Mithu Maheswaranathan, MD

Inflammatory back pain (IBP) is a key clinical feature that can help diagnose 

. Importantly, IBP can also be caused by infections, drugs (such as isotretinoin), and various malignancies. Commonly known infections that may mimic IBP include Brucella and tuberculosis infection. Hematologic malignancies and solid tumors can also cause IBP through paraneoplastic mechanisms or via metastasis. Thus, a recent study by Albayrak et al sought to present characteristics of patients presenting with IBP in the past 10 years with a final diagnosis of malignancy.

This retrospective, multicenter study was performed in Turkey at multiple tertiary care rheumatology centers. They enrolled patients who presented with IBP in the previous 10 years who were ultimately diagnosed with malignancy as the final diagnosis. Thirty six patients with AxSpA, with similar age/sex ratio of 1:1 from each center, were included as the control group.IBP was defined according to Calin criteria. They collected demographic data as well as disease activity measures (Bath ankylosing spondylitis disease activity index or BASDAI) and laboratory testing (ESR, CRP, CBC, LDH, calcium). All patients had pelvic and lumbar radiographs, with sacroiliac MRI obtained in necessary cases.

Ultimately, 34 patients were included in the malignancy group (mean age 42.6) compared to 36 patients in the control group (mean age 43.6). There were statistically significant differences in the time interval between IBP and diagnosis (21 months in the control vs 4 months in the malignancy group) and in the BASDAI scores (6.1 in malignancy group vs 5.1 in the control group). Of the malignancy group, there were 16 hematologic malignancies (multiple myeloma, acute leukemia, lymphoma) and 18 solid tumors (including breast, lung cancer, bone tumors, prostate, colon). Pain due to metastasis was seen in 27 of the malignancies, and 7 cases of IBP were due to a paraneoplastic condition. Compared to the control group, patients with IBP due to malignancy had higher inflammatory markers (ESR, CRP), higher LDH values, and lower hemoglobin levels.

The authors believe this is the largest case series of IBP with a final diagnosis of malignancy in the literature. They note some unique features of malignancy-related IBP include short interval between symptom onset and diagnosis, with much higher acute phase reactants and LDH levels, and lower hemoglobin values compared to AxSpA.Imaging can also help differentiate AxSpA from malignancy: IBP due to malignancy is often associated with lytic lesions, collapse fractures and infiltrations, compared to bone marrow edema or new bone formation in AxSpA.The authors did not have HLA B27 results in the malignancy cases, which may be a risk factor for IBP in malignancy. Rheumatologists should consider mimics of inflammatory axial spondyloarthritis when evaluating patients with inflammatory back pain.

Albayrak F, Kısacık B, Gündüz İ et al. Inflammatory low back pain-associated malignancies mimicking spondylarthritis. Clinical Rheumatology, September 2024.

Articles

Malignancy-related IBP has distinct features: shorter diagnosis time, higher ESR/CRP/LDH, lower hemoglobin, and often involves metastasis or paraneoplastic causes.

Inflammatory Back Pain in Malignancy Mimics Spondyloarthritis

Mithu Maheswaranathan, MD
Credit: Duke Health

Systemic lupus erythematosus has known pathogenesis that includes a combination of inherited genetic predisposition as well as environmental and lifestyle factors. While some environmental triggers have been identified to date - including cigarette smoking, oral contraceptive use, and alcohol – the potential role of diet in development of SLE is not entirely clear. Past cohort studies have not demonstrated strong associations of SLE risk and dietary patterns; however, these studies also did not explore the role of ultraprocessed foods.

Ultraprocessed foods (UPFs) are ready-to-heat/eat formulations of processed food substances and additives that result from high levels of processing with stabilizers, emulsifiers, and other non-nutritional additives. UPFs include food items such as chips, soda, and donuts; a high consumption of UPFs is linked to obesity and other chronic diseases like cardiovascular disease, type 2 diabetes, and increased mortality. This study by Rossato et al examined whether consumption of UPFs was associated with increased incidence of SLE among women in the prospective Nurses’ Health Study (NHS) cohorts (1).

This study was an observational study of prospective cohort of US registered nurses, the NHSI and NHSII which enrolled over 121,000 and 116,000 women respectively in their 20s to 50s from 1976 (NHS) and 1989 (NHSII). Participants completed self-reported dietary intake via the validated semiquantitative food frequency questionnaire (SQFFQ), which assessed dietary intake every 4 years including frequency of consumption of UPF.

The UPF intake was calculated including servings of UPF/day, g, or mL of UPF intake per day, and the percentage of total food intake that were UPF. Covariates were self-reported on mailed questionnaires administered every two years. Incidental diagnoses of SLE that were self-reported were confirmed by rheumatologists.

The authors calculated the cumulative average of UPF intake, which were ranked in tertiles to compare highest to lowest tertile group, which was used as the reference group. Time-varying Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals for patients with incident SLE. Models were adjusted for age, race, age at menarche, body mass index (BMI), menopausal status, total caloric intake and alcohol intake, smoking, oral contraceptive use, household income, and postmenopausal hormone use.

Risk of SLE with and without anti-double stranded DNA (dsDNA) antibody at time of diagnosis was assessed. Stratified analysis was obtained to investigate potential effect modification by BMI, stratifying participants by BMI, adjusting for total caloric intake.

The study enrolled approximately 99,000 women from NHSI and nearly 106,000 women in NHSII. The average age was 50 and 36 in NHSI and NHSII respectively; over 90% of participants identified as White race. There were 212 patients with incident SLE identified. In the multivariable pooled analyses, the risk for developing SLE was higher in the third versus first UPF tertile (servings/day) with HR 1.56 (

The results were stronger for dsDNA positive SLE (servings/day) with HR 2.05 (

 = .01). Thus, higher cumulative UPF intake was associated with an over 50% increased risk for developing SLE. Additional analyses showed both artificially sweetened and sugar-sweetened beverages were most strongly associated with the risk of developing SLE. Limitations of the study include majority of white female nurses within the United States with relatively high baseline age (especially NHS around 50 years old, after peak incidence of SLE); future studies should be replicated in more diverse and younger cohorts.

This study provides novel data demonstrating an association between higher daily consumption of ultraprocessed foods and higher incidence of developing lupus. UPFs are known to increase systemic inflammation. Potential mechanisms of how UPFs cause the increased risk of SLE include deleterious epigentic changes or changes to gut epithelia and the microbiome. Given UPF intake represents over half of total caloric intake in the average US diet, it is critical to work on educating the public on reducing this for overall health benefits, with a potential influence in reducing the rates of incident SLE and other chronic diseases.

Rossato S, Oakes EG, Barbhaiya M et al. Ultraprocessed Food Intake and Risk of Systemic Lupus Erythematosus Among Women Observed in the Nurses' Health Study Cohorts. Arthritis care & research, June 2024. 10.1002/acr.25395.

Systemic lupus erythematosus (SLE) pathogenesis involves genetic, environmental, and lifestyle factors, with diet's role being unclear. A study by Rossato et al. explored the association between ultraprocessed food (UPF) consumption and SLE incidence in the Nurses’ Health Study cohorts. The study found a significant association between higher UPF intake and increased SLE risk, particularly for dsDNA-positive SLE. The study highlights the need for public education on reducing UPF consumption, given its prevalence in the US diet and potential impact on SLE and other chronic diseases.

A study found that high ultraprocessed food consumption increases the risk of SLE by 56%, with an even higher risk for anti-dsDNA positive SLE at 105%.

Understanding Ultra-Processed Food Intake and Risk of Lupus

Belimumab is an anti-B-cell activating factor (BAFF) monoclonal antibody and biologic therapy commonly used in the treatment of 

. While uncommon, belimumab has potential adverse effects like infection and has a high cost relative to other conventional synthetic disease-modifying antirheumatic drug (DMARD) therapy. In this new article in 

, Rua-Figueroa et al report results of their study investigating impact of reduced dose of belimumab in SLE, based on evidence from meta-analyses of randomized clinical trials suggesting possible efficacy of doses lower than those recommended in the approved dosing (10mg/kg IV every 4 weeks or 200mg SQ every week).1

This was a retrospective cohort study of patients with SLE on belimumab in multiple centers in Spain. Patients who met American College of Rheumatology (ACR) criteria for SLE previously treated with IV or SQ Benlysta in a clinical setting were enrolled. Demographic characteristics, disease activity using Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Physician Global Assessment (PGA) were obtained. Laboratory parameters collected included basic labs, urinalysis, dsDNA antibodies, and complement levels (C3/C4).The authors used the Definition of Remission in SLE (DORIS) 2021 for remission and the Lupus Low Disease Activity State (LLDAS) for low disease activity. Organ damage was assessed using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI); damage was evaluated at baseline, at 12 months, and the last visit.

The study included 324 patients with SLE treated with belimumab, with median duration of follow-up under belimumab treatment of 3.2 years. The belimumab dose was reduced in around 9% of the cohort (n = 29/324). All patients on SQ BEL had the administration interval increased from 7 days to 10-21 days. For patients on IV BEL administration, some received a reduced dose every 4 weeks (ranging 5-8mg/kg) and others received an extended interval to every 5 or 6 weeks.At the pre-reduction evaluation, 15 patients (around 58%) were taking DMARDs concomitantly with belimumab and similarly 58% were taking glucocorticoids. The median baseline PGA was .33 and median baseline SLEDAI was 0; a total of nearly 58% of patients were in remission according to 2021 DORIS and 88.5% in low-disease activity state (LLDAS) at baseline.

Following the belimumab dose reduction, at 6 months after reduction, approximately 58% and 81% of patients were in remission according to 2021 DORIS definition and LLDAS, respectively.At 12 months, the percentages increased to 67% and 90%. There were no statistically significant differences in the proportion of patients who lost DORIS or LLDAS status, and no significant difference in disease activity by SLEDAI. There was a statistically significant difference in complement levels, with more patients having low complements at 6 and 12 months. However, the changes in serologic activity did not lead to relevant or significant changes in therapy.

Ultimately, this study provides some evidence of the ability to potentially reduce belimumab dose in a subset of patients with SLE, particularly those with more quiescent disease activity.While a significant change in serologic activity (complement levels) was observed post-belimumab reduction, there were no changes in treatment. There are several limitations including patients all from one country (unclear generalizability), small sample size, and retrospective study design with its inherent biases and limitations. Additionally, there were no patients with lupus nephritis; thus, whether results are applicable to those with SLE nephritis or more severe disease is unknown, and the precise durability of these results long-term is also uncertain.

However, this study suggests a proportion of patients with non-renal SLE can have reduction in belimumab dose with no significant increase or worsening of their clinical disease activity.

Rua-Figueroa I, Altabás-González I, Mouriño C, et al. Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?. Rheumatology (Oxford), May 2024 online. doi:10.1093/rheumatology/keae270

A recent study provides some evidence of the ability to potentially reduce belimumab dose in a subset of patients with SLE. 

Reducing Dose of Belimumab in Patients with Lupus

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.

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