Comment on: Sirolimus for patients with connective tissue disease-related refractory thrombocytopenia: a single-arm, open-label clinical trial

Dear editor, We read with interest the report by Wu et al. wherein the authors have demonstrated the use of sirolimus for management of refractory thrombocytopenia in a cohort of patients with connective tissue disorders, especially SLE [1]. We would like to present additional interpretations and concerns regarding this study. The authors report a cohort of 20 patients (predominantly adults), 14 of whom had SLE. Among the SLE cohort, a few patients were ≤20 years of age at the time of enrolment (patients 15, 17 and 18). We note that two out of these three patients failed to show complete response to sirolimus (33% response rate); whereas three patients among the remaining SLE cohort (who were >20 years old at the time of enrolment) failed to show complete response to sirolimus (73% response rate). Although the absolute number of patients is small, these results suggest that the efficacy of sirolimus in refractory thrombocytopenia in patients with SLE ≤20 years of age may be suboptimal. One of these patients (patient 17) who had symptom onset early in childhood had received several immunosuppressive agents to control the thrombocytopenia. The authors have found no difference in the age when stratified according to the response to sirolimus therapy (responders vs non-responders). However, it may be more informative to compare age at disease onset rather than age at the time of enrolment.

It would also be interesting to know about the presence of additional features in the SLE cohort described, such as autoimmune haemolytic anaemia (four patients had Coombs positivity) and lymphoproliferation; and if these features showed a response to sirolimus therapy. In addition, we would also like to know if any of these patients were evaluated for underlying monogenic defects including complement deficiency. This evaluation would be especially important for patient 17 (who appears to have an early-onset disease) and patient 15 (paediatric-onset SLE with male gender) as both did not respond to sirolimus therapy. In our experience, we have observed several patients with monogenic complement deficiency (especially C1q deficiency) who present with early-onset SLE [2]. Additionally, patients with mutations in genes involved in type I interferon, RAS, self-tolerance, and other pathways can present with SLE [3]. Sirolimus has shown promising results in the treatment of autoimmunity, especially refractory cytopenias, and lymphoproliferation associated with monogenic forms of common variable immunodeficiency [such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency, lipopolysaccharide (LPS)-responsive and beige-like anchor protein (LRBA) deficiency], autoimmune lymphoproliferative syndrome (ALPS), activated phosphoinositide 3-kinase δ syndrome (APDS), and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome [4–9]. A description of the queries raised would be a valuable addition to the publication by Wu et al. and potentially expand the spectrum of utility of sirolimus in the management of autoimmune diseases.

Through this letter, we also wish to highlight the need to evaluate patients with autoimmune diseases for monogenic causes, especially in the presence of atypical or unusual clinical manifestations and those who show unusual response to treatment [10]. In case of SLE, especially, in the case of complement deficiency lupus (the most common class of monogenic disorders that can present with SLE), the clinical pointers for an underlying genetic defect could be early age at disease onset, normal complement levels (C3 and C4) in the presence of disease activity, a non-homogeneous pattern of antinuclear antibody [on indirect immunofluorescence (often with negative anti-dsDNA titers)], and male gender [2]. It is important to emphasize that autoimmune manifestations may be the only clinical presentation of IEIs and, hence, rheumatologists would be at the forefront of establishing these diagnoses.

Acknowledgement

A.Z.B.: writing of initial draft of manuscript, editing and revision of manuscript at all stages of its production and final approval, review of literature; A.K.J.: inception of idea, evaluation, and critical revision of the manuscript at all stages of production and final approval.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: The authors have declared no conflicts of interest.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

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