Immunogenicity
Bruce Strober, MD, PhD
In this presentation, Dr Strober discusses the important concept of immunogenicity as it relates to the management of psoriasis and the use of biologic therapy. There are several factors that lead to the loss of therapeutic response. These factors include drug level reduction, specifically immunogenicity, suboptimal dosing schedules (e.g. etanercept step-down dosing, infliximab every eight weeks and ustekinumab given every 84 days) and poor patient adherence. Another issue is that of altered pathophysiology of the disease in the face of the therapy applied, i.e., one can see a loss of therapeutic response without immunogenicity.
What is Immunogenicity?
By definition, foreign proteins are immunogenic. Biologic therapies for the treatment of psoriasis are all foreign, even though they are based on natural forming molecules. Immunogenicity requires that a protein has to be more than just “foreign”, i.e., different biologic drugs exhibit different degrees of immunogenicity. Immunogenicity inhibits therapeutic response and may increase risk.
Do Biologic Medications Lose Efficacy When Treating Psoriasis?
Infliximab begins with very high efficacy, PASI 75 scores are nearly 80%; however, after about one year of Q 8 week dosing, one loses about one third of patients who initially achieved a PASI 75. This could be due to pharmacokinetics; however, in part, it is probably due to immunogenicity.
Initially, 100 % of adalimumab responders achieved a score of PASI 75, but after about two years, only three quarters of those patients were still at a PASI 75.
At week 48, 61% and 63% of patients on etanercept achieved a PASI 75; however, at week 96, that number had fallen by 18%.
Ustekinumab also demonstrated a drop-off regarding therapeutic efficacy.
Clinical Pearl-Loss of therapeutic response is part of the issue when treating psoriasis patients with biologic therapies
The Manufacturers of Biologics Acknowledge Immunogencity
Infliximab
In psoriasis clinical trials, antibodies were observed in 20-36% of patients treated with 5 mg/kg every eight weeks for one year. A higher incidence of antibodies to infliximab was observed in Crohn’s disease patients receiving infliximab after drug free intervals for more than 16 weeks. In psoriatic arthritis studies, patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and infusion reactions, which is an important safety issue. Antibody development was lower among RA and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/azathioprine or methotrexate.
Adalimumab
Approximately 5% of RA patients developed low-titer antibodies to adalimumab at least once during one year of treatment, which were neutralizing in vitro. Patients who were treated with concomitant methotrexate had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. ACR 20 responses are lower among antibody-positive patients than among those patients who are anti-body negative.
Etanercept
Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS, or PsO. Antibodies were all non-neutralizing. The percentage of patients testing positive increases with an increase in the duration of study. There was not a correlation of antibody development to clinical response nor were there any adverse events. There was no effect with methotrexate.
Ustekinumab
In Study 1 and Study 2 looking at ustekinumab and immunogenicity, 3-5% of patients, respectively, showed antibodies against drug. 48% to 90% of patients studied were inconclusive. Data presented at a recent EADV meeting demonstrates that immunogenicity against ustekinumab correlates with reduction in response long-term.
Clinical Pearl-More frequent administration of a biologic tends to reduce immunogenicity
Should we care about “neutralizing” vs. “non-neutralizing” antibodies?
Dr Strober feels that dermatologists should really care about whether or not a drug has an antibody raised against it and if so, does the body remove the drug from circulation…?
In patients, antibodies against adalimumab and infliximab usually bind to the antigen (TNF) binding domain; therefore, they “neutralize” the ability of the drug to bind to TNF. Antibodies that are raised against etanercept fall into what’s referred to as the hinge domain that really mediates the linkage between the Fc domain and the TNF receptor domain. So, while they bind to the molecule, they do not neutralize its ability to block TNF, i.e. “non-neutralizing”.
Open Label Studies
Switching to Etanercept after Failure to either Adalimumab or Infliximab for Treatment of RA
This study evaluated 292 patients with rheumatoid arthritis. 203 patients were anti-TNF naïve. 89 of the patients had been previously treated with either infliximab (n=30) or adalimumab (n=59), and then switched to etanercept. 32% of the patients were non-responders since the start of the treatment with either infliximab or adalimumab and 68% of the patients had lost the initial response. Out of the 89 patients who switched to etanercept, 47 patients (53%) had antibodies against adalimumab or infliximab as measured at baseline prior to the start of etanercept treatment. Patients with detectable anti-drug antibodies had significantly lower doses of methotrexate at baseline compared to patients without antibodies (p=0.031).
Patients who were anti-TNF naive were compared to switchers without antibodies and a DAS28 improvement was significantly larger in patients who were anti-TNF naïve after 28 weeks of etanercept treatment. There was no significant difference in the improvement in DAS28 between patients who were TNF naïve compared to switchers with antibodies. The improvement in DAS28 was significantly larger in switchers with anti-drug antibodies compared to switchers without antibodies. This study concludes that altered disease pathophysiology may play a greater role in patients who lose response without showing immunogenicity. Immunogenicity is only part of the equation.
Anti-adalimumab Antibodies are Associated with Lower Adalimumab Concentrations and Treatment Non-response
This was a prospective observational cohort study looking at 121 consecutive RA patients treated with adalimumab and a concomitant DMARD or adalimumab alone. During 28 weeks of follow-up, antibodies were detected in 21 (17%) of patients. Serum adalimumab concentrations in patients with anti-adalimumab antibodies were significantly lower than in patients without these antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/ l, range 2.0–33.0; p,0.001). Non-responders had anti-adalimumab antibodies significantly more often than good responders (p=0.006).
Higher concentrations correlate with better clinical response
Extent and Clinical Consequences of Antibody Formation Against Adalimumab in Patients with Plaque Psoriasis
This was a prospective observational cohort study looking at 29 psoriasis patients, 17% (5 of 29) also had psoriatic arthritis. Patients were given standard adalimumab dosing (40 mg) every other week after an initial dose of 80 mg and a dose of 40 mg the week thereafter. Adalimumab trough concentration was measured 12 and 24 weeks after the initiation of treatment. This study correlates with the data presented above (RA) in that the lower the concentration of drug, the lower the response and low antibodies to drug demonstrates better clinical response. Three patients used concomitant methotrexate and none of these patients developed antibodies to adalimumab.
There are a lot of data that suggest that methotrexate blocks immunogenicity. There should be no doubt regarding methotrexate and therapeutic efficacy.
Patients Not Responding to Etanercept Show Lower Trough Etanercept Concentrations Compared to Responding Patients
This was a prospective, single center observational cohort study from Amsterdam. The study looked at 292 consecutive patients with active RA who were given a new etanercept prescription. Clinical response and etanercept levels were collected at baseline and after 1, 4 and 6 months of etanercept treatment. Trough serum etanercept levels were measured by ELISA.
The study showed that patients with good clinical response display significantly higher levels of etanercept than patients who were not responding. Anti-etanercept antibodies were measured by 4 different assays and no anti-etanercept antibodies were detected which is a different response from that of infliximab and adalimumab. The absolute differences in etanercept levels between responding and non-responding patients were small. Immunogenicity may not explain the lack of response in RA patients treated with etanercept.
Effect of MTX on Efficacy with Etanercept
When looking at patients who are methotrexate non-responders and who were either given methotrexate with etanercept and then tapered off the methotrexate or continued the methotrexate, it is clear that those who tapered off the methotrexate did not respond as well; therefore, demonstrating that methotrexate has some effect on etanercept response.
A Basic Approach to Moderate to Severe Psoriasis or Psoriatic Arthritis
Healthcare providers should initiate therapy with methotrexate and allow 12 weeks to demonstrate a response. If methotrexate monotherapy is inadequate, a biologic should be added. Dr Strober continues the methotrexate indefinitely because of the data that demonstrates a better clinical response.
Conclusions
- Biologics should be dosed without interruption and at intervals that make sense with regard to the drug’s half-life.
- Concomitant MTX (or, possibly, azathioprine) blunts immunogenicity
- When given with MTX, biologic agents invariably show greater and more durable efficacy, even when MTX is ineffective as monotherapy
- A sensible practice is to add a biologic therapy to MTX, not vice versa, as once immunogenicity occurs it may be difficult to reverse
