Mithu Maheswaranathan, MD

The use of musculoskeletal or rheumatologic ultrasound (RhUS) in clinical practice has expanded tremendously in the past decade. This imaging modality provides many advantages including low cost, lack of exposure to radiation, and assisting in diagnosing and classifying disease to help inform treatment decisions. Fairchild et al from Stanford University Division of Rheumatology published this recent study with the objective to assess the growth, utilization, and impact of RhUS on physicians and patients.

 They found that with implementation of RhUS there was a reduction in use of other imaging modalities and often changes in diagnosis and medication management as a result of ultrasound results.

The Stanford RhUS program began in 2017. The authors quantified imaging orders from 2017 to 2022 by rheumatologists at their academic medical center as well as comparator rheumatology community practices. Claims for RhUS were quantified using Current Procedural Terminology (CPT) codes for diagnostic exams and procedures (joint injection/aspiration using ultrasound).Additionally, they reviewed RhUS clinic records over a 9-month period to assess post-RhUS visit medication changes and RhUS-determined diagnoses.Finally, they also obtained surveys of both patients and rheumatologists referring to ultrasound to determine their thoughts on the experience.

Between 2017 and 2022, there were 13 to 16 active clinical rheumatologist at their academic medical center, including 1 to 3 rheumatologists trained in performing RhUS. Comparing 2018 to 2021, they found RhUS diagnostic procedures increased. After adjusting for overall clinic growth, they found XR utilization fell at their center versus community practices, average MRI use was decreased at both and ultrasound use grew by an average of 61%.

The retrospective record review (2021 to 2022) found median time from referral to RhUS clinic visit was 41 days, with 12% seen in less than 10 days. The most common diagnostic indications for referral were “evaluate for inflammatory arthritis” (34%) and joint pain (26%). Around 55% of these ultrasound visits resulted in new diagnostic information, including clarifying differential diagnosis (48%) or resulting in alternative diagnosis compared to referring provider (20%). Of referrals noting “active disease” by their assessment, the RhUS demonstrated no activity in 32% of cases. Of patients with follow-up, medication changes were observed in 22% of the patients with most changes being escalation of therapy.

Robert Fairchild, MD, PhD, assistant professor of medicine at Stanford University School of Medicine and the director of Stanford's Rheumatology Ultrasound Diagnostic and Interventional Clinic, said the frequent discordance in disease activity assessment between referring provider and RhUS results was the most surprising finding of this study.

“There were many instances were referring providers believed disease to be inactive when RhUS found inflammatory disease activity and vice versa,” he said. “While I have encountered this in the care of my own patients, I was surprised by the frequency in which this occurred in our study.”

Survey results of patients also provided some interesting responses.They found overall high patient satisfaction scores with over 80% feeling “extremely satisfied” or “extremely likely to recommend.” Patients reported statistically significant increase in disease understanding after US visit, compared with pre-visit responses. Looking at physicians, they found referrals to an ultrasound clinic to be “very” or “extremely” useful.

This study offers unique examination of the impact of RhUS clinic at an academic medical center. It helps provide evidence that use of RhUS often results in a change in the diagnosis, and for those with known inflammatory arthritis, can often show discordance compared to disease activity assessed by the referring provider. The authors noted a potential limitation of selection bias, given patients referred due to degree of uncertainty regarding diagnosis or time therapeutic changes were being considered. Fairchild also reported challenges of ensuring enough RhUS trained and skilled providers are available to fulfill increasing demand.

Fairchild noted rheumatology ultrasound clinics are poised to play an increasingly central and dynamic role in rheumatology practices.

“I believe their growth is likely to continue as they emerge as a cornerstone in imaging for rheumatic diseases for disease diagnosis, monitoring disease activity and therapeutic response, and point of care interventions,” he said.

These findings demonstrate the impact and practice-changing nature of incorporating RhUS into our clinical practices, likely improving accuracy of diagnostic and therapeutic decisions in management of our patients.

Fairchild RM, Deluna MD, Golovko V et al. Evolution and impact of a dedicated ultrasound clinic on clinical rheumatology practice at an academic medical center. Seminars in Arthritis and Rheumatism, October 2023.

Articles

Results of a recent study indicated rheumatology ultrasound clinics may play an increasingly central and dynamic role in rheumatology practices.  

Impact of Dedicated Ultrasound Clinic on Clinical Rheumatology Practice

Pegloticase (PEGylated uricase) is an excellent option for patients with refractory, uncontrolled, or tophaceous gout. Use of pegloticase is often hindered by development of antidrug antibodies, which are associated with lower rate of urate lowering response and higher risk of infusion reaction. 

The MIRROR randomized controlled trial (RCT) compared pegloticase in combination with methotrexate versus placebo (PBO) in terms of efficacy and safety, finding pegloticase plus methotrexate (MTX) 15mg weekly resulted in significantly higher rate of sustained urate-lowering response through month 6 of treatment (71% vs 38.5%, respectively). Additionally, patients on pegloticase/MTX combination therapy had a lower rate of infusion reaction (2.4% vs 30.6%) than patients receiving pegloticase monotherapy.

A recent phase 4 randomized, double-blinded, PBO-controlled study provided an update on longitudinal safety and efficacy data as a follow-up to the MIRROR RCT.

 Patients received pegloticase 8 mg intravenous infusion every 2 weeks and were randomized 2:1 to receive pegloticase with blinded methotrexate (15 mg weekly) or PBO for a total of 1 year. Adult patients with uncontrolled gout, defined as serum uric acid level (sUA) ≥7 mg/dL, oral urate-lowering therapy failure or intolerance, and at least 1 ongoing gout symptom (1 or more tophi, 2 or more flares in the year prior to screening, and/or chronic gouty arthritis) were enrolled.Patients with methotrexate contraindication or intolerance were among those excluded from this trial.

The trial’s primary efficacy endpoint evaluated proportion of treatment responders through month 6 (sUA <6 mg/dL for at least 80% of weeks 20 – 24). Secondary endpoints included proportion of treatment responders during month 12 (sUA <6 mg/dl for at least 80% of weeks 48 – 52) and the proportion of patients with detectable tophi at baseline with complete resolution of ≥1 tophi at week 52. 

They also measured pegloticase serum concentrations and anti-drug antibodies. Treatment safety and tolerability were assessed, and tophi were photographed and classified as measurable or unmeasurable. “Complete response” was defined as 100% tophus area reduction in measurable tophi and unmeasurable tophi no longer visible.

The study included 152 patients who were predominantly male (89%) and White (69%). The study found significantly more patients in the MTX group, vs PBO, having sustained lowering of urate levels during month 6 (71% vs 38.5%; 

 <.0001). This response rate was significantly higher in patients cotreated with methotrexate vs PBO by month 12 (60% vs 30.8%). Fewer patients on methotrexate met the serum urate discontinuation criteria vs PBO (22.9% vs 63.3%; 

Additionally, a higher proportion of patients on MTX (vs PBO) had complete resolution of one or more tophi (53.8% vs 31%; 

 = .048). When evaluating immunogenicity, they found a higher proportion of PBO patients did not have “evaluable” pegloticase concentrations; the MTX group had higher pegloticase serum concentrations and lower immunogenicity. There was a higher proportion of new anti-PEG antibodies in the placebo group compared to the methotrexate group (58.3% vs 31.6%), and development of new anti-PEG antibodies was associated with lower treatment response rate and higher rate of infusion reactions. Of note, no infusion reactions were observed after week 24 in either treatment group.

Ultimately, this follow-up of the MIRROR RCT demonstrates significant benefits of coadministration of methotrexate with pegloticase, maintaining the initial findings from observations through 6 months. Patients who are cotreated with MTX have higher urate-lowering response rates through month 12 and lower infusion reaction rates (regardless of anti-PEG antibody status). 

While optimal duration of pegloticase therapy is unknown, this study provides support for continued therapeutic benefit of pegloticase beyond month 6 and benefits of concomitant methotrexate administration with pegloticase.

Botson JK, Saag K, Peterson J, et al. A randomized, placebocontrolled study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase: primary efficacy and safety findings. Arthritis Rheumatol 2023;75:293–304

Gorter A, Bakker MM, Ten Klooster PM. The impact of health literacy: associations with disease activity and medication prescription in patients with rheumatoid arthritis. Rheumatology, 2023

This follow-up of the MIRROR trial demonstrates significant benefits of coadministration of methotrexate with pegloticase, maintaining the initial findings from observations through 6 months.  

Safety and Efficacy of Pegloticase and Methotrexate in Gout

Health literacy is an important social determinant of health which includes personal competencies and resources that are needed for individuals to access, understand, and use health information and services to make decisions about their health.

 Limited health literacy has been shown to be associated with worse health outcomes, including lower medication adherence, problems seeking preventive care, and poorer health outcomes. 

A recent study by Gorter and Bakker et al sought to build upon previous work identifying 10 distinct health literacy profiles of patients with rheumatic diseases, categorizing them based on strengths and weaknesses related to their health literacy.

 The aim of the study was to explore longitudinal associations between health literacy profiles, disease activity and medication prescription in patients with 

The study enrolled 108 patients with RA at a hospital in the Netherlands who previously completed the Health Literacy Questionnaire (HLQ) in 2019. They retrieved up to 1 year of follow-up data on disease activity and medication prescription from the electronic health record.Disease activity was assessed using Disease Activity Score-28 for Rheumatoid Arthritis with erythrocyte sedimentation rate (DAS28-ESR) scores. Medication prescription information was also retrieved.Linear mixed modelling was used to analyze association between health literacy groups and disease activity over 1 year. To compare medication prescription use between groups, Chi squared tests and logistic regression analysis were used.

The study found 21 patients had “several health literacy limitations,” 33 had “some health literacy limitations,” and 54 had “good health literacy.” The mean age was 66 years and 62% of the cohort were female; around half of patients were seropositive (rheumatoid factor [RF] 57%, cyclic citrullinated peptide [CCP] 54%). The linear mixed modelling showed significant effect of health literacy group on DAS28-ESR scores over time. Patients with “good health literacy” had significantly lower disease activity over time than those with “several health literacy limitations,” adjusting for age, gender, and education level. Interestingly, patients with “good health literacy” were most often prescribed a biologic DMARD (50%), whereas those with “some health literacy limitations” more commonly received a conventional synthentic disease-modifying antirheumatic drugs (csDMARDs) only (72.7%, odds ratio [OR] 4.24), and those with “several health literacy limitations” were more often prescribed steroids (52.4%, OR 3.56).

The authors explained how their results demonstrated patients with more health literacy needs had higher disease activity over time, independent of their education level.An intriguing finding was that patients with “several health literacy limitations” were prescribed prednisolone more often, which they postulate may be due to insufficient control of disease activity or patients with more health literacy needs asking for prednisolone more often. They found significantly more biologic DMARD (bDMARD) prescriptions in the “good health literacy” group, which could be due to reluctance amongst patients with lower health literacy to change therapy or having more concerns about bDMARDs.

They also highlighted some limitations, including need to replicate their findings, due to the small size of the groups, grouping different health literacy profiles into 3 groups analyzed, and the homogeneity of the population from a specific region of the Netherlands.

Finally, the authors of this article raised suggestions on how to “level the playing field” through health literacy, noting health literacy is a modifiable determinant of health but hard to improve within the limited timeframe of a clinic visit. They suggested improving our services to better respond to health literacy limitations of our patients, such as using understandable and actionable information materials (including plain language and illustrations) and offering patients additional guidance and support. Another suggestion was to use a “universal precautions” approach, assuming every patient is at risk of reduced access to care and potentially poor outcomes of care due to limited health literacy.

This study highlights the influence of health literacy in outcomes of patients with RA and even potential implications in specific DMARD therapy selection, and why rheumatologists should be aware of the impact of health literacy in clinical care.

Broder J, Chang P, Kickbusch I et al. IUHPE position statement on health literacy: a practical vision for a health literate world. Glob Health Promot, 2018.

Gorter A, Bakker MM, Ten Klooster PM. The impact of health literacy: associations with disease activity and medication prescription in patients with rheumatoid arthritis. Rheumatology, 2023.

Patients with “good health literacy” had significantly lower disease activity over time than those with “several health literacy limitations,” adjusting for age, gender and education level.  

Impact of Health Literacy in Disease Activity, Medications in Rheumatoid Arthritis

Pneumocystis jiroveci pneumonia (PJP) is an opportunistic fungal infection that typically affects immunocompromised patients. Guidelines recommend PJP prophylaxis in patients with ANCA-associated vasculitis,

 but no formal recommendations exist for giant cell arteritis (GCA) or polymyalgia rheumatica (PMR). Studies have demonstrated antibiotic prophylaxis reduces incidence of PJP in immunocompromised patients, but little data has evaluated the role of prophylaxis in GCA or PMR. The authors of a recent study by Natalie Anumolu et al sought to answer the question of PJP incidence in this population, given patients with GCA/PMR often receive prolonged courses of steroids, particularly GCA with high doses and often concomitant immunosuppression with tocilizumab.

In this study, authors utilized a United States-based electronic health records database (TriNetX), including de-identified information from 54 healthcare organizations and over 86 million patients across the United States. The cohort identified patients with GCA and PMR, using ICD-9/ICD-10 diagnosis codes, who had a glucocorticoid prescription. Patients were excluded if they had human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), any reported transplant, or leukemia. They also excluded patients with any PJP code within a specified time period surrounding the index date (defined as first glucocorticoid prescription, required to occur within 30 days after first diagnosis code). The team extracted demographic data, medications used, and type of prophylaxis as well as medical comorbidities and assessed incidence rate of PJP.To identify other cases of PJP, a systematic review was also performed.

The study found a total of 1168 incident cases of GCA and over 15,575 incident cases of PMR.During follow-up, steroid-sparing agents included tocilizumab (9.5% GCA, 0.7% PMR) and methotrexate (7.1% GCA, 6.7% PMR). A minority of patients received prophylaxis, including trimethoprim/sulfamethoxazole (TMP/SMX) (6.1% GCA, 1.6% PMR), atovaquone (0.4% GCA, 0.1% PMR), or dapsone (0.6% GCA, 0% PMR) for presumed PJP prophylaxis. Among 1168 patients with GCA, there were no cases, positive tests or hospitalizations for PJP (0/1,000 person-years). Among 15,575 patients with PMR, there was 1 case of PJP within 6 months and 1 positive case within 12 months, with no hospitalizations (0.07/1,000 person-years). Evaluating the systematic reviews, in GCA they found 28 total cases of PJP with 4 cases of mortality; in PMR, there were 4 cases of PJP prophylaxis and no deaths reported.

Combining results of the cohort study and systematic review, the authors conclude PJP infection occurred rarely among patients with GCA or PMR. They noted their cohort study identified no cases of PJP in those with GCA and only 5 cases in those with PMR, which may approximate rates observed in the general population. Patients with GCA/PMR often require high cumulative glucocorticoid dosage for treatment, and they hypothesize a few reasons for why the incidence rate of PJP is not higher, including: 1) medications do not affect T-cells to the same degree active HIV does and 2) patients with GCA/PMR lack disease-mediated lung disease. The authors noted some limitations, such as reasons prophylaxis treatment not being listed in some cases and having to be inferred, and lack of granular data on corticosteroid dosing. Additionally, I will note the low percentage of patients on tocilizumab or methotrexate in the GCA cohort. It is possible the rate of PJP incidence may vary in those on prednisone monotherapy versus prednisone in combination with other immunosuppressant.

Ultimately, as rheumatologists we are balancing control of underlying disease and risks of immunosuppressive treatment. This data suggests the risk of PJP in patients with GCA or PMR are low, and it is important to recognize the potential range of adverse events from PJP prophylaxis are vast, including methemoglobinemia and agranulocytosis. Given these findings, the authors concluded “these data do not support routine prescribing of PJP prophylaxis for patients with GCA or PMR.”

Chung SA, Langford CA, Maz M, Abril A, Gorelik M, Guyatt G, et al. American college of rheumatology/vasculitis foundation guideline for the management of antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Care Res 2021; 73:1088–105.

Anumolu N, Henry K, Sattui SE, Putman M. Is there a role for Pneumocystis jiroveci pneumonia prophylaxis in giant cell arteritis or polymyalgia rheumatica? Seminars in Arthritis and Rheumatism 2023; 58:152154.

Results of a recent study showed that the risk of pneumocystis jiroveci pneumonia (PJP) is low in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), therefore discouraging the routine prescribing of PJP prophylaxis for this patient population. 