Infliximab for the treatment of refractory polyarteritis nodosa

Kim

2020

Preprint

Background: Polyarteritis nodosa (PAN) is a systematic necrotizing vasculitis involving medium-sized arteries. Childhood-onset PAN ranges from mild to severe systematic disease causing damage and early mortality. As it is a rare disease in children, there is less study on clinical features, diagnosis and treatment than adults. And diagnosis occurs relatively late in most paediatric patients with polyarteritis nodosa. Therefore, this study aimed to investigate clinical manifestations, laboratory findings, treatment strategies, and long-term outcomes among patients with childhood-onset polyarteritis nodosa treated at a single-centre in Korea. We further aimed to evaluate the usefulness of the Birmingham Vasculitis Activity Score (BVAS) and Five-Factor Score (FFS) in paediatric patients.Methods: We retrospectively analysed data collected from patients with childhood-onset PAN treated at our institution from March 2003 to February 2020. Results: Nine patients (6 male and 3 female) were included in the study. The median ages at symptom onset and diagnosis were 7.6 (3–17.5) and 7.7 (3.5–17.6) years, respectively. The median follow-up duration was 7.0 (1.6–16.3) years. Eight patients were diagnosed with systemic PAN, while one was diagnosed with cutaneous PAN. All patients exhibited skin manifestations, while five exhibited Raynaud’s phenomenon. Organ involvement was observed in one patient. Constitutional symptoms such as fever, arthralgia, myalgia, and weight loss were also observed. Antineutrophil cytoplasmic antibodies were absent in all patients. The median BVAS at diagnosis was 8 (range: 2–29), and one patient had an FFS of 1. Prednisolone was initially used for induction in all patients, and other drugs were added in cases refractory to prednisolone. All patients survived despite some complications such as intracranial haemorrhage or digital necrosis requiring amputation.Conclusions: Early diagnosis and treatment may minimise sequelae in patients with childhood-onset PAN. Further multicentre studies are required to clarify the unique characteristics of childhood-onset PAN and establish treatment guidelines, early detection strategies, and biomarkers. Trial registration: Retrospectively registered.

Section: Discussionsupporting

confidence: 51%

“…The discovery of this association between ADA2 and vasculitis has led to reconsideration in most cases of childhood-onset PAN. Hence, it remains critical to evaluate family history and identify ADA2 mutations when considering a diagnosis of PAN, as anti-TNF-α agents and ADA2 replacement therapy may be warranted in some cases [30].…”

Section: Discussionmentioning

confidence: 99%

Clinical presentations and long-term prognosis of childhood-onset polyarteritis nodosa in a single centre: a retrospective study

Kim

2020

Preprint

“…In PAN, infliximab has been used in refractory forms of the disease or because of intolerance to conventional drugs and seems to be effective [48]. In a small case series, nine refractory PAN patients were treated with infliximab and 8 of 9 patients (89%) achieved significant improvement and prednisone dose reduction of 50% [49].…”

Section: Tumor Necrosis Factor (Tnf) α Inhibitormentioning

confidence: 99%

Vasculitis: From Target Molecules to Novel Therapeutic Approaches

Chung

2021

Biomedicines

Systemic vasculitis is a group of diverse diseases characterized by immune-mediated inflammation of blood vessels. Current treatments for vasculitis, such as glucocorticoids and alkylating agents, are associated with significant side effects. In addition, the management of both small and large vessel vasculitis is challenging due to a lack of robust markers of disease activity. Recent research has advanced our understanding of the pathogenesis of both small and large vessel vasculitis, and this has led to the development of novel biologic therapies capable of targeting key cytokine and cellular effectors of the inflammatory cascade. It is anticipated that these novel treatments will lead to more effective and less toxic treatment regimens for patients with systemic vasculitis.

“…Recently, we have also reported our positive experience with another agent, infliximab, for refractory PAN and reviewed the literature 5. The ever-expanding spectrum of biological treatments is confusing for the practitioner and although case reports and case series are important to guide us in rare refractory patients, we should still follow guidelines and use evidence-based treatments that were evaluated in large randomised controlled clinical trials as first-line therapy.…”

mentioning

confidence: 99%

“…Furthermore, we did not find tocilizumab clinically or radiologically beneficial in another patient with severe refractory PAN involving skin and coronary arteries-evidenced by positron emission tomography-CT scan revealing active inflammation in an aneurism within a coronary artery and by MRI demonstrating active deep skin involvement while under treatment with tocilizumab (unpublished data).Thus, in considering the review by Akiyama et al, publication bias should always be considered when evaluating case reports, as we all tend to prefer publishing our positive experience.Recently, we have also reported our positive experience with another agent, infliximab, for refractory PAN and reviewed the literature. 5 The ever-expanding spectrum of biological treatments is confusing for the practitioner and although case reports and case series are important to guide us in rare refractory patients, we should still follow guidelines and use evidence-based treatments that were evaluated in large randomised controlled clinical trials as first-line therapy.New technologies may help us diagnose and treat refractory patients. Whole-exome sequencing studies may reveal novel mimickers, the monogenic vasculitides, as deficiency of adenosine deaminase 2, stimulator of interferon genes-associated vasculopathy with onset in infancy, and haploinsufficiency of A20 that should be considered in refractory cases.…”

mentioning

confidence: 99%

Response to: ‘Tofacitinib for the treatment of polyarteritis nodosa: a literature review’. Correspondence on ‘Tofacitinib for polyarteritis nodosa: a tailored therapy’ by Rimaret al

et al. 2020

Self Cite

We appreciate the interest of Akiyama et al in our report and thank them for the data presented in their letter. 1 2 Akiyama et al have presented a thorough literature review and have described a positive and efficacious effect of tocilizumab in 11 cases of refractory polyarteritis nodosa (PAN) described in 6 case series. Indeed, the use of tocilizumab, an interleukin (IL)-6 inhibitor, in vasculitis is gaining evidence in the literature, specifically in large vessel vasculitis including giant cell arteritis and Takayasu arteritis. 3 4 Nevertheless, it should be noted that although the IL-6 pathway is the major inducer of STAT 3, and therefore was used by us in vitro to stimulate this pathway in order to evaluate STAT 3 activation, clinically blocking the IL-6 pathway in our patient, using tocilizumab, was not beneficial, contrasting with our positive result with tofacitinib. We hypothesised that redundancy or other stimulators of the STAT 3 pathway like IL-23 may explain this discrepancy. Furthermore, we did not find tocilizumab clinically or radiologically beneficial in another patient with severe refractory PAN involving skin and coronary arteries-evidenced by positron emission tomography-CT scan revealing active inflammation in an aneurism within a coronary artery and by MRI demonstrating active deep skin involvement while under treatment with tocilizumab (unpublished data).Thus, in considering the review by Akiyama et al, publication bias should always be considered when evaluating case reports, as we all tend to prefer publishing our positive experience.Recently, we have also reported our positive experience with another agent, infliximab, for refractory PAN and reviewed the literature. 5 The ever-expanding spectrum of biological treatments is confusing for the practitioner and although case reports and case series are important to guide us in rare refractory patients, we should still follow guidelines and use evidence-based treatments that were evaluated in large randomised controlled clinical trials as first-line therapy.New technologies may help us diagnose and treat refractory patients. Whole-exome sequencing studies may reveal novel mimickers, the monogenic vasculitides, as deficiency of adenosine deaminase 2, stimulator of interferon genes-associated vasculopathy with onset in infancy, and haploinsufficiency of A20 that should be considered in refractory cases. Finally, precision medicine, as we suggested in our report, may guide us in the future, helping us to find the right fit for each patient. 6 7