Siponimod following Alemtuzumab in secondary progressive MS: investigating sequential therapy-A case series.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of highly active relapsing multiple sclerosis (MS) but requires vigilant post-treatment monitoring due to associated risks. The prescription of subsequent therapies following Alemtuzumab, as mandated by label guidance for a treatment-free period of at least 5 years, presents a complex challenge, particularly if there is concurrent conversion to secondary progressive disease course. We described a case-series of five patients starting therapy with Siponimod and followed up for 12 months period converted to secondary progressive MS previously exposed to Alemtuzumab. All patients received Siponimod 2 mg. Clinical evaluation measured with Expanded Disability Status Scale and cognitive evaluation measured with Brief International Cognitive Assessment for Multiple Sclerosis were stable after 12 months on therapy. No severe lymphopenia was recorded, nor serious adverse events. In conclusion, the long-term management of patients treated with Alemtuzumab transitioning to secondary progressive MS requires a proactive and multidisciplinary approach. By addressing the challenges associated with treatment limitations and short-term monitoring recommendations while considering alternative therapeutic options like Siponimod, clinicians can optimize outcomes and ensure continuity of care for individuals with MS.

A Case of Scrofuloderma in a Patient on JAK Inhibitor Treatment for Rheumatoid Arthritis.

A 78-year-old woman with rheumatoid arthritis, who was started on baricitinib five or six months earlier, was referred to our hospital due to a subcutaneous abscess in her right axilla. Contrast-enhanced chest, abdomen, and pelvis computed tomography showed subcutaneous abscesses in her right axilla and lymphadenopathy with calcification. Cultures from the subcutaneous abscess and skin biopsy specimens were positive for Mycobacterium tuberculosis. These findings led to the diagnosis of scrofuloderma associated with tuberculous lymphadenitis. She was started on an antitubercular regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol as the initial phase treatment (first 2 months), followed by isoniazid and rifampicin for 4 months (total 6 months). After 6 months of antitubercular treatment, the abscesses and lymphadenitis disappeared. Although cases of tuberculosis during JAK inhibitor treatment are rare, they are serious adverse events that require caution.

Comparative efficacy and safety of systemic steroids, oral JAK inhibitors and Contact Immunotherapy in the Treatment of severe alopecia areata: a systematic review and network meta-analysis.

Severe alopecia areata (AA) is a nonscarring hair loss for immune disorder and SALT score ≥ 50%. The guidelines for managing patients with severe AA suggest treatments: systemic steroids, JAK inhibitors, and contact immunotherapy. However, there is a lack of evidence indicating the superiority of one treatment over another. Therefore, this study aimed to identify the most effective treatment for severe AA through network meta-analysis. Following the PRISMA guidelines, we conducted a network meta-analysis. The literature search was retrieved across four databases. The Cochrane 5.1 risk of bias assessment tool and ROBINS-I tool assessed quality of the included studies. Subsequently, efficacy and safety comparisons among the three treatments were conducted using Stata 14.0 on account of the frequency method. The SUCRA rank indicated that oral dexamethasone (95.9%) > diphenylcyclopropenone(DPCP) (74.5%) > oral ritlecitinib (62.6%) > oral baricitinib (46.9%) > squaric acid dibutyl ester(SADBE) (20.1%) > placebo (0.0%) from high to low in the aspect of improving efficacy. As for safety, placebo(88.4%) > oral ritlecitinib (86.5%) > oral baricitinib (62.1%) > SADBE (37.0%) > oral dexamethasone(22.3%) > DPCP(3.8%) in the aspect of decreasing adverse events. Oral dexamethasone and DPCP showed superior efficacy compared to oral ritlecitinib and oral baricitinib. However, in terms of safety, oral ritlecitinib was preferable. Some adverse events associated with oral dexamethasone and DPCP were intolerable to patients, whereas those related to oral ritlecitinib and oral baricitinib were more manageable. Overall, ritlecitinib and baricitinib remain promising drugs in the future treatment of severe AA.

Real-world comparative study of drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.

Cumulative incidence and risk of infection in patients with rheumatoid arthritis treated with janus kinase inhibitors: A systematic review and meta-analysis.

Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19-1.52) and opportunistic (RR 2.69; 95% CI: 1.22-5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05-1.39), peficitinib (RR 1.40; 95% CI: 1.05-1.86) and upadacitinib (RR 1.30; 95% CI: 1.09-1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.

Prior herpes zoster occurrence and high-dose corticosteroids increase herpes zoster risk in rheumatoid arthritis patients receiving janus kinase inhibitors in a retrospective and observational study.

Herpes zoster (HZ) risk is increased in rheumatoid arthritis (RA) patients receiving Janus kinase inhibitors (JAKi) therapy. Identifying and evaluating the risk factors of HZ development in patients receiving JAKi therapy would be clinically helpful. We investigated HZ's incidence rates (IR), identified the risk factors, and further assessed their influence on HZ development in RA patients undergoing JAKi therapy. We retrospectively evaluated 249 RA patients who received JAKi therapy between 2015 and 2023. Data regarding clinical characteristics, HZ reactivation, HZ vaccination status, and concomitant medication use were collected. Among 249 JAKi-treated patients, 44 developed new-onset HZ (tofacitinib, 28/142; baricitinib, 6/35; upadacitinib,10/72), with an IR of 5.11/100patient-years. Multivariate analysis revealed significant predictors of HZ development: a long JAKi exposure period, prior HZ or COVID-19 history, and concomitant high-dose corticosteroids use. The interval between JAKi initiation and HZ development was significantly shorter in patients with prior HZ history than in those without (median, 6.5 months versus 33.5 months, p < 0.001), suggesting "biphasic" emergence of HZ. Only one patient who had experienced an HZ episode while receiving JAKi developed recurrent HZ. None of the seventeen patients immunized with the non-live recombinant zoster vaccine developed HZ. Our JAKi-treated patients had elevated HZ risks, a class effect across different JAKi. A long exposure period, prior history of HZ or COVID-19, and concomitant high-dose corticosteroid treatment may further increase the risk. The emergence of HZ shows a biphasic pattern: early HZ development in patients with prior HZ and late development in those without. Key Points • An increased risk of HZ was observed in Taiwanese RA patients treated with JAKi, presenting as a class effect. • Patients with a long JAKi exposure period, prior history of HZ or COVID-19, and concomitant use of high-dose corticosteroids were at high risk of HZ while receiving JAKi therapy. • The interval between JAKi initiation and HZ occurrence was shorter in patients with prior HZ than in those without, showing "biphasic" emergence.

Effectiveness of baricitinib in acquired reactive perforating collagenosis: a case report.

Background: Acquired reactive perforating collagenosis (ARPC) poses a clinical challenge with an unclear pathogenesis. This disease has been frequently proven resistant to immunosuppressive treatments, significantly affecting the quality of life of patients. In this report, we highlight the efficacy of baricitinib as a viable option for maintenance therapy in ARPC. Case summary: An 81-year-old woman presented to our hospital with recurrent pruritus and cup-like ulcerated lesions on her trunk and limbs persisting for 1 year. She exhibited limited response to oral antihistamines and topical steroids. Past medical history revealed a prolonged history of coronary heart disease and type 2 diabetes spanning several years to decades. Histopathological examination revealed cup-shaped depressions filled with necrotic inflammatory debris. In the dermis, a mixed inflammatory infiltrate composed of lymphocytes and histiocytes was observed. Van Gieson staining indicated the elimination of fibrous tissue extending from the dermis into the epidermis. Consequently, a diagnosis of ARPC was established. Due to the inadequate response to conventional treatments and the severe itching, we initiated baricitinib therapy for ARPC, resulting in gradual symptom improvement. Follow-up assessments showed no adverse reactions and normal laboratory findings. Conclusion: The case report suggests that baricitinib might offer significant therapeutic benefits for ARPC.

A rare case of symptomatic creatine kinase elevation in a patient with rheumatoid arthritis treated with baricitinib.

The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.

The efficacy and safety of different Janus kinase inhibitors as monotherapy in rheumatoid arthritis: A Bayesian network meta-analysis.

OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.

Case report: Sequential therapy with dupilumab and baricitinib for severe alopecia areata with atopic dermatitis in children.

An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the features of active stage alopecia areata, with a Severity of Alopecia Tool (SALT) score of 70%. The diagnosis was severe alopecia areata. The patient had a history of atopic dermatitis since infancy, with recurrent episodes of scattered papules and pruritus for 8 years. Initial treatment involved subcutaneous injections of dupilumab 300mg every 2 weeks for 6 months, resulting in a reduction of SALT score to 20% and improvement of atopic dermatitis symptoms. Discontinuation of Dupilumab and initiation of daily oral Baricitinib at a dose of 2mg for a duration of 5 months. According to the SALT score evaluation, the severity of hair loss was less than 10% and there was significant regrowth of hair. No significant adverse reactions were observed during the treatment period.

PERFECTRA: a pragmatic, multicentre, real-life study comparing treat-to-target strategies with baricitinib versus TNF inhibitors in patients with active rheumatoid arthritis after failure on csDMARDs.

OBJECTIVE: To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a real-life treat-to-target (T2T) setting. METHODS: Patients with biological and targeted synthetic DMARD (b/tsDMARD) naïve RA with disease duration ≤5 years without contraindications to b/tsDMARD were randomised to either TNFi or baricitinib when csDMARD failed to achieve disease control in a T2T setting. Changes in clinical and patient-reported outcome measures (PROMs) were assessed at 12-week intervals for 48 weeks. The primary endpoint was non-inferiority, with testing for superiority if non-inferiority is demonstrated, of baricitinib strategy in the number of patients achieving American College of Rheumatology 50 (ACR50) response at 12 weeks. Secondary endpoints included 28-joint count Disease Activity Score with C reactive protein (DAS28-CRP) <2.6, changes in PROMs and radiographic progression. RESULTS: A total of 199 patients (TNFi, n=102; baricitinib, n=97) were studied. Both study groups were similar. Baricitinib was both non-inferior and superior in achieving ACR50 response at week 12 (42% vs 20%). Moreover, 75% of baricitinib patients achieved DAS28-CRP <2.6 at week 12 compared with 46% of TNFi patients. On secondary outcomes throughout the duration of the study, the baricitinib strategy demonstrated comparable or better outcomes than TNFi strategy. Although not powered for safety, no unexpected safety signals were seen in this relatively small group of patients. CONCLUSION: Up to present, in a T2T setting, patients with RA failing csDMARDs have two main strategies to consider, Janus Kinases inhibitor versus bDMARDs (in clinical practice, predominantly TNFi). The PERFECTRA study suggested that starting with baricitinib was superior over TNFi in achieving response at 12 weeks and resulted in improved outcomes across all studied clinical measures and PROMs throughout the study duration in these patients.

Adverse cardiovascular events in rheumatoid arthritis patients treated with JAK inhibitors: An analysis of postmarketing spontaneous safety reports.

OBJECTIVES: The ORAL Surveillance trial, a postmarketing safety clinical trial, found an increased risk of adverse cardiovascular events and venous thromboembolism (VTE) in patients treated with Janus Kinase (JAK) inhibitors compared to tumor necrosis factor (TNF) inhibitors. However, additional studies yielded mixed results and data on other JAK inhibitors are limited. METHODS: A retrospective, pharmacovigilance study using the FDA adverse event reporting system (FAERS) to assess reporting of adverse cardiovascular events following treatment with JAK inhibitors in rheumatoid arthritis (RA) patients between January 2015 and June 2023. To identify disproportionately increased reporting, an adjusted reporting odds ratio (adj.ROR) was calculated with a multivariable logistic regression model. RESULTS: We identified safety reports of 75,407 RA patients treated with JAK inhibitors (tofacitinib, n = 52,181; upadacitinib, n = 21,006; baricitinib, n = 2,220) and 303,278 patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs; TNF inhibitors, rituximab, and tocilizumab). The mean age was 61.2(±12) and 59.0(±13), respectively; 82 % and 81 % were women. Compared to bDMARDs, JAK inhibitors were associated with an increased reporting of VTE [n = 1,393, adj.ROR=2.11 (1.97-2.25)], stroke [n = 973, adj.ROR=1.25 (1.16-1.34)], ischemic heart disease [IHD, n = 999, adj.ROR=1.23 (1.13-1.33)], peripheral edema [n = 2699, adj.ROR=1.22 (1.17-1.28)], and tachyarrhythmias [n = 370, adj.ROR=1.15 (1.00-1.33)]. Most of the events occurred in the first year after treatment initiation. When different JAK inhibitors were compared, VTE, stroke, and IHD were more frequently reported with upadacitinib and baricitinib than tofacitinib. When stratified by age category, all safety signals were statistically significant in patients aged≤65 years. CONCLUSION: In this global postmarketing study, JAK inhibitors are associated with increased reporting of VTE, stroke, IHD, and tachyarrhythmias. These adverse events were reported following all JAK inhibitors that were studied, suggesting a class effect.

Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus.

BACKGROUND: Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE. METHODS: Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety. RESULTS: A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05). CONCLUSION: Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.

Higher infection risk for JAK inhibitors tofacitinib and baricitinib compared to subcutaneous biological DMARDs.

INTRODUCTION: Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. METHODS: From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. RESULTS: In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. CONCLUSION: In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points • Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages • An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed • No significant differences in infection incidence were found between tofacitinib and baricitinib.

Baricitinib for refractory Takayasu arteritis: a prospective cohort study in a tertiary referral centre.

OBJECTIVE: To investigate the treatment efficacy and safety of baricitinib in patients with refractory Takayasu arteritis (TAK). METHODS: We performed a prospective cohort study in which baricitinib 4 mg daily was prescribed to patients with refractory TAK, combined with oral glucocorticoids (GCs). RESULTS: 10 patients with refractory TAK were enrolled with a median age of 28 (IQR=22-37) years, median disease duration of 50 (IQR=24-65) months. The median dose of GCs was 10 (IQR=8.1-22.5) mg prednisone or equivalence dosage at baseline. At 6 months of baricitinib treatment, 6/10 (60%) patients had an overall treatment response. During an average follow-up of 15.3 (range 4-31) months, 4/10 (40%) patients maintained overall treatment response. 8/10 (80%) patients tapered or maintained the same dose of GCs with no change of the combined classical synthetic disease-modifying antirheumatic drugs. Two patients discontinued GCs at 18 and 24 months and were in continuous remission till the end of the study. One patient withdrew baricitinib due to liver dysfunction. CONCLUSION: Baricitinib 4 mg daily is effective for refractory TAK and is well tolerated.

Peripheral oedema as an adverse effect of treatment of secondary progressive multiple sclerosis with siponimod: A case series.

Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.