Intravenous immunoglobulin (IVIG)
Case studies report the use of intravenous immunoglobulin (IVIG) in patients with non-HBV (hepatitis B virus)-related polyarteritis nodosa (PAN) who do not respond to conventional therapy.[86]Asano Y, Ihn H, Maekawa T, et al. High-dose intravenous immunoglobulin infusion in polyarteritis nodosa: report on one case and review of the literature. Clin Rheumatol. 2006;25:396-398.
http://www.ncbi.nlm.nih.gov/pubmed/16234996?tool=bestpractice.com
[87]Gonzàlez-Fernàndez MA, Garcia-Consuegra J. Polyarteritis nodosa resistant to conventional treatment in a pediatric patient. Ann Pharmacother. 2007;41:885-890.
http://www.ncbi.nlm.nih.gov/pubmed/17405822?tool=bestpractice.com
[88]Kroiss M, Hohenleutner U, Gruss C, et al. Transient and partial effect of high-dose intravenous immunoglobulin in polyarteritis nodosa. Dermatology. 2001;203:188-189.
http://www.ncbi.nlm.nih.gov/pubmed/11586025?tool=bestpractice.com
There are also reports that IVIG can be used as a corticosteroid-sparing agent in less severe disease.[89]Balbir-Gurman A, Nahir AM, Braun-Moscovici Y. Intravenous immunoglobulins in polyarteritis nodosa restricted to the limbs: case reports and review of the literature. Clin Exp Rheumatol. 2007;25(1 suppl 44):S28-S30.
http://www.ncbi.nlm.nih.gov/pubmed/17428360?tool=bestpractice.com
[90]Gedalia A, Correa H, Kaiser M, et al. Case report: steroid sparing effect of intravenous gamma globulin in a child with necrotizing vasculitis. Am J Med Sci. 1995;309:226-228.
http://www.ncbi.nlm.nih.gov/pubmed/7900746?tool=bestpractice.com
One case report demonstrated a good response with IVIG in a corticosteroid-resistant patient with HBV-related PAN.[91]Boman S, Ballen JL, Seggev JS. Dramatic responses to intravenous immunoglobulin in vasculitis. J Intern Med. 1995;238:375-377.
http://www.ncbi.nlm.nih.gov/pubmed/7595175?tool=bestpractice.com
Tumour necrosis factor (TNF)-alpha antagonists
TNF-alpha antagonists are the gold standard of therapy in patients with DADA2.[92]Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. J Clin Immunol. 2018 Jul;38(5):569-578.
https://www.doi.org/10.1007/s10875-018-0525-8
http://www.ncbi.nlm.nih.gov/pubmed/29951947?tool=bestpractice.com
Case studies suggest that patients with resistant PAN may respond to infliximab.[93]Wu K, Throssell D. A new treatment for polyarteritis nodosa. Nephrol Dial Transplant. 2006;21:1710-1712.
http://ndt.oxfordjournals.org/cgi/content/full/21/6/1710
http://www.ncbi.nlm.nih.gov/pubmed/16421155?tool=bestpractice.com
Some of these historic treatment refractory patients may have had DADA2. The use of etanercept in idiopathic PAN is not recommended on the basis of the findings of a study in granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis).[94]Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005;352:351-361.
http://www.nejm.org/doi/full/10.1056/NEJMoa041884#t=article
http://www.ncbi.nlm.nih.gov/pubmed/15673801?tool=bestpractice.com
B-cell therapy
Rituximab is a chimeric monoclonal antibody specific for human CD20-positive B lymphocytes. In patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, one trial showed that rituximab was non-inferior to oral daily cyclophosphamide for induction of remission.[95]Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221-232.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137658
http://www.ncbi.nlm.nih.gov/pubmed/20647199?tool=bestpractice.com
A subsequent trial showed that regular low dose rituximab is superior to azathioprine for the maintenance of remission in patients with ANCA-associated vasculitis.[96]Guillevin L, Pagnoux C, Karras A, et al; French Vasculitis Study Group. Rituximab versus
azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371:1771-1780.
http://www.nejm.org/doi/full/10.1056/NEJMoa1404231#t=article
http://www.ncbi.nlm.nih.gov/pubmed/25372085?tool=bestpractice.com
There have been no clinical trials with PAN, but there are a few case reports of patients with classical (non-HBV related) PAN refractory to standard therapies whom have subsequently had a good clinical response with rituximab.[97]Sonomoto K, Miyamura T, Watanabe H, et al. A case of polyarteritis nodosa successfully treated by rituximab. Nihon Rinsho Meneki Gakkai Kaishi. 2008;31:119-123.
http://www.ncbi.nlm.nih.gov/pubmed/18446015?tool=bestpractice.com
[98]Seri Y, Shoda H, Hanata N, et al. A case of refractory polyarteritis nodosa successfully treated with rituximab. Mod Rheumatol. 2015 Mar 12 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/25671401?tool=bestpractice.com
[99]Ribeiro E, Cressend T, Duffau P, et al. Rituximab efficacy during a refractory polyarteritis nodosa flare. Case Rep Med. 2009;2009:738293.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838226
http://www.ncbi.nlm.nih.gov/pubmed/20300599?tool=bestpractice.com
Rituximab, especially when used concomitantly with corticosteroids, can lead to the reactivation of HBV in those who have had previous HBV infection and 'clearance' (i.e., surface and core antibody positive). There are case reports of fulminant hepatic failure in this context, and prophylactic antiviral therapy needs to be given with rituximab. Rituximab should not be used in the context of current HBV infection.[100]Pattullo V. Hepatitis B reactivation in the setting of chemotherapy and immunosuppression - prevention is better than cure. World J Hepatol. 2015;7:954-967.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419099
http://www.ncbi.nlm.nih.gov/pubmed/25954478?tool=bestpractice.com
Interferon alfa
In mild or moderate HBV-related PAN that is resistant to standard therapy, the addition of interferon alfa to the standard therapy has been described in case studies.[26]Erhardt A, Sagir A, Guillevin L, et al. Successful treatment of hepatitis B virus associated polyarteritis nodosa with a combination of prednisolone, alpha-interferon and lamivudine. J Hepatol. 2000;33:677-683.
http://www.ncbi.nlm.nih.gov/pubmed/11059878?tool=bestpractice.com
[101]Wicki J, Olivieri J, Pizzolato G, et al. Successful treatment of polyarteritis nodosa related to hepatitis B virus with a combination of lamivudine and interferon alpha. Rheumatology (Oxford). 1999;38:183-185.
http://rheumatology.oxfordjournals.org/cgi/reprint/38/2/183
http://www.ncbi.nlm.nih.gov/pubmed/10342635?tool=bestpractice.com
High-dose immunosuppression with corticosteroids and cyclophosphamide in HBV-related PAN
In critically ill patients with HBV-related PAN who have uncontrolled vasculitis, one option may be to consider a course of high-dose immunosuppression with corticosteroids and cyclophosphamide. However, this approach carries the risk of promoting the underlying HBV infection, so the course should be as short as possible and accompanied by lamivudine prophylaxis.[84]Guillevin L, Mahr A, Cohen P, et al. Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus-related polyarteritis nodosa. Arthritis Rheum. 2004;51:482-487.
http://www3.interscience.wiley.com/cgi-bin/fulltext/109062062/HTMLSTART
http://www.ncbi.nlm.nih.gov/pubmed/15188337?tool=bestpractice.com