After the first 6 months of disease-modifying antirheumatic drugs (DMARDs) use in patients with rheumatoid arthritis (RA), most very abnormal results newly seen in long-term routine laboratory toxicity monitoring (lt-RLTM) were either already expected or the result of causes unrelated to DMARDs, according to findings from a new study in Annals of Internal Medicine. 

Such results were exceedingly rare, occurring in only 0.15% of cases, and the vast majority of clinical outcomes (93.4%) were mild or moderate or did not involve life-threatening consequences. Further, about four in five very abnormal results were in patients with RA who would have undergone testing anyway because of clinical indications. 

Cumulative 5-year incidence of very abnormal results ranged from 0.3% for low leukocyte counts to 11% for low estimated glomerular filtration rate (eGFR), reported Evy Ulijn, MD, MSc, of Sint Maartenskliniek in Nijmegen, the Netherlands, and her colleagues. 

‘A Large Amount of Unnecessary Testing’

Although incidence was higher for less serious abnormal results — up to 39% for low eGFR and 61% for low hemoglobin — the low occurrence of very abnormal results “suggests the general safety of DMARDs in patients with RA” and matches data seen in large cohorts and clinical trials on DMARDs’ safety, “which show that long-term DMARD treatment rarely causes new clinically relevant hematologic, liver, or renal adverse effects.” Adverse events that do occur, they added, are often not preventable through routine testing beyond 6 months of DMARD use.

“Our findings suggest that the current lt-RLTM practice leads to a large amount of unnecessary testing for some laboratory parameters,” the authors wrote, although they acknowledge that it’s unclear what testing intervals are optimal. Past research has shown wide variation of lab monitoring for conventional DMARDs in clinical practice, and at least one model has been developed to attempt to predict the risk of side effects in patients taking methotrexate.

Current recommendations for long-term routine monitoring for DMARD toxicity past 6 months vary depending on the medical organization and the drug. Generally, it is approximately every 3 months for conventional synthetic DMARDs (both monotherapy and combination therapies) and for rituximab and tocilizumab monotherapy, with no long-term monitoring considered necessary for hydroxychloroquine and for biologic DMARDs.

The lack of harm seen with reduced monitoring during the COVID pandemic has led to discussion about the necessity of current monitoring frequency, the authors noted, adding that less frequent monitoring “could lessen patient and health care burden and costs.”

“I find this study provides compelling evidence that our current intensive monitoring practices for stable DMARD patients may be excessive and not clinically warranted,” Thanda Aung, MD, MS, an assistant clinical professor of rheumatology at the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News. “The very low incidence of markedly abnormal results (0.2% to 6.6% over 2 years) — with nearly half anticipated clinically and over one third requiring no intervention — suggests that much of the testing performed adds little value to patient care.”

Aung said that the findings challenge the current recommendations from ACR and EULAR and “instead support a more individualized, risk-stratified approach.” She still believes in the importance of intensive monitoring during the first 6 months of DMARD therapy, but patients on stable regimens could be safely tested every 6 months. 

“That said, the key limitation is that this was an observational study in which regular monitoring was still performed, so definitive evidence of safety with less frequent testing is lacking,” Aung added. “The practical challenge will be educating both patients and physicians that less frequent monitoring represents higher-value care rather than neglect. Overall, this study provides important justification for moving beyond a ‘one-size-fits-all’ monitoring strategy and toward a more thoughtful, patient-centered approach in rheumatology practice.” 

An Analysis of Retrospective Testing Data 

The authors analyzed retrospective testing data from a cohort of 4774 patients with RA who were undergoing lt-RLTM after taking DMARDs for at least 6 months. The researchers determined the probabilities of abnormal and very abnormal results for alanine aminotransferase (ALT), eGFR, hemoglobin, leukocyte count, and platelet count from 59,555 test sets over 18,383 patient-years, with an average of 12 test sets per patient. 

All participants were patients between July 2008-April 2020 at one of eight locations of the Sint Maartenskliniek rheumatology practice in the Netherlands. The researchers censored data starting in January 2020 because of practice changes at the start of the pandemic. Patients had undergone routine lab toxicity monitoring at 4, 8, 12, and 24 weeks after starting DMARDs and then underwent testing every 3-6 months thereafter, with more frequent testing after dose escalation and when judged clinically appropriate, following recommendations from the European Alliance of Associations for Rheumatology. The median time from starting DMARD treatment to the first long-term monitoring test was 9.4 months. 

Data were excluded for those taking baricitinib or tofacitinib because of their rare use, for DMARDs no longer available or used for treating RA, and for combinations of biologic DMARDs. The analysis, therefore, included five conventional synthetic DMARDs — methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, and azathioprine — and 10 biologic DMARDs: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, rituximab, sarilumab, tocilizumab, and anakinra. 

Abnormal results during the first 6 months of DMARD monotherapy or combination therapy occurred in 0.9%-1.3% of patients’ exposure periods for ALT, leukocyte count, and platelet count while 5.3% of eGFR and 12% of hemoglobin tests were abnormal. Very abnormal results were even rarer: 1.3% for eGFR, 0% for ALT, and under 0.5% for hemoglobin, leukocyte count, and platelet count.

Overall, 5.8% of individual tests were abnormal, and 0.69% were very abnormal, including 0.15% that were new very abnormal results (449 tests). The cumulative probabilities of abnormal results for the five tests ranged from 4.4% to 47% at 2 years and 7.5% to 61% at 5 years. Cumulative probabilities for very abnormal results had a smaller and lower range of 0.2% (in leukocyte count) to 6.6% (eGFR) at 2 years and 0.3% (leukocyte count) to 11% (eGFR) at 5 years.

Nearly half of the new very abnormal results (47.7%) were already known or suspected by the provider, and most (82.2%) occurred in tests that would have been done based on indication because of signs, symptoms, or recent history. About one in five new very abnormal results were in patients who had had a very abnormal result in their first 6 months of that DMARD (20.7%) or during use of previous DMARDs (22.8%). The new very abnormal result occurred after a dose increase in 6.5% of instances. 

Nearly a quarter of new very abnormal results (24.1%) were determined not to be related to DMARD use but were instead caused by renal and urinary disorders, other non-DMARD medications, wound complications, or hemorrhage during or after surgery. 

More than a third of the new very abnormal results (35.8%) did not lead to any action. Actions taken in other cases included decreasing or stopping DMARD use (14.2%), additional diagnostics (12.9%), lifestyle advice (3.3%), changing treatment (5.6%), referral to another physician (29.6%), and hospital admission (7.1%)

Clinical outcomes in patients with new very abnormal results were mostly mild or moderate (73.8%) or severe but without life-threatening consequences (19.6%). Three patients (0.7%) experienced life-threatening consequences, and one patient died.

The research did not use external funding. Some authors disclosed receiving grants from or serving as a consultant to pharmaceutical companies unrelated to the current study. Some of the companies manufacture DMARDs included in the study. Aung had no relevant financial disclosures.

August 25, 2025 — Editor's note: This article has been updated to include an interview with an independent commentator.

Tara Haelle is a science and health journalist based in Dallas.