody	Testing for drug levels and antibodies in patients with secondary loss of response is more effective when compared with empiric drug escalation. ^15,16 Increasing levels of IFX beyond 8 µg/ml produced only minimal increases in the rate of mucosal healing. ¹⁷ Dose reduction in IBD patients with supra optimal IFX concentrations has been shown not to lead to flares or an increase in inflammatory markers, but did result in a significant cost saving. ⁵
IFX>10 µg/ml	Not Detected
Interpretation/Action**
In good responders, consider a reduction in dose to reduce potential AEs.

Vedolizumab

Vedolizumab Level	Detectable Antibody	Literature Findings**
VDZ<40 µg/ml*	Not detected	In the induction phase of the VDZ clinical trials (week 6), VDZ levels were higher in responders than non-responders. ^{1, 2} In a study of endoscopic outcomes in patients with UC treated with VDZ, at week 6 mucosal healing was more common and endoscopic scores were lower in patients with higher VDZ trough concentrations. ³ Patients with sustained remission at induction week 6 had higher VDZ trough levels (41.7µg/ml vs 21µg/ml p = 0.07). ⁴ A cutoff for VDZ at week 6 was predictive of sustained remission without need for optimization. ⁴ Data on dose adjustment of VDZ are limited. However, in one study of patients with IBD who had lost response to VDZ every 8 weeks, clinical remission and clinical response rates increased after VDZ dosing frequency was increased to every 4 weeks. ⁵ Data on maintenance levels of VDZ are limited. However, in three studies in which patients were treated for approximately one year, higher drug levels were associated with higher rates of response. ^{1, 2, 5}
Interpretation/Action**
In poor responders, shortening the dosing interval may be appropriate.

Vedolizumab Level	Detectable Antibody	Data are limited. Some patients on biologic therapy may develop antibodies that resolve over time. ^6,7,8 In clinical trials, approximately 4% of patients treated with VDZ had samples that were positive for ATV at any time and 1% or less had samples that were persistently positive. ^1,2
VDZ<40 µg/ml*	Detected
Interpretation/Action**
In poor responders, shortening the dosing interval may be appropriate.

Vedolizumab Level	Detectable Antibody	Data are limited. In patients with UC that lose response to VDZ but are receiving 300mg every 4 weeks, clinical guidelines suggest a switch to another drug class. ⁹
VDZ>40 µg/ml*	Not Detected
Interpretation/Action**
In poor responders who do not have antibodies, a change to another drug regimen may be appropriate.

¹ Feagan B, Rutgeerts P, Sands B, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. NEJM. 2013 Aug;369(8):699-710.
² Sandborn W, Feagan B, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. NEJM. 2013 Aug;369(8):699-710.
³ Rosario M, Abhyankar B, Sankoh S, et al. Relationship between Vedolizumab pharmacokinetics and endoscopic outcomes in patients with ulcerative colitis. ECCO Abstract. 2015. Session 5: DOP 040.
⁴ Williet N, Fovet M, Claudez P, et al. Serum Vedolizumab assay at week 6 predicts sustained clinical remission and lack of recourse to optimization in IBD. ECCO abstract. 2016.
⁵ Sands B, Dubinsky M, Vermeire S, et al. Effects of increased Vedolizumab dosing frequency on clinical remission and response in ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2014;20:S67.
⁶ Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015 Mar;13(3):522-530.
⁷ Ungar B, Chowers Y, Yavzori M et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014 Aug;63(8):1258-64.
⁸ Roblin X, Marotte H, Leclerc M, et al. Combination of C-reactive protein, infliximab trough levels and stable but not transient antibodies to infliximab are associated with loss of response to infliximab in inflammatory bowel disease. J Crohn’s Colitis. 2015 Jul;9(7):525-31.
⁹ Dassopoulos T, Cohen R, Scherl T, et al. Ulcerative colitis clinical care pathway. Gastroenterology. 2015 Jul;149(1):238-45.

Ustekinumab

Ustekinumab Trough Level	Detectable Antibody	Clinical Evidence
UST<1 µg/ml	Not detected	The maintenance study showed that both UST 90 mg IM q8w and q12w maintained clinical response and remission through Week 44. However, the q8w regimen more consistently demonstrated efficacy across the range of endpoints.¹ In a sub study of patients (n=102) with endoscopy at baseline and Week 44, the proportions of patients achieving endoscopic response, endoscopic remission, and mucosal healing were higher in the 2nd (> 0.5 µg/ml -1.39 µg/ml), 3rd (>1.39 µg/ml – 2.67 µg/ml), and 4th (>2.67 µg/ml) concentration quartiles.² A second study of patients with CD treated with UST showed 78% of patients were receiving UST 90 mg IM every 4 weeks after > 6 months.³
Interpretation/Action**
In poor responders, shortening the dosing interval may be appropriate.

Ustekinumab Trough Level	Detectable Antibody	Data are limited. In the phase II clinical trial, the incidence of antibodies to UST was 0.7% at week 36.² In the pooled results of the phase III clinical trial, the incidence of antibodies to UST was 2.3% through one year.¹ Some patients on biologic therapy may develop antibodies that resolve over time. ^{7, 8, 9}
UST < 1 µg/ml	Detected
Interpretation/Action**
In poor responders, a change to another drug regimen may be appropriate.

Ustekinumab Trough Level	Detectable Antibody	Data are limited.
UST >/ 1 µg/ml	Not Detected
Interpretation/Action**
In patients who do not have antibodies that do not respond or lose response, a change to another drug regimen may be appropriate.

¹ Adedokun O, Xu Z, Gasink C, et al. Pharmacokinetics and exposure-response relationships of ustekinumab during IV induction and SC maintenance treatment of patients with Crohn’s disease with ustekinumab: results from the UNITI-1, UNITI-2, and IM-UNITI studies. Program and abstracts of Digestive Disease Week 2016; May 21-24, 2016; San Diego, California. Abstract Sa1934.
² Sandborn W, Gasink C, Gao L, CERTIFI Study Group, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012 Oct18;367(16):1519-28.
³ Feagan B, Sandborn W, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease patients. N Engl J Med. Nov 2016;375:1946-1960.
⁴ Sandborn W, Feagan B, Gasink C, et al. A randomized multicenter, double blind, placebo-controlled study of ustekinumab maintenance therapy in moderate-to-severe Crohn’s disease patients: Results from IM-UNITI. Gastroenterology. April 2016;150(4):S157-S158.
⁵ Battat R, Kopylov U, Bessissow T, et al. Association of ustekinumab trough concentrations with clinical, biochemical and endoscopic outcomes. Program and abstracts of Digestive Disease Week 2016; May 21-24, 2016; San Diego, California. Abstract 696.
⁶ Data on file, Janssen.
⁷ Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015 Mar;13(3):522-530.
⁸ Ungar B, Chowers Y, Yavzori M et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014 Aug;63(8):1258-64.
⁹ Roblin X, Marotte H, Leclerc M, et al. Combination of C-reactive protein, infliximab trough levels and stable but not transient antibodies to infliximab are associated with loss of response to infliximab in inflammatory bowel disease. J Crohn’s Colitis. 2015 Jul;9(7):525-31.

Golimumab

Golimumab Trough Level	Detectable Antibody	Clinical Evidence
Week 6 – GLM<2.5μg/ml Maintenance – GLM<1.4 μg/ml	Not detected	In both the induction and maintenance phases of the GLM phase II/III trials in patients with UC, the quartile of patients with the highest serum levels of GLM had the best clinical responses.¹ During the induction phase of the GLM phase II trials in patients with UC, patients with the highest GLM exposure showed the highest rates of clinical response (p=0.024) and clinical remission (p=0.036) at week 6.² Among 398 patients who were non responders by week 6 (induction), 15.6% achieved partial Mayo score remission and 28.1% achieved response by week 14. Further continued therapy produced minimal incremental benefit.³ In the phase III trial, higher serum GLM concentrations at week 54 were associated with greater proportions of patients who maintained clinical response through week 54 and clinical remission through weeks 30 and 54.⁴Further, higher GLM trough concentrations at week 28 were indicative of future efficacy outcomes.⁵ Two studies have demonstrated a serum GLM concentration of 2.5μg/ml at week 6 (induction) is estimated to be a desirable target for optimal clinical outcomes.^{5, 6} In the phase III trial, a maintenance steady state trough GLM concentration of 1.4μg/ml is estimated to be a desirable target for optimal clinical outcomes.⁵ Several studies have shown higher concentrations of IFX and ADA are needed to induce mucosal healing^{7, 8}and, similarly, higher serum golimumab concentrations were observed in patients achieving more stringent efficacy outcomes.⁹ No clinical data are available regarding shortening dosing intervals because the steady-state concentration was stable from week 8 through week 54 in the phase III clinical trial.¹⁰
Response Interpretation/Action
In poor responders, shortening the dosing interval may be appropriate.

Golimumab Trough Level	Detectable Antibody	In the phase III study, the overall incidence of antibodies to GLM through week 54 was 2.9%. Antibodies were more common in patients not receiving concomitant immunomodulators (3.8% vs 1.1% p=0.013).³ In the phase III study, median steady state serum GLM concentrations were slightly higher in patients receiving concomitant immunomodulators with the 50 mg GLM dose, but use of immunomodulators did not affect serum GLM concentrations in patients receiving the 100mg GLM dose.⁵ Some patients on anti-TNF therapy may develop antibodies that resolve over time.^{11, 12, 13}
GLM<2.5μg/ml Maintenance – GLM<1.4 μg/ml	Detected
Response Interpretation/Action
In poor responders, addition of immunomodulators or a change to another drug regimen may be appropriate.

Golimumab Trough Level	Detectable Antibody	Data are limited.
GLM >/= 2.5μg/ml	Not Detected
Response Interpretation/Action
In patients who do not have antibodies that do not respond or lose response, a change to another drug regimen may be appropriate.

ADAb* = Anti-Drug Antibodies