Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis that predominantly affects medium-sized muscular arteries [61]. Small arteries may be involved, but small vessels, including arterioles, capillaries, and venules, are usually spared. Therefore, glomerulonephritis is not part of the spectrum of PAN [62].
PAN may encompass a spectrum of disorders. It may be idiopathic or triggered by specific agents. The most typical is hepatitis B virus (HBV). Before vaccination against HBV was available, more than one-third of adults with PAN were infected by HBV. Currently, less than 5% of patients with PAN are HBV-infected in developed countries [63].
In some cases other viruses such as hepatitis C (HCV), HIV, parvovirus B19 and cytomegalovirus have been detected. Interestingly, hairy cell leukaemia has also been implicated in the pathogenesis of PAN in some cases [64-66]. PAN may be a systemic disease however variants are single-organ disease and cutaneous PAN (cPAN) [62].
cPAN lacks significant internal organ involvement. The aetiology is unknown. Clinical manifestations include tender subcutaneous nodules, livedo reticularis, cutaneous ulcers and necrosis. Mild cases may resolve with nonsteroidal anti-inflammatory drugs. If more severe, treatment with systemic corticosteroids generally achieves adequate response; however, adjunctive therapy is often necessary to allow reduction in steroid dosage. Patients with isolated cutaneous disease when first seen and initially treated may relapse with disease in other organs, and should be monitored periodically [65, 67].
Single-organ PAN is usually a monocyclic disease, which typically does not relapse. It is often discovered by histological examination of surgical specimens. Treatment beyond surgical excision (e.g., isolated PAN of the gallbladder) is usually not necessary [62]. Like
cPAN follow up is recommended to determine if additional organs or other clinical features are present or developing [65].
In this section we will concentrate on PAN. The annual incidence of PAN currently ranges from 0 to 1.6 cases/million inhabitants in European countries [68, 69] and its prevalence is about 31 cases/million [63, 70]. PAN affects patients of all ethnic groups. It typically occurs in patients in their 4th and 6th decade of life and women are less frequently
affected than men [71].
The grounds on which patients with necrotising vasculitis have been classified as PAN have evolved over the years. Therefore it is difficult to conclude what the optimal therapy for PAN is as most studies have been performed on mixed cohorts of patients with PAN and AAV [64].
The prognosis of PAN depends on the organs involved, which guides treatment. The French Vasculitis Study Group (FVSG) proposed the Five Factor Score (FFS), a prognosis index with the following factors: presence of renal involvement (serum creatinine >149 µmol/L) or proteinuria (>1 g/day), severe gastrointestinal tract disease, cardiac disease and central nervous system involvement. When present, each of these is given a score of 1 [72].
In patients with FFS >2 a 46% 5-year mortality was observed. This is only 12% in patients with a score of 0 [72]. In 2011 this score was revised and now includes only four factors. The FVSG group excluded the central nervous system involvement and proteinuria, thereby replacing them with age >65 which is considered a poor prognostic indicator [73].
Mild forms of PAN (FFS 0) and cPAN as mentioned earlier are usually treated solely with corticosteroids. First-line corticosteroid treatment is able to achieve and maintain remission in only about more than half of patients with mild PAN. The remaining 40% of patients require additional immunosuppressive therapy [71].
There are few randomised trials of treatment; however observational studies of PAN have shown the efficacy of glucocorticoids and CYC in patients with more severe disease. Monthly doses of CYC are preferred over daily oral CYC due to a better safety profile [74].
As previously discussed in this chapter, rituximab has been beneficial in treating AAV. There have been a few case reports suggesting that rituximab is also effective against corticosteroid-resistant PAN without HBV. However therapeutic trials are needed to determine the real efficacy and place of rituximab in the treatment of PAN [75].
In the past HBV-PAN was treated in the same way as non-viral PAN and patients received corticosteroids and immunosuppressive agents, such as CYC. This is no longer recommended as this regime promoted viral persistence and replication [65]. Eradication of hepatitis B is part of the management for HBV-PAN as once seroconversion is achieved, complete remission usually occurs without relapse. Combining an anti-viral drug with plasmapheresis may facilitate seroconversion and prevent the development of long-term hepatic complications of HBV [76].
Unlike HBV PAN there are no large series describing treatment approaches for HCV PAN and HIV PAN. The approach used in HBV PAN (short glucocorticoid treatment followed by specific anti-viral therapy) may be suitable for other virus-associated PAN [64, 65].
In a few case reports, infliximab has been used in refractory forms of PAN or when standard therapies are unsuccessful or contraindicated, and it seems to be effective, which raises the possibility that this may have a role in challenging cases of PAN [39, 77].
In summary, current treatment policy includes high-dose corticosteroids, which are combined with immunosuppressive agents when critical organ involvement or life- threatening complications occur. A frequently used therapy is IV pulse CYC in the remission induction phase, later switched to a safer immunosuppressant for remission maintenance [64]. The literature has shown that there is a role for biologics in PAN with a few cases reports highlighting a possible role for rituximab and TNF inhibition therapy. However, as definition of this vasculitis evolves and the pathogenesis of PAN becomes clearer, the role of targeted biological treatments should evolve.
Kawasaki Disease
Kawasaki disease (KD), formerly called muco-cutaneous lymph node syndrome, is one of the most common vasculitides of childhood. It is the leading cause of childhood-acquired heart disease in the developed world [78]. The stimulus for the cascade of inflammation in KD is unknown. If untreated, approximately 20–25% of children develop coronary artery aneurysms, which may lead to myocardial infarction and death [79-80].
KD has a universal distribution and can manifest in children of any ethnicity. However it is more prevalent in Asian countries, especially in Japan where in 2010, the annual incidence was found to be 240 per 100,000 in children <5 years of age [81]. In France the incidence of KD is 9 per 100,000 children <5 years of age [82].
Standard initial therapy is IVIg and aspirin. Non-responders to initial therapy remain a challenge. Interestingly the mechanism of action of IVIg is unknown, a single dose given together with aspirin within 10 days of fever onset results in rapid resolution of clinical symptoms in 80–90% of patients, and has been shown to reduce the risk of coronary disease from 20–25% to about 2–4% [83].
Adult-onset KD (AKD) is rare and often misdiagnosed. A recent review including post- infectious cases described 100 cases of AKD [84]. A French group looked at 43 patients, the largest series of patients with AKD. The findings showed that these patients had a high frequency of cardiac involvement and complications and that early IVIg treatment seems to improve the outcome. These results seem similar to those found for childhood KD [85].
Approximately 10–15% of patients with KD fail to respond to standard therapy. Unfortunately, the optimal treatment of patients with ‘refractory’ KD has not been determined, as there are few controlled data available. The general consensus is administration of a second dose of IVIg if symptoms do not resolve with the first dose [86]. However, if there is failure to respond to two doses of IVIg there is no consensus in the literature regarding the next step and most experts consider a third dose of IVIg, whereas others may trial methylprednisolone or use biologics such as TNF inhibitors [87].
TNFα and TNFα soluble receptors I and II concentrations are increased in the acute phase of KD, and are highest in children who subsequently develop coronary artery aneurysms. Therefore, TNF inhibitor agents, such as etanercept and infliximab have been studied as both adjuvant therapy for primary disease and as monotherapy for refractory KD.
A recent randomised double-blind, placebo-controlled trial assessed the benefit of adding infliximab to the primary standard therapy of KD. This study showed that adding a dose of infliximab prior to the IVIg treatment did not reduce IVIg treatment resistance, as measured by coronary artery z scores at 5 weeks. However, infliximab was safe, reduced fever duration, some markers of inflammation and IV immunoglobulin reaction rates [88].
Starting in 2004, isolated case reports of infliximab treatment of refractory KD began to appear in the literature [89]. A multicenter, randomised and prospective trial showed that infliximab is an effective and safe agent for treatment in refractory KD [90]. Thereafter, a large retrospective review showed that in patients with IVIg-resistant KD, whose first re- treatment was infliximab rather than IVIg, had faster resolution of fever and fewer days of hospitalisation. Coronary artery outcomes and adverse events were similar however the power of the study was limited [91].
In 2010 the first prospective, open-label clinical trial using TNF inhibition as adjunctive therapy for IVIG treatment of acute KD was published. Patients, aged 6 months to 5 years, received etanercept over a 2-week period as adjunctive treatment for the first IVIg dose. None of the 15 patients completing the trial required retreatment or rescue therapy. Thus etanercept appears to be safe and well-tolerated in children with KD [92]. Currently, there is a study undergoing, which is investigating the use of etanercept along with IVIg as a first-line treatment, aiming to reduce need for re-treatment [93].
A single case has been reported in the literature of the use of rituximab in a child with KD refractory to IVIg and glucocorticoids. The case was associated with significant lesions of the coronary arteries which were treated successfully with rituximab. Rapid clinical, biological, and cardiac improvement was observed with rituximab. The patient tolerated the treatment well. No recurrence was noted when steroids and aspirin were discontinued [94]. These results need to be confirmed with future studies.