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Therapeutic Drug Monitoring in IMIDs
When and how to use therapeutic drug monitoring (TDM) differs among gastroenterology, rheumatology, and dermatology, largely due to the ‘go-to’ medications each specialty relies on and the doses required to treat, agreed panelists at the 2023 virtual Interdisciplinary Autoimmune Summit.
Adam Cheiftez, MD, is director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School. Jeffrey Sparks, MD, is a rheumatologist and researchers at Brigham and Women's Hospital and associate professor of medicine at Harvard Medical School; and Martina Porter, MD, is director of the Clinical Laboratory for Epidemiology
Dr Sparks defined TDM as “clinical laboratory measurement of a clinical parameter that, with appropriate medical interpretation, will directly influence drug prescribing.” Key clinical parameters include drug level and antidrug antibody levels, he explained.
Outside of rheumatology, he said, variations of therapeutic drug monitoring are conducted for such medications as lithium, antiepileptics, vancomycin, and warfarin. With the practice of rheumatology, there is a role for TDM for biologic disease-modifying antirheumatic drugs (DMARDs), especially tumor necrosis factor inhibitors (TNFi); conventional DMARDs, like hydroxychloroquine, “given recent concerns regarding dosing guidelines;” urate-lowering therapy when treating to uric acid target or with pegloticase; and B cell depleting therapies.
Among the biologics, Dr Sparks said, “Infliximab is pretty commonly used in rheumatology, often with concomitant methotrexate. He explained that patients with inflammatory rheumatic diseases often begin therapy on immunomodulators like methotrexate. “Then if they need infliximab as well we often keep them on methotrexate, which gives a better response.”
He noted, “The humanization of monoclonal antibodies has reduced but not eliminated the immunogenicity of monoclonal antibodies commonly used to treat immune-mediated inflammatory diseases.” Immunogenicity causes some patients to develop antidrug antibodies (ADAs), which in turns makes the drug less effective and causes loss of response. The use of immunomodulators can help reduce the risks of ADAs developing and boost the levels of the biologic, making them more effective.
Dr Sparks reviewed the Norwegian Drug Monitoring Study (NOR-DRUM). Part A of this randomized, open-label trial focused on the effect of therapeutic drug monitoring on remission rates in patients treated with infliximab for a variety of IMIDs, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. All patients enrolled had active disease and had not received infliximab in the preceding 6 months. They received 5 mg/kg (3 mg/kg for RA) of infliximab biosimilar at 0, 2, and 6 weeks, then every 8 weeks during the induction phase. The dose was adjusted by decreasing the time between infusions if serum infliximab was low.
“There was no difference in remission rates between the TDM group and the group that received standard care,” during induction, Dr Sparks noted. He pointed out that this study combined patients with different indications for infliximab, which in turn are associated with different risks for drug antibody formation. “Patients at high risk for ADA, like those with RA, represented a small proportion of patients enrolled in this trial,” he also noted.
NOR-DRUM B was an open-label, randomized controlled trial evaluating the effect of TDM during maintenance of remission with infliximab, Dr Sparks said. These patients had to have been in remission and on treatment with infliximab for at least 30 weeks and no more than 3 years. Dose adjustments in TDM were based on infliximab level and ADA formation and the primary outcome was sustained remission at 52 weeks.
“This study favored TDM,” Dr Sparks noted, with 75% of the TDM group showing sustained disease control vs 56% of the standard care group. “It seems that maintaining drug concentration and preventing ADAs may be more important in maintenance than during induction, perhaps because it takes some time for ADAs to form.”
The NOR-DRUM A and B studies left Dr Sparks with several questions, including whether proactive TDM may not be beneficial during remission induction, or whether it has not been studied in the right population. “Should we start using proactive TDM in patients in remission?” he asked. “Are there certain subgroups in which TDM during remission induction or maintenance may be more important—those with a predisposition to ADA formation? Those with RA? Or those not on concomitant immunosuppression?”
He also noted that the study does not answer how reactive TDM might be used among patients showing evidence of drug failure or infusion reaction/hypersensitivity, or for neutralizing ADA formation.
A number of factors can influence the pharmacokinetics of conventional DMARDs, Dr Sparks pointed out. “For some DMARDs, we may use the biomarkers reflecting targets of treatment such as B cells and antineutrophil cytoplasmic antibodies (ANCAs) to guide the use of therapies.”
Dr Porter remarked, “We in dermatology have learned a lot from what other specialists are doing; we don’t really use TDM in dermatology right now but perhaps we will.” She noted that the NOR-DERM B study “is the only paper in dermatology on TDM thus far.” And in that trial, she said, proactive TDM led to longer sustained disease control in psoriasis among patients treated with infliximab.
However, dermatology has “greatly benefited” from the introduction of interleukin (IL)-17 and IL-23 inhibitors, which have shown dramatic efficacy for patients with psoriasis, with patients in trials achieving Psoriasis Area and Severity Index (PASI) scores of 90 and above.
“And although some ADAs were noted in clinical trials, it doesn’t seem to affect overall treatment efficacy,” Dr Porter said. “This is why dermatology hasn’t really pursued TDM.”
The only condition in dermatology in which TNFis is commonly used is in hidradenitis suppurative (HS), she explained. “Adalimumab is the only FDA-approved medication for HS, and it’s often dosed off-label at 80 mg weekly. Infliximab is used almost as often off-label for HS, particularly for those with severe disease.”
This is the prime area in her specialty in which proactive TDM could be most applicable, Dr Porter said. “The presence of ADAs is associated with subtherapeutic response in HS. We are seeing our patients need higher levels and have high rates of clearance of TNFis.” A study found that multiple patients with severe HS “had no detectable drug or antibody levels 3 weeks after infusion” of 10 mg/kg of infliximab infusion or 80 mg of adalimumab weekly.
“With Dr Cheifetz’s help, we are working on a study of HS patients. We’re using drug levels published for GI and are starting to figure out therapeutic responders,” Dr Porter said. “We need drug levels over 25 to achieve good response; levels of 10-15 give only partial response in half of our patients.”
Dr Cheifetz agreed that “HS is almost like perianal Crohn’s disease. That’s where we see patients who require the highest drug concentrations,” and where patients are most likely to respond best to infliximab.
He explained that in IBD, reactive TDM is the measurement of drug concentration and antibody levels in the setting of primary nonresponse or secondary loss of response to a biologic agent. It is more cost-effective and associated with better outcomes than empiric optimization of anti-TNF therapy. The consensus of guidelines for TDM today calls for ensuring drug concentrations of at least 10-15 µg/mL prior to discontinuing infliximab or adalimumab.
Although most data relating to proactive TDM is from maintenance, he said, “I think it’s most important to do proactive TDM during induction, to keep tabs on drug concentrations and help identify the patients with high clearance of drug.” In the rare patient whose drug level checks “show plenty of drug on board but no response, that’s the indicator that you need to switch mechanisms,” Dr Cheifetz continued.
However, he asked, “Why wait for a patient to lose response?” There are data in showing proactive TDM is associated with better outcomes vs empiric dose escalation and reactive TDM.”
The consensus reached in 2021 calls for implementing proactive TDM after induction and at least once during maintenance; after reactive TDM; and when considering combination therapy with immunomodulators. He pointed out that optimizing anti-TNF monotherapy can be an alternative to combination anti-TNF therapy with immunomodulator, and involves lower risks to the patient. Proactive TDM is called for whenever considering de-escalation of a TNFi or stopping an immunomodulator.
“This is most important among patients who clear drug rapidly,” Dr Cheifetz stated. High drug concentration is associated with progression from clinical response to remission, he explained, while low drug concentration is associated with ADAs and loss of response.
Proactive TDM is associated with remission, less surgery, fewer hospitalizations and fewer infusion reactions, according to research, he said. Further, prospective TDM of adalimumab among pediatric patients was associated with higher rates of steroid-free remission at all visits.
“The biggest problem with treatment of IBD is underdosing,” Dr Cheifetz insisted. He reviewed a study of dashboard-driven dosing of infliximab, “which tells you how much drug is needed to reach a certain drug level,” that showed it outperformed typical monitoring. Patients in the precision dosing group reached higher levels of clinical remission (95%) compared to the conventional dosing group (68%) at 1 year. In addition, patients with perianal Crohn disease who were de-escalated to an infliximab level of 3 µg/mL experience reopening of their old fistulae.
Knowledge gaps remain, the panelists agreed. The novel biologics are much less immunogenic and better dosed, they found. There are genetic factors that, when identified, could indicate which patients are likely to more rapidly clear drug. Genetic testing could also help identify patients most at risk for adverse reactions. And more prospective data is needed.
Other questions that remain to be answered include:
- What are the optimal drug concentration thresholds to target?
- What are the right timepoints? Is there a role of peak drug concentrations in TDM?
- How can we properly interpret antidrug antibodies among different assays?
- Is there a role for TDM in non-TNFi biologics?
—Rebecca Mashaw
Sparks JA, Porter M, Cheifetz AS. Therapeutic drug monitoring. Presented at: Interdisciplinary Autoimmune Summit. April 29, 2023. Virtual
