Rare diseases are defined in European legislation as life-threatening, chronic, or debilitating conditions affecting fewer than 1 in 2,000 people. Many are genetically determined and manifest in early childhood, but a growing subset of patients is now reaching older age, a shift driven by improved medical care and the development of new therapeutic options. Conditions such as chronic myeloid leukemia and cystic fibrosis have seen average life expectancy increase by more than 10 years in recent decades. This breakthrough, however, has created an unexpected challenge: a widening gap in the continuum of care for geriatric patients, whose aging bodies must cope with both the rare disease itself and the cumulative burden of multiple medications prescribed over a lifetime.

Drug-related problems are events or circumstances related to the effectiveness or safety of therapy that may negatively impact therapeutic outcomes. According to the Pharmaceutical Care Network Europe classification, version 9.1, DRPs encompass a broad range of issues, including adverse drug reactions, suboptimal therapeutic response, overdose, inappropriate prescribing, dosing problems, and medication-related safety concerns. Older adults with rare diseases are particularly vulnerable because of delayed diagnosis, limited evidence from clinical trials, multimorbidity, polypharmacy, and the need for lifelong therapy. Age-related changes such as reduced physiological reserve and altered homeostasis, combined with complications from the rare disease itself, require timely and adequate responses, as any delay in adjusting therapy can lead to rapid clinical deterioration.

The research team, led by investigators at the University Hospital for Active Treatment in Endocrinology (USHATE) Acad. Ivan Penchev in Sofia, applied a three-step methodology. First, they conducted a systematic review following the PRISMA statement, searching PubMed and Google Scholar from February 2015 to February 2025 for studies on DRPs in geriatric patients with rare diseases. Second, they performed a retrospective analysis of patients with acromegaly hospitalized at the national Expert Center for Rare Endocrine Diseases in 2021, applying the STOPP/START criteria to identify potentially inappropriate prescribing. Third, they explored the odds of experiencing a DRP according to the presence of polypharmacy and multimorbidity, using crude odds ratios with 95% confidence intervals.

The systematic review identified 188 publications in the primary search, but after applying inclusion and exclusion criteria, only six studies made the final analysis. Two were conducted in Italy, two in the United States, and one each in Greece and China. Four of the publications were case reports or case series. The majority of diagnoses belonged to oncological diseases, with additional studies covering infectious, immune, nervous, and renal system disorders. The medicines involved included orphan drugs such as bortezomib, lenalidomide, dabrafenib, trametinib, rituximab, and colchicine. Critically, none of the studies reported the use of a standardized method for DRP identification or classification, and due to heterogeneity in reporting, the total number of geriatric patients and their distribution by sex remain unknown.

The most common DRPs were associated with therapeutic failure and adverse drug reactions, which were inherently serious because they led to hospitalization or death. Safety-related problems often resulted from improper dosing. In patients with plasma cell dyscrasias, dose reduction or treatment modification was described as a key intervention to minimize the risk of neutropenia, anemia, infections, and thrombocytopenia. In Erdheim-Chester disease, drug-induced congestive heart failure required discontinuation of the MEK inhibitor trametinib and a dose reduction of the BRAF inhibitor dabrafenib, resulting in partial remission. In Philadelphia chromosome-positive chronic myeloid leukemia, older age and a history of diabetes were identified as factors associated with cardiovascular events in patients receiving tyrosine kinase inhibitors, with coronary artery disease, acute myocardial infarction, and congestive heart failure among the most common serious adverse events.

Effectiveness-related DRPs were often linked to the complexity of the patients’ clinical conditions. In a patient with chronic inflammatory demyelinating polyneuropathy, problems included non-adherence to therapy, late diagnosis of pulmonary nocardiosis secondary to immunosuppressive therapy, and non-compliance with preventive treatment. The patient subsequently died despite prescribed antibiotic therapy. In a case of Goodpasture syndrome, no restoration of renal function was achieved despite therapy with apheresis, immunomodulators, rituximab, and corticosteroids. In a 65-year-old patient with familial Mediterranean fever, the patient proved to be a colchicine non-responder, and subsequent administration of anakinra, due to issues with canakinumab availability, further worsened the condition, ultimately resulting in peritoneal mesothelioma due to lack of effective therapy.

The retrospective cohort study focused on acromegaly, a rare chronic endocrine disease caused by excessive growth hormone secretion from a pituitary tumor. Of 180 hospitalized patients with acromegaly, 42 (23.3%) met the geriatric age criterion of 65 years or older. The majority were women (71%), with an average age at diagnosis of 52 years. Somatostatin analog monotherapy was the most frequently prescribed therapy. Polypharmacy, defined as the use of five or more medications, affected 83% of the study population, while multimorbidity, defined as the presence of two or more diseases, affected 95%. Using the STOPP/START criteria, the team identified 14 DRPs in 14 patients (33%), with 10 potentially inappropriate medications and 4 cases of prescribing omissions. An additional 2 DRPs were identified through comparison with the Summary of Product Characteristics.

The potentially inappropriate medications mainly affected the endocrine, cardiovascular, and central nervous systems. These included the use of extended-acting sulfonylureas in five patients, long-term benzodiazepine use in two patients, concomitant use of drugs with anticholinergic effects, and duplicate nootropic therapy. Prescribing omissions included the lack of proton pump inhibitors in patients with severe gastropathy and deficiencies in beta-blocker prescription for coronary heart disease. The additional SmPC-based DRPs involved torasemide prescribed to a patient with gout, a stated contraindication, and the concomitant use of empagliflozin with diuretics and ACE inhibitors, which increases the risk of hypovolemia. These cases fall outside the scope of standard STOPP/START criteria but highlight the clinical relevance of individualized structured medication review.

Interestingly, the exploratory odds ratio analyses did not demonstrate statistically significant associations between polypharmacy (OR = 1.3043, p = 0.7701) or multimorbidity (OR = 3.9804, p = 0.3720) and the occurrence of DRPs. The researchers attribute this to the limited sample size, which reduced statistical power, as reflected by the extremely wide confidence intervals. The high prevalence of polypharmacy in both groups, at 83% overall, might also explain the lack of a differentiating effect. The team emphasizes that these analyses should be considered exploratory and hypothesis-generating rather than definitive. Comparison with international data suggests the prevalence of potentially inappropriate prescribing observed in the present study was lower than that reported for other chronic diseases, where PIM prevalence according to STOPP criteria has ranged between 67.8% and 87.7%. The relatively lower prevalence may reflect the regular follow-up these acromegaly patients receive at a tertiary center with proven expertise in rare endocrine disease management.

The study’s conclusions carry significant implications for clinical practice. The researchers demonstrated the potential value of tools such as the STOPP/START criteria in evaluating therapy in geriatric patients with rare diseases, showing that some DRPs can be identified and prevented through comprehensive pharmacotherapeutic analysis. They call for more in-depth research on risk factors and long-term follow-up by clinical pharmacists to optimize pharmacotherapy. Larger, prospective studies focused on geriatric patients with rare diseases are needed to allow for more detailed analysis of the role of polypharmacy, multimorbidity, and other potential risk factors. The integration of structured pharmacotherapeutic assessment tools into routine clinical practice, alongside the development of disease-specific recommendations, may contribute to reducing both the incidence and severity of DRPs over the long term, ultimately improving medication safety for a population that has long been overlooked in pharmacotherapy research.

Subject of Research: Pharmacology

Article Title: Detection of DRPs in geriatric patients with rare diseases: a systematic review and retrospective analysis

Article References: Parvanova, A., Milushewa, P., Tachkov, K., Vandeva, S., & Elenkova, A. (2026). Detection of DRPs in geriatric patients with rare diseases: a systematic review and retrospective analysis. Pharmacia, 73, Article e201120. https://doi.org/10.3897/pharmacia.73.e201120

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e201120

Keywords: drug-related problems, rare diseases, geriatric patients, acromegaly, STOPP/START criteria, polypharmacy, medication safety, pharmacotherapy, clinical pharmacy, adverse drug reactions, Detection, DRPs