TDM in Rheumatology: Optimizing Drug Monitoring & Overcoming Barriers
The potential of therapeutic drug monitoring (TDM) to personalize treatment for patients with rheumatic and autoimmune diseases is increasingly recognized, yet significant hurdles remain before it becomes standard practice. While the benefits – real-time insights into medication efficacy and the ability to adjust dosages based on individual patient responses – are clear, challenges related to cost, operational complexity, and a lack of standardized guidelines continue to stymie widespread implementation.
Personalizing Treatment in Complex Conditions
Patients facing challenging rheumatic conditions often receive combinations of expensive medications with intricate mechanisms of action. Understanding how these medications perform in individual patients could significantly improve treatment outcomes. Still, despite growing interest, realizing the full potential of TDM in rheumatology requires addressing existing barriers. As Jeffrey A. Sparks, MD, MMSc, of Brigham and Women’s Hospital, explains, “Therapeutic drug monitoring has great potential to personalize the dosing of biologics and identify neutralizing antibodies that may interfere with efficacy and cause side effects. However, implementation is challenging.”
The fundamental rationale behind personalized dosing lies in the substantial variation in serum drug levels observed among patients receiving the same dose of biologic medications. Eirik Klami Kristianslund, MD, PhD, a senior consultant in rheumatology at Diakonhjemmet Hospital in Oslo, Norway, emphasizes that these serum drug levels correlate with clinical effect. “With TDM, the drug dose is adjusted with the aim of maintaining a serum drug level within a therapeutic range,” he says.
Navigating Therapeutic Ranges and Clinical Complexity
While well-defined therapeutic ranges exist for TNF inhibitors like infliximab (Remicade, Janssen) and adalimumab (Humira, AbbVie), applying TDM to other medication classes proves more complex. The clinical challenges inherent in rheumatic autoimmune conditions further complicate the equation.
Europe has generally been ahead of the curve in adopting TDM. Examining the European experience may offer insights into overcoming domestic barriers in the United States. Robust data for TDM in specific disease and medication combinations, such as infliximab in inflammatory bowel disease-associated arthritis and hydroxychloroquine in lupus, could illuminate how to optimize treatments.
Addressing a ‘Major Problem’ in Lupus
A 2025 study published in Arthritis &. Rheumatology, led by Shivani Garg, MD, PhD, director of the Yale Lupus Clinical Research and co-director of the Yale Lupus Program, aimed to define the upper threshold of hydroxychloroquine (HCQ) blood levels linked to toxicity. Analyzing data from over 1,224 patients enrolled in the Systemic Lupus International Collaborating Clinics studies, researchers identified an optimal therapeutic window between 750 ng/mL and 1,150 ng/mL. Levels exceeding 1,150 ng/mL were associated with a 2.1-fold higher risk of toxicity, specifically retinal toxicity, without providing additional benefit in controlling disease activity.
The study similarly revealed that patients with chronic kidney disease stage 3 or higher were 2.3 times more likely to experience HCQ-related toxicities, likely due to reduced drug clearance. “These levels were associated with a 2.1-fold higher risk for toxicity, specifically retinal toxicity, without providing additional benefit in controlling disease activity,” Garg explained. This finding shifts the focus from simply checking adherence to assessing whether a patient is receiving the appropriate dose, considering factors like kidney function, absorption, and metabolism. Garg emphasizes that this data provides the first concrete evidence that HCQ levels beyond a certain threshold are not beneficial and can be harmful, supporting the employ of TDM as a safety tool alongside regular eye exams.
For patients with chronic kidney disease, checking HCQ levels is no longer optional, but a critical safety measure to prevent permanent vision loss. Michelle Petri, MD, MPH, professor of medicine and director of the Lupus Center at Johns Hopkins University School of Medicine, agrees, noting that monitoring HCQ can also help assess adherence, a major problem in systemic lupus erythematosus (SLE). She argues that both ophthalmology and rheumatology guidelines should reflect these data.
Expanding TDM to Other Medications
Beyond HCQ, mycophenolic acid (MPA) may also be a fruitful avenue for TDM in lupus. A study published March 9, 2026, in Arthritis Care & Research, conducted by Garg and colleagues, examined therapeutic ranges of MPA levels associated with improved outcomes and safety in extra-renal SLE. Their systematic review and meta-analysis found clinical response at MPA AUC 0-12 30-35 mg h/L or Ctrough 1.5 mg/L, demonstrating a 12-fold higher odds of overall clinical SLE response and a 15-fold higher odds of response in patients with extra-renal disease.
“Early evidence highlights the clinical utility of measuring MPA levels in lupus and lupus nephritis,” said Garg. “Staying within the therapeutic range not only helps avoid side effects that reduce tolerability/adherence — eg, stomach upset and diarrhea — but it also yields a 12-fold higher likelihood of a positive clinical response in severe lupus, including lupus nephritis. Moving forward, we need more clinical trials to validate TDM-informed dosing and address concerns about the ‘hype’ surrounding TDM.”
The Role of TDM in Inflammatory Bowel Disease
Konstantinos Papamichail, MD, PhD, and Adam Cheifetz, MD, both of the Center for Inflammatory Bowel Diseases at Beth Israel Deaconess Medical Center and Harvard Medical School, published a key paper on TDM in TNF inhibitors in 2022 in Lancet Gastroenterology Hepatology. Cheifetz stated, “The primary take-home message of the 2022 paper was that TDM can significantly improve outcomes in IBD. The strongest data that support TDM is for anti-TNF therapies, where drug concentrations and anti-drug antibodies are associated with clinical remission, endoscopic healing and treatment durability. We emphasize that proactive TDM can help optimize outcomes and dosing, minimize immunogenicity, and prevent secondary loss of response.”
Sparks notes that much of the research into TDM has focused on infliximab due to its relatively higher rates of immunogenicity. The NOR-DRUM B randomized controlled trial, led by Silje W. Syversen, MD, of the Clinic for Rheumatology, Outpatient Clinic and Research at Diakonhjemmet Hospital, showed that patients undergoing maintenance therapy with infliximab who received proactive TDM had a lower probability of disease worsening at 52 weeks compared to the standard therapy group. However, the NOR-DRUM A trial found that TDM of infliximab did not improve remission rates during the induction period, but did prevent infusion reactions.
Barriers to Implementation and Future Directions
Despite the potential benefits, TDM is not a “magic bullet.” Challenges include the reliability of single-point assessments, the need for specialized knowledge to interpret results, and the lack of complete exposure-response data for many newer agents. Cost considerations and the need for new workflows to act on TDM results also pose barriers.
Europe appears to be further ahead in TDM adoption, potentially due to more centralized healthcare systems, greater emphasis on cost containment, and more affordable assay costs.
Looking ahead, more research is needed, including dose-optimization trials and studies to address concerns about the “hype” surrounding TDM. Standardization of assays and anti-drug antibody levels, along with improved clinician education, are also crucial. A collaborative effort between researchers, clinicians, and guideline developers is needed to unlock the full potential of TDM in rheumatology and improve outcomes for patients with rheumatic and autoimmune diseases.
Sources/Disclosures: Healio Interviews
Therapeutic drug monitoring would seem like an obvious match with rheumatology.
References:
Garg S, et al. Arthritis Rheumatol. 2025;doi:10.1002/art.70010.
Krieckaert CL, et al. Ann Rheum Dis. 2023;doi:10.1136/annrheumdis-2022-222155.
Kawano-Dourado L, et al. BMJ. 2024;doi: 10.1136/bmj-2024-079830.
Papamichail K, et al. Lancet Gastroenterol Hepatol. 2022;doi:10.1016/S2468-1253(21)00223-5.
Qamhieh Z, et al. Arthritis Care Res. 2026;doi:10.1002/acr.80035.
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