Belimumab add-on therapy eased fatigue and disease activity in Saudi lupus cohort over 12 months

Patients with systemic lupus erythematosus who received belimumab as an add-on to their existing treatment showed substantial and sustained improvement in fatigue, disease activity and patient-reported outcomes over a full year of follow-up, according to a prospective observational cohort study conducted at two tertiary care centers in Saudi Arabia. The study, published in Egyptian Rheumatology and Rehabilitation, followed 36 patients with clinically significant fatigue from April 2022 to April 2023 and measured their outcomes at baseline, six months and twelve months after starting the drug.

Fatigue is one of the most burdensome and stubborn symptoms of lupus. The authors cite a European study, the FATILUP study, in which the prevalence of fatigue among patients with systemic lupus erythematosus fluctuated between 67 and 90 percent, describing it as a multidimensional phenomenon that significantly influences overall functionality. Many patients report that fatigue negatively affects their work, cognition, emotions and activities of daily living, with consequences for both mental and physical health. Because fatigue can persist even in patients whose disease activity is otherwise well controlled, it remains one of the most challenging patient-reported outcomes to manage in routine clinical practice.

Belimumab is a fully human monoclonal IgGλ antibody that inhibits soluble B lymphocyte stimulator, known as BLyS, reducing the levels of this factor available for the selection and survival of autoreactive B cells. The United States Food and Drug Administration approved the drug for systemic lupus erythematosus in March 2011, and at the time it was the only biologic B cell–directed therapy approved in the previous sixty years. In December 2020 it gained approval for patients with active lupus nephritis, one of the most common serious manifestations of the disease. It is approved as an add-on therapy for serologically active adults already on standard therapy; its efficacy as monotherapy has not been fully established.

The research team, led by Sultana Abdulaziz with colleagues including Basant Elnady and Hoda Draz, designed the study specifically as a fatigue-focused cohort. Adult patients aged eighteen or older with confirmed lupus according to the American College of Rheumatology 2019 classification criteria were eligible if they had clinically significant fatigue, defined as a score of at least four on the Fatigue Severity Scale, and were beginning belimumab as add-on therapy at a dose of 10 mg/kg intravenously monthly or 200 mg subcutaneously weekly after a loading dose. Patients completed twelve months of follow-up. The investigators excluded pregnant patients, those with end-stage renal disease, active central nervous system involvement, active or recent infection within the past sixty days, overlap connective tissue disease, hypothyroidism, fibromyalgia, or incomplete data.

Recruitment was selective. Of 390 patients with lupus screened from outpatient clinics, 170 reported fatigue, and 36 fulfilled the predefined inclusion criteria of clinically significant fatigue together with clinically active disease. The mean age at belimumab initiation was 35.44 years, 83.3 percent of patients were female, and the mean disease duration was 10.42 years. About half had at least one comorbidity, most commonly hypertension, obesity and dyslipidemia. Lupus nephritis affected 44.4 percent of the cohort, and the most common initial manifestations were mucocutaneous, musculoskeletal and hematological. Thirty-three patients had previously been exposed to at least one immunosuppressant, including methotrexate, azathioprine, mycophenolate mofetil, hydroxychloroquine, rituximab and cyclophosphamide.

The primary outcome was the longitudinal change in fatigue over twelve months, assessed with two validated patient-reported measures: the nine-item Fatigue Severity Scale, scored from one to seven, and the Visual Analog Fatigue Scale, scored from zero to ten, in which higher scores reflect greater severity. At baseline the cohort carried a high fatigue burden, with a mean Fatigue Severity Scale score of 5.79 and a mean Visual Analog Fatigue Scale score of 5.68. By six months the mean FSS had fallen to 3.36, and by twelve months to 2.22, a mean difference of minus 3.57 with a 95 percent confidence interval of 1.86 to 2.59 and a p value below 0.001. The VAFS followed the same trajectory, decreasing to 3.77 at six months and 1.77 at twelve months, a mean difference of minus 4.44, also statistically significant.

Disease activity improved in parallel. The mean SLE Disease Activity Index 2000 score fell from 10.83 at baseline to 5.19 at six months and 2.65 at twelve months, a mean difference of minus 8.18 with a p value below 0.001. The proportion of patients achieving mild disease activity increased progressively over the follow-up period. Patient global assessment also improved significantly, decreasing from 5.56 at baseline to 3.00 at six months and 1.76 at twelve months. Clinical manifestations moved in the same direction: the proportion of patients without tender joints rose from 22.2 percent at baseline to 79.4 percent at twelve months, patients without swollen joints increased from 38.9 to 85.3 percent, and cutaneous manifestations decreased, all with p values below 0.001. Laboratory parameters remained generally stable, with improvement in complement levels, particularly C3, and no clinically significant deterioration in renal or hepatic function.

The lupus nephritis subgroup also fared well. Both fatigue and disease activity improved over time in these patients, with p values below 0.001, alongside a significant reduction in proteinuria from a mean of 1573.78 to 595.33, with a 95 percent confidence interval of 425.54 to 765.13 and a p value of 0.012, and improvement in complement levels with a p value of 0.024. The authors note that a reduction in urinary protein levels below 0.5 to 0.8 grams per day represents a favorable long-term renal outcome. They frame the result against the observation that increased expression of B-cell activating factors in the kidneys and serum of lupus nephritis patients makes neutralizing this factor a compelling therapeutic approach, and they state that their observations align with recent EULAR 2025, ACR 2025 and KDIGO 2024 recommendations for lupus nephritis management.

Safety findings were notable in this cohort. Belimumab was well tolerated, and the investigators report that no serious adverse events, infusion reactions or hypersensitivity reactions occurred during the study. The authors caution, however, that until more patients are treated with belimumab for longer periods, the incidence of rare, serious or severe adverse events remains unknown. They also note that the drug’s generally recognized adverse effects include infections, headache, nausea, hypersensitivity, infusion reactions and fatigue, and that the 2025 EULAR recommendations position belimumab for patients with inadequate response to hydroxychloroquine alone or with glucocorticoids, those unable to reduce glucocorticoid doses, those with lupus nephritis, or those with relapsing or refractory disease after first-line therapies.

The study’s authors are candid about its limitations. The sample was small, the observational design and potential selection bias limit generalizability, and the absence of a control group precludes direct comparison with standard therapy alone. The subgroup analyses were exploratory, and because fatigue improvement paralleled the reduction in disease activity, the relationship between the two outcomes requires further investigation in larger controlled studies. Patients with severe active central nervous system lupus and end-stage renal disease were excluded, which restricts interpretation for patients with severe organ involvement. The strength of the study, the authors argue, lies in its prospective multicenter design and serial longitudinal assessment of fatigue, disease activity and renal outcomes over twelve months, providing real-world data from a region where few prospective studies have specifically evaluated longitudinal fatigue outcomes in belimumab-treated patients. They conclude that, within these constraints, the findings support the potential benefit of belimumab as an add-on therapy in regular clinical practice, and they call for future multicenter controlled studies with larger sample sizes to confirm the results.

Subject of Research: The effect of belimumab add-on therapy on fatigue and disease activity in systemic lupus erythematosus patients over 12 months

Article Title: Impact of belimumab on fatigue and disease activity in the management of systemic lupus erythematosus

Article References: Abdulaziz, S., Elnady, B., Halabi, H., Alhalwani, A., Albeladi, R., Alakkas, Z., & Draz, H. (2026). Impact of belimumab on fatigue and disease activity in the management of systemic lupus erythematosus. Egyptian Rheumatology and Rehabilitation, 53(1), Article 85. https://doi.org/10.1186/s43166-026-00456-3

Image Credits: AI Generated

DOI: 10.1186/s43166-026-00456-3

Keywords: systemic lupus erythematosus, belimumab, fatigue, SLEDAI-2K, lupus nephritis, patient-reported outcomes, prospective cohort study, Saudi Arabia, biologic therapy, BLyS inhibitor, rheumatology, proteinuria