Use of Anti TNF-α Therapy in Systemic Vasculitis

There are several vascultic disorders still labeled as difficult-to-treat cases. Effective treatment for those patients is warranted to reduce the mortality and morbidity that resulting from these disorders. An extensive review for the literatures that addressed using of ant TNF-alpha in several vascultic disorders was conducted. Use of anti TNFalpha agents is a promising modality in several vascultic disorders. Despite lacking well-conducted randomized controlled trials, more open-label studies are required to examine in-depth the safety and efficacy of those agents.


Introduction
The available anti TNF-α agents are Infliximab, Adalimumab, Etanercept, Certolizumab pegol and Golimumab. Infliximab is a chimeric monoclonal antibody composed of a murine variable region attached to human Fc (constant) portion of IgGκ. Adalimumab is a fully humanized monoclonal antibody, dosed every second week as a subcutaneous injection. While etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody. On the other hand, Certolizumab pegol is a humanized antigen binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol [6]. Finally, Golimumab is a human immunoglobulin G1 kappa (IgG1) monoclonal antibody specific for human tumor necrosisfactor (TNF; TNF α) [7].
Concerns were present toward increased risk for infections, malignancy and cardiovascular disease with the use of anti TNF-α. However, one study demonstrates that among 16,000 patients treated with anti TNF-α for rheumatoid arthritis there was no increase of the serious bacterial infections in comparison to patients treated with methotrexate (MTX) [8]. Overall, the use of anti TNF α is associated with an increased risk of infections. Caution should be addressed while using these drugs in daily clinical practice. Regarding the risk of malignancy; recent analysis from Lombardy Rheumatology Network (LORHEN) registry addressed no increase in the malignancy risk in comparison to the general population, however the risk of hematological malignancy especially lymphoma was significantly increased in people who are older than 65 years [9].
In comparison to conventional DMARDs; anti TNF-α agents do not increase the risk for cardiovascular events [10]. Table 1 summarizes the all available anti TNF-α agents used in treatment of vasculitis.
In this article, we have conducted extensive review of different publications that addressed the use of anti TNF-α agents in vasculitis as shown in (Figure 1). Aiming to deliver a comprehensive overview of the best and the latest evidence in this field.

Takayasu Arteritis
Takayasu arteritis (TA) is an idiopathic panarteritis affects the large and medium vessels especially the aorta and its branches, with onset of age before 30. It is characterized by granulomatous inflammation in the involved site [11]. TNF-α is an important cytokine for granuloma formation. Activated T cells, natural killer cells, γ/δ cells and macrophages are also important pathophysiological principles of TA's development [11]. The mainstay therapy consists of glucocorticoid (GC) and methotrexate (MTX [12]. Only 40-60% of patients with TA achieve remission on conventional therapy [12]. Thus, the need of new modality of treatment is warranted to achieve remission in the remaining patients. The clinical benefit of anti TNF-α in TA has been demonstrated via several case reports and series. One case series observed 15 patients with resistant TA [13], in all patients who received GC the relapses were observed while the dose was tapered down. In this study, patients were divided into two groups, 7 patients received etanercept, the remaining 8 patients were started on infliximab. Out of these 15 patients, 93% showed significant improvement, while 67% experienced GC-free remission for 3 years after follow-up. Another case series described the effect of anti TNF-α on TA [14]. Five patients with TA failed to achieve remission on conventional therapy. Infliximab was initiated with MTX as a concomitant immunosuppressive agent in 4 cases, one case was on AZA. The follow-up duration was ranging from 3 to 72 months. It showed only one relapsed case. The other four cases showed successful tapering of GC dose with no relapse upon follow-up. Additionally, a literature review of 79 cases with TA showed significant response on infliximab and etanercept [14]. Global improvement was observed in 90%, complete remission in 37% and partial remission in 53%, patients who do not respond to anti TNF-α therapy were only 9%. One study evaluated 8 patients with refractory TA; two of them were refractory to infliximab therapy and 3 patients did not achieve remission on GC and MTX. However, all patients received tocilizumab (interleukin-6 receptor antagonist) therapy and the follow-up showed 7 out of 8 patients achieved remission. This data shows an interesting finding that tocilizumab can be a potential therapy for refractory TA to anti-TNF-α therapy [15]. Case series of 10 patients showed a sustainable remission on tocilizumab therapy in 60%, the other 40% failed to satisfy the criteria of sustainable remission, requiring either clinical or biochemical criteria of remission [16]. Interestingly, out of 6 patients who achieve sustainable remission on tocilizumab underwent followup after discontinuation, only 2 patients maintain their complete remission on post-tocilizumab follow-up period (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) months [16]. These finding can raise the concerns regarding the effectiveness of tocilizumab as a steroid-sparing agent.
In conclusion, anti TNF-α can be a potential therapy for patients with steroid-resistant TA. However, relapsed cases on anti TNF-α agents were reported as well. Tocilizumab can be a potential option in these cases, although there are reports of relapses after holding the tocilizumab. Overall, further placebo-controlled studies should be conducted to improve the current quality of evidence available for practicing clinicians. Table 1 shows a summary of studies that addressed the use of anti TNF-in patients with TA [17][18][19][20][21].

Figure1: Summary Of Anti-TNF α Agents In Systemic Vasculitis
Out of these 15 patients, 93% showed significant improvement, while 67% experienced GC-free remission for 3 years after follow-up. Another case series described the effect of anti TNF-α on TA [14]. Additionally, a literature review of 79 cases with TA showed a significant response to infliximab and etanercept (14). Global improvement was observed in 90%, complete remission in 37% and partial remission in 53%, patients who do not respond to anti TNF-α therapy were only 9%. One study evaluated eight patients with refractory TA; two of them were refractory to infliximab therapy, and three patients did not achieve remission on GC and MTX. However, all patients received tocilizumab (interleukin-6 receptor antagonist) therapy, and the follow-up showed 7 out of 8 patients achieved remission. This data shows an interesting finding that Tocilizumab can be a potential therapy for refractory TA to anti-TNF-α therapy [15]. Case series of 10 patients showed a sustainable remission on tocilizumab therapy in 60%, the other 40% failed to satisfy the criteria of sustainable remission, requiring either clinical or biochemical criterion of remission [16].  Five patients with TA failed to achieve remission on conventional therapy. Infliximab was initiated with MTX as a concomitant immunosuppressive agent in 4 cases, one case was on AZA. The follow-up duration was ranging from 3 to 72 months. It showed only one relapsed case. The other four cases showed successful tapering of GC dose with no relapse upon follow-up. Additionally, a literature review of 79 cases with TA showed significant response on infliximab and etanercept [14]. Global improvement was observed in 90%, complete remission in 37% and partial remission in 53%, patients who do not respond to anti TNF-α therapy were only 9%. One study evaluated 8 patients with refractory TA; two of them were refractory to infliximab therapy and 3 patients did not achieve remission on GC and MTX. However, all patients received tocilizumab (interleukin-6 receptor antagonist) therapy and the follow-up showed 7 out of 8 patients achieved remission. This data shows an interesting finding that Tocilizumab can be a potential therapy for refractory TA to anti-TNF-α therapy [15]. Case series of 10 patients showed a sustainable remission on tocilizumab therapy in 60%, the other 40% failed to satisfy the criteria of sustainable remission, requiring either clinical or biochemical criteria of remission [16]. Interestingly, out of 6 patients who achieve sustainable remission on Tocilizumab underwent followup after discontinuation, only 2 patients maintain their complete remission on post-tocilizumab follow-up period 3-14 months [16]. These finding can raise the concerns regarding the effectiveness of Tocilizumab as a steroid-sparing agent.

Giant Cell Arteritis
Giant cell arteritis (GCA) is a most common form [22,23] as a multisystem granulomatous vasculitis predominantly targets large and medium sized arteries [24,25]. Classical disease therapy relies on a high dose of GC administration once the clinical finding is suggestive of the disease [25,26]. Relapse is common in 60-70% of patients thus, other therapeutic modalities are required [23,27,28]. A meta-analysis in 2014 [29], included five studies about anti TNF alpha agents in GCA. It failed to prove any beneficial effect. Table 3 shows a summary of studies that addressed the use of anti TNF-α agents in patients with GCA [30][31][32].

Behçet's Disease
Behçet's Disease (BD) is an inflammatory disorder characterized by recurrent oral aphthous ulcer and systemic manifestations: genital ulcer, skin lesion and neurological manifestations [33]. The ability of BD to involve more than one type of vessels makes it unique and remarkable vasculitic disease.  Table 2: Summary of the studies that investigate using of anti TNF-α agents in Takaysu arteritis.
The current therapeutic modalities for BD came from case reports and case series, with few follow-up studies. Currently, for minor disease manifestations; a regimen consists of colchicine initially and GC for patients who do not respond well for colchicine [34,35]. For major disease manifestations; typical regimen is high dose of GC (1 mg/Kg/day) not exceeding 80 mg/day. The effect of anti TNF-α in BD has been investigated thoroughly, the beneficial effect of infliximab, adalimumab, and etanercept was reported [36,37]. In a multicenter observational study including 164 patients with BD with uveitis received infliximab for more than a year, infliximab was found reducing the number of ocular attacks per year [38].   Table 3: Summary of the studies that investigate using of anti TNF-α agents in Giant cell arteritis.
Surprisingly, relapsed uveitis has been reported in 60% of the patients on infliximab therapy especially in the first year, and symptoms were controlled by increasing the topical GC dose and shortening the interval of infliximab therapy. In retrospective analyses of 28 patients with moderate to severe intestinal BD [39], patients were followed and achieved a clinical response reaching 75%. (Median duration of follow-up is 30 months). In a double blind study on BD [40], more patients remained free of oral lesions after etanercept therapy (45% versus 5% in control group), in terms of nodular skin lesion (85% versus 25%) were observed. Benefit of adalimumab has been reported in one case series [41]. However, some patients who failed infliximab therapy might achieve remission on adalimumab, 17 of 69 patients investigated for this purpose [42], out of those 17 patients only 12 achieved improvement on adalimumab therapy. Anti TNF-α can be a valuable modality inducing and maintaining remissions with steroid and immunosuppressive sparing effect for patients with severe BD who failed to achieve remission on conventional therapy. High-quality level of evidence is warranted to assist the practicing rheumatologist in toward difficult-to-treat cases of BD. Table 4 shows a summary of studies that addressed the use of anti TNF-α agents in patients with BD [43].

Cryoglobulinemic Vasculitis
It is a systemic inflammatory condition that involve small to medium sized vessel vasculitis caused by cryoglobulin contained immune complex deposition [44]. Conventional treatment of this vasculitis started by treatment of underlying cause as in hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis [45]. Rituximab (RTX) (Anti-CD20) showed benefit in life threatening conditions [46],   Table 5: Summary of the studies that investigate using of anti TNF-α in cryoglobulinemic vasculitis.
Single dose of infliximab 5mg/kg results in complete resolution of the symptoms; followed by uneventful clinical course for one patient complaining of cryoglobulinemic vasculitis with gastrointestinal bleeding. Table 5 shows a summary of studies that addressed the use of anti TNF-α agents in patients with cryoglobulinemic vasculitis [48,49].

Kawasaki Disease
Kawasaki disease (KD) is a form of medium sized vasculitis most commonly affects coronary arteries. In children KD is the second most common vasculitis [50]. Marked elevation of serum TNF-α found in sera of KD patients [51].
Acute KD management strategy involves administration of 2 g/kg as a single infused intravenous immunoglobulin (IVIG) with high dose aspirin. Aspirin can be continued as a low dose until echocardiograms is normal [52]. Almost 15-20% of patients failed to respond to initial IVIG [52]. In those refractory KD patients, anti TNF α agents have been investigated [53]. Several retrospective studies, case series, and case reports addressed infliximab effectiveness in refractory KD.
From 2004-2006 [54], 24 patients with refractory KD received either infliximab or a second dose of IVIG. Each group contained 12 patients. Symptoms subsided in 11 patients on infliximab group versus in 8 who were on IVIG. Two out of 4 who did not respond were in IVIG group, had responded to infliximab later on. Another 2 studies addressed the effect of adding infliximab to the standard therapy. In 2014 [55] a phase 3, randomised, double-blind, placebo-controlled trial was conducted on 196 patients to assess the benefit adding of infliximab to the conventional therapy. The results came to show infliximab didn`t reduce the disease resistance rate.
Etanercept is an under-studied anti TNF-α agent for refractory KD. A prospective open label trial of 17 patients with KD [56], all enrolled patients received IVIG plus aspirin, etanercept was administrated immediately after IVIG infusion. No complications or side effects have occurred in all 15 patients. Table 6 shows a summary of studies that addressed the use of anti TNF-α agents in patients with Kawasaki disease [57][58][59][60][61][62][63].

Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects small and medium-sized arteries [64]. The treatment and the prognosis are highly variable depending on the extent of the disease if it is systematic or localized to the skin. Despite aggressive medical management with GC and CYC, many patients develop aggressive disease refractory to all available modalities with high incidence of mortality reaching up 22.4% within five years from the disease onset [65]. Several reported cases showed remission after failing of conventional therapy [65][66][67]. The selected cases cover a broad spectrum of clinical presentation representing different age groups. In each case, patients were treated with one or a combination of GC and immunosuppressant with little or no response to treatment.  Table 7: Summary of the studies that investigate using of anti TNF-α agents in Polyarteritis nodosa.
Few cases were treated with etanercept [65][66][67], one with infliximab [68], tocilizumab [69], adalimumab [70] and lastly, a case treated with rituximab [71]. All cases showed a good response to treatment with achieved remission upon clinical and biochemical basis without serious side effects. Although we found no prospective studies or large trials addresses the role of anti-TNF in inducing or maintaining remission in patients with PAN, there are several case reports that suggest the benefits of anti-TNF-alpha in severe and refractory cases. More studies are required to determine the safety and efficacy of anti-TNF treatment in PAN. Table 7 shows a summary of studies that addressed the use of anti TNF-α agents in patients with PAN.

Conclusion
Use of anti TNF-α agents is a promising modality in the field of vasculitis management. Despite lacking of well-conducted randomized controlled trials in several vasculitic disorders, anti TNF-α agents remain an optional therapy for difficult-to-treat cases. It has to be noted that anti-TNF alpha agents showed no beneficial effects in ANCA-associated vasculitis (AAV) [72]. In fact, these agents can induce autoimmune syndromes like vasculitis e.g. Henoch-schönlein purpura [73]. Collectively, we encourage clinicians, in the field of taking care of vasculitis patients, to raise their collaboration level; with the aim to reach a better evidence-based clinical practice.