Does glucocorticosteroid-resistant large-vessel vasculitis (giant cell arteritis and Takayasu arteritis) exist and how can remission be achieved? A critical review of the literature.

University Hospital Tübingen, Department Internal Medicine II, Otfried-Mueller Str. 10, 72076 Tübingen, Germany.
Clinical and experimental rheumatology (Impact Factor: 2.97). 30(1 Suppl 70):S114-29.
Source: PubMed

ABSTRACT The mainstay in the treatment of the large-vessel vasculitides giant cell arteritis (GCA) and Takayasu arteritis (TA) are glucocorticosteroids (GC) for induction of remission as well as for its maintenance in low doses for 1 to 2 years. However, clinical practice includes GC-resistant cases without sufficient response to standard GC for induction of remission and GC-dependent cases where a dose reduction of GC without relapse is impossible after successful induction of remission. The aim of this study was to evaluate the data on treatment options in these situations.
A literature search in PubMed matching the terms TA and GCA as well as temporal arteritis with all possible immunosuppressive and biological agents as well as with the terms 'treatment, therapy and management' was performed.
Sixty-four publications were found. Five case series described large cohorts of patients with GCA (n=2) or TA (n=3) showing that 40.8% to 48% of GCA patients and 46% to 84% of TA patients require additional immunosuppressive agents to achieve remission and taper GC. Most were on biologic agents (mainly infliximab, 24 publications/123 patients), followed by methotrexate (MTX) (14/113), cyclophosphamide (CYC) (9/27), azathioprine (AZA) (8/51), cyclosporine A (CSA) (6/47), mycophenolate mofetil (MMF) (3/32), leflunomide (LEF) (2/2), chlorambucil (1/1) and antimalarials (1/36). There were also 2 case reports on autologous stem cell transplantation. The distribution of the two entities TA and GCA was as follows: MTX: 98% GCA, 2% TA; IFX: 26.8% GCA, 73.2% TA; CYC: 70.4% GCA, 29.6% TA; AZA: 100% GCA; LEF: 100% TA; MMF: 100% TA; antimalarials: 100% GCA, autologous stem cell transplantation: 100% TA. A distinction between GC-resistant and GC-dependent cases could not be made from the data available. However, 50 (79%) of the publications described GC-resistant cases. Whereas almost all case reports and retrospective case series (with the exception of CSA) revealed steroid-sparing effects, the 3 prospective randomised trials and 2 open prospective controlled trials on MTX gave conflicting results. However, a recent meta-analysis which recalculated the original data resulted in superiority of MTX after 24 months, there were less relapses and lower GC doses in the MTX group. The prospective controlled IFX trial where IFX was randomised against placebo after GC-induced remission of GCA did not show advantages for IFX over GC alone for maintenance of remission. The prospective controlled ETA trial, which comprised 17 GCA patients, showed small, non-significant advantages but was too small to draw definite conclusions.
Although GCA is the commonest systemic vasculitis, prospective randomised trials on steroid sparing agents are rare and mostly included only small patient numbers. Inclusion and response criteria were heterogeneous, and observation periods and follow-up were often short. Criteria for GC-resistance or GC-dependence and for disease remission have not been uniformly defined. There is still an urgent need for prospective randomised trials with larger patient groups, longer follow-up and well defined inclusion criteria and criteria for response and relapse, using standardised disease activity scoring systems, in order to be able to give evidence-based recommendations for patients not responding to GC alone in the future.

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    ABSTRACT: Giant cell arteritis (GCA) and Takayasu's arteritis (TAA) are large vessel vasculitides (LVV) for which corticosteroids (CS) are the mainstay for treatment. In patients with LVV unable to tolerate CS, biological agents have been used with variable effectiveness. To systematically review the effectiveness and safety of biological agents in patients with LVV. We searched 5 electronic databases (inception to October 2012) and conference abstracts with no language restrictions. Two reviewers independently selected studies, extracted data and assessed methodological quality. Our protocol was registered in PROSPERO. We included 25 studies (3 RCTs and 22 case series with ≥2 cases). 95 GCA and 98 TAA patients received biological agents. The RCTs using anti-TNF agents (infliximab, etanercept and adalimumab) did not suggest a benefit in GCA. GCA patients receiving tocilizumab, in case series, achieved remission (19 patients) and reduction of corticosteroid dose (mean difference, -16.55 mg/day (95% CI: -26.24, -6.86)). In case series, 75 patients with refractory TAA treated with infliximab discontinued CS 32% of the time. Remission was variably defined and the studies were clinically heterogeneous which precluded further analysis. This systematic review demonstrated a weak evidence base on which to assess the effectiveness of biological treatment in LVV. Evidence from RCTs suggests that anti-TNF agents are not effective for remission or reduction of CS use. Tocilizumab and infliximab may be effective in the management of LVV and refractory TAA, respectively, although the evidence comes from case series. Future analytical studies are needed to confirm these findings.
    PLoS ONE 12/2014; 9(12):e115026. DOI:10.1371/journal.pone.0115026 · 3.53 Impact Factor
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    ABSTRACT: Adequate suppression of the inflammatory process using steroids and immunosuppressive drugs is an established strategy in the treatment of active phase of Takayasu arteritis. Methotrexate, Azathioprine, Cyclophosphamide, Mycophenolate mofetil and Tacrolimus hydrate are generally used as supplement or substitute for steroids to achieve better remission in ‘Refractory Cases’. In recent past newer biologic molecules like Anti-TNF-Alfa inhibitors, B-cell deletion agents, anti-interleukin-6 therapies and Immune-modulating agents have been tried for the management of ‘refractory’ cases with varied success; but the experience is still limited. This is a short review of possible role of each of these novel agents in management of refractory Takayasu arteritis.
    12/2014; DOI:10.1016/j.jicc.2014.08.010
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    ABSTRACT: Takayasu's arteritis is a rare disorder characterized by granulomatous and necro-inflammatory disease of the aorta and its major branches. Its etiology remains unknown. We report a young woman with Takayasu's arteritis affecting the aortic arch, carotid, mesenteric, celiac and bilateral renal arteries resulting in severe hypertension, unilateral renal atrophy and renal insufficiency. The immunosuppressive therapy did not halt the progression of her vascular disease, which required revascularization procedures on numerous occasions. Here, the clinical manifestations and histopathological features of Takayasu's arteritis are reviewed. In addition, the available medical treatment options including glucocorticoids, cytotoxic agents and TNF-alpha inhibitors are discussed. Furthermore, current revascularization procedures such as percutaneous transluminal angioplasty and reconstructive vascular surgery in the treatment of occlusive vasculopathy due to Takayasu's arteritis are discussed. Although the prognosis of this debilitating disease has improved over the past two decades, a better understanding of its etiology and pathogenesis will facilitate the discovery of effective target-specific treatment strategies with a narrow adverse effects profile.
    The Open Urology & Nephrology Journal 01/2013; 6:14-19. DOI:10.2174/1874303X01306010014