Treatment of Different Types of Vasculitis

Vasculitis is classified by the size of the blood vessels affected by inflammatory reactions. In vasculitis of skin, many patients show obvious purpura and ulceration. Because many vasculitides can be noticed by these skin manifestations, dermatologists should be well informed about vasculitis. It is difficult to manage vasculitis after the diagnosis has been performed, and it is particularly difficult to treat systemic vasculitides, because they are potentially life threatening. The purpose of this chapter is to provide treatment guidelines for the primary vasculitic diseases.


Introduction
Vasculitis is classified by the size of the blood vessels affected by inflammatory reactions.In vasculitis of skin, many patients show obvious purpura and ulceration.Because many vasculitides can be noticed by these skin manifestations, dermatologists should be well informed about vasculitis.It is difficult to manage vasculitis after the diagnosis has been performed, and it is particularly difficult to treat systemic vasculitides, because they are potentially life threatening.The purpose of this chapter is to provide treatment guidelines for the primary vasculitic diseases.

Giant cell arteritis
Giant cell arteritis is an inflammation of medium-and large-sized arteries that characteristically affects one or more branches of the carotid artery, particularly the temporal artery (Salvarani C et al., 2002), but it is a systemic disease that can affect arteries in multiple locations, particularly the aorta and its main branches.Polymyalgia rheumatica, which is characterized by stiffness, aching, and pain in the muscles of the neck, shoulders, lower back, hips, and thighs, can occur with giant cell arteritis (Langford CA, 2010).It is very important for patients who are strongly suspected of having giant cell arteritis to be treated immediately in order to protect their vision.When patients show ischemic symptoms, treatment should be started before checking the results of a temporal artery biopsy.A temporal artery biopsy after treatment has begun is exceedingly useful for making a diagnosis (Langford CA, 2010).The aim of treatment is to improve the symptoms such as headache, jaw claudication, tenderness of scalp, and polymyalgia rheumatica and to prevent complications occurring as a result of vascular occlusion causing tissue infarction.Glucocorticoids rapidly improve cranial and systemic symptoms and prevent visual complications in patients with giant cell arteritis rapidly.Aiello et al. reported that the probability of loss of vision developing after initiating oral glucocorticoid treatment was determined to be 1% (Aiello PD et al., 1993).The initial dose of prednisone is usually 40 to 60 mg/day (Langford CA, 2010), but the other report has stated that a dose under

Takayasu arteritis
Takayasu arteritis, which has also been known as the aortic arch syndrome, is an inflammatory and stenotic disease of medium-and large-sized arteries characterized by a strong predilection for the aortic arch and its branches (Langford CA & Fauci AS, 2008).For the first 1 to 3 months, patients are treated with 1 mg/kg/day prednisone as an initial dose.After that, the dose is tapered to withdrawal over a 6-to 12-month period (Langford CA, 2010).If the disease activity persists in spite of treatment with glucocorticoids or the dose of glucocorticoids cannot be tapered, cytotoxic therapy is primarily administrated (Langford CA, 2010).Doses of 15 to 25 mg/week methotrexate in combination with glucocorticoids may induce remission and minimize glucocorticoid therapy and toxicity in most of these patients (Hoffman GS et al., 1994).Azathioprine is used for the patients who are steroidresistant or have severe side effects by glucocorticoids.Cyclophosphamide has been used in patients with Takayasu arteritis refractory to glucocorticoids (Shelhamer JH et al., 1985).In the patients with intractable Takayasu arteritis, anti-TNF therapy may lead to durable remission in a majority of patients and facilitate dose reduction or discontinuation of prednisone and other immunosuppressive therapy (Molloy ES et al., 2008).Vascular reconstructive surgery or angioplasty are adjunctive therapeautic options in some patients (Gota CE & Mandell BF, 2008).

Polyarteritis nodosa
Polyarteritis nodosa constitutes a necrotizing inflammation of medium-sized or small arteries (Cox NH et al., 2010;Jennette JC et al., 1994).Polyarteritis nodosa does not show glomerulonephritis or vasculitis in arterioles, capillaries or venules (Cox NH et al., 2010).Affected patients may have several signs and symptons involving multiple organ systems (Cox NH et al., 2010).Ischaemia, infarcts and haemorrhage result from the vasculitis and lead to end-organ damage in patient with polyarteritis nodosa (Cox NH et al., 2010).Therapy for polyarteritis nodosa is still somewhat empiric.If patients have critical organ involvement, such as renal insufficiency, gastrointestinal ischemia, cardiomyopathy, dense peripheral neuropathy, or central nervous system involvement, they should be treated with 2 mg/kg/day cyclophosphamide and glucocorticoids (Gayraud M et al., 2001).In patients who do not have immediate critical organ involvement, glucocorticoids alone may be sufficient therapy.Patients who cannot taper glucocorticoids and are unresponsive to other therapy may be treated by cyclophosphamide with glucocorticoids (Langford CA, 2010).In patients whose disease is strongly suspected to be caused by streptococcal infection and repeat recurrence, penicillin antibiotics may be given as preventive treatment.But it has not been reported that penicillin antibiotics alone are effective and the efficacy of this therapy has not been proved in randomized trials (Katsuoka K et al., 2008).Nonsteroidal anti-inflammatory drugs may be administratered to polyarteritis nodosa patients with little or no evidence of systemic disease (Katsuoka K et al., 2008).Vasodilator and antithrombotic agents may be used together with other drugs and have been especially promoted to be used in patients with skin ulcers and necrosis (Choi SW et al., 2006;Gonzalez-Fernandez MA & Garcia-Consuegra J, 2007;Lim MJ et al., 2006;Zulian F et al., 2004;Zulian F et al., 1998).Dapsone and colchicines may be given to patients who are refractory to other therapy (Guillevin L, 1986;Thompson DM et al., 1976;Vignes S et al., 2005).When active hepatitis B or C infection is present, an antiviral agent should be part of the treatment regimen, with the goal of containing viral replication and cause seroconversion (Langford CA, 2010).Glucocorticoids, alone or combined with cyclophosphamide, might be given to patients in combination with apheresis (Guillevin L et al., 2005).The possibility of drug-induced polyarteritis nodosa syndromes should always be considered.Propylthiouracil, hydralazine, leukotriene inhibitors, sulfasalazine, minocycline, D-penicillamine, ciprofloxacin, phenytoin, and allopurinol are included among the drugs that may cause these symptoms (Gota CE & Mandell BF, 2008).

Wegener granulomatosis
Wegener granulomatosis is a relatively uncommon, potentially lethal, and multisystem disease characterized by clinical disease involving the upper and lower respiratory tracts and kidneys with histological evidence of granulomatous inflammation, vasculitis of the small-to medium-sized vessels, and a pauci-immune glomerulonephritis (Hoffman GS et al., 1992).Active Wegener granulomatosis is potentially life-threatening, therefore glucocorticoids combined with a cytotoxic agent are required as initial treatment.Patients with active severe Wegener granulomatosis should initially be treated with 2 mg/kg/day cyclophosphamide and simultaneously with prednisone at 1 mg/kg/day (Langford CA, 2010).After 4 weeks of treatment, the prednisone is tapered and withdrawn by 6 to 12 months, if the treatment improves the patient's condition.Cyclophosphamide treatment for 3 to 6 months is performed, and then, cyclophosphamide is discontinued and the treatment is switched to a less toxic medication for remission maintenance (Langford CA, 2010).If patients have active but non-severe disease, the treatment by prednisone together with 20 to 25 mg/week methotrexate is effective at inducing and then maintaining remission (De Groot K et al., 2005).It has been reported that the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse (Jayne D et al., 2003).Treatment with trimethoprim-sulfamethoxazole (co-trimoxazole) reduces the incidence of relapse in patients with Wegener's granulomatosis in remission (Stegeman CA et al., 1996).Plasma exchange increased the rate of renal recovery in patients that presented with renal failure (Jayne DR et al., 2007).

Microscopic polyangiitis
Microscopic polyangiitis was originally considered to be a branch of polyarteritis nodosa; it includes glomerulonephritis and occasionally pulmonary hemorrhage.According to the Chapel Hill Consensus Conference in 1994, the definition of primary systemic vasculitis (PSV) has become clear, and the disease group included microscopic polyangiitis.Microscopic polyangiitis is a systemic necrotizing vasculitis affecting the small blood vessels or small-to medium-sized arteries.2 mg/kg/day cyclophosphamide and 1 mg/kg/day prednisone should be given as initial therapy to patients who have life-threatening disease including lung, kidney, and nerve involvement (Langford CA, 2010).The therapy follows the schedule outlined for Wegener granulomatosis.It was reported that the combination therapy with cyclophosphamide and prednisone decreased the frequency of renal failure and recurrence (Hogan SL et al., 1996), and improved survival rates (Gayraud M et al., 2001).However, infectious events were strongly associated with the combination of corticosteroid and cyclophosphamide, and were more frequent in patients older than 65 years (Gayraud M et al., 2001).Moreover, cyclophosphamide increases the incidence rate of bladder cancer and induces gonadal failure dose-dependently.Therefore the remission induction should be followed by azathioprine or methotrexate administration for remission maintenance.Patients with active non-severe disease may be treated with methotrexate for remission and maintenance.Mychophenolate mofetil (Villiger PM & Guillevin L, 2010), rituximab (Villiger PM & Guillevin L, 2010), trimethoprim-sulfamethoxazole (Jennette JC et al., 2001), plasma exchanges (Villiger PM & Guillevin L, 2010), intravenous immunoglobulins (Villiger PM & Guillevin L, 2010) can also be effective in microscopic polyangiitis, and etanercept has been recommended as well (Keogh KA et al., 2005).

Churg-strauss syndrome
Churg-Strauss syndrome is a rare systemic necrotizing vasculitis of small-to medium-sized vessels that was first described in the early 1950s.In patients with late-onset asthma it is characterized by vasculitic manifestations, such as fever, cutaneous purpura and mononeuritis multiplex (Pagnoux C, 2010).In ANCA-associated vasculitides, the prognosis of Churg-Strauss syndrome is better than those of Wegener granulomatosis and microscopic polyangiitis (Guillevin L et al., 1999;Keogh KA & Specks U, 2006).Systemic administration of steroids is effective in Churg-Strauss syndrome, and many cases show remission by this therapy.Patients are treated by administration of 1 intravenous pulse of methylprednisolone (15 mg/kg) at the start of treatment (Ribi C et al., 2008).Oral prednisone (1 mg/kg/day) is given to patients for 3 weeks.After that, the dose is tapered slowly as the symptoms and laboratory data, especially the eosinophil count, are improving.Cases that are steroid-resistant or relapse repeatedly by steroid treatment alone are additionally given 2 mg/kg/day cyclophosphamide or 50 to 100 mg/day azathioprine (Gayraud M et al., 2001).However, cyclophosphamide with glucocorticoids should be given early to patients with life-threatening disease (Gayraud M et al., 1997;Guillevin L et al., 1999;Guillevin L & Pagnoux C, 2003;Keogh KA & Specks U, 2006;Noth I et al., 2003;Solans R et al., 2001).To decrease the side effect of cyclophosphamide, cyclophosphamide pulse therapy is recommended (Cohen P et al., 2007;Gayraud M et al., 1997;Guillevin L & Pagnoux C, 2003).

Cutaneous vasculitis
Cutaneous vasculitis is a frequent and often significant component of many systemic vasculitic syndromes such as lupus or rheumatoid vasculitis and ANCA-associated primary vasculitic syndromes (Carlson JA et al., 2006).It is manifested as urticaria, purpura, hemorrhagic vesicles, ulcers, nodules, livedo, infarcts, or digital gangrene.In most instances, cutaneous vasculitis shows the features of a self-limiting, single-episode phenomenon.If the primary diseases or exposures are clarified, those are treated first.If the patients have idiopathic cutaneous vasculitis, glucocorticoids are frequently used.Other drugs, such a nonsteroidal anti-inflammatory agents, antihistamines, dapsone, hydroxychloroquine, colchicines, and cyclophosphamide, may also be given to the patients.But there is no optimal dosage schedule.

Cryoglobulinemic vasculitis
Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins in serum.
In the majority of cases of cryoglobulinaemia, the disease remains asymptomatic but immune complexes can form and be deposited in tissues, causing cryoglobulinemic vasculitis (Braun GS et al., 2007;Lamprecht P et al., 1999).Asymptomatic cryoglobulinemia does not need to be treated.In symptomatic cryoglobulinemia, the treatment of the underlying disease can then proceed.If the underlying disease cannot be determined, it is idiopathic and symptomatic treatment is performed.It is important to determine the particular type of cryoglobulinemia, because the underlying disease may be associated with a particular type.Because type I cryoglobulins usually are associated with haematological disorders, these disorders are treated preferentially.Types II and III (mixed) cryoglobulinemias have strong connection with HCV infection (Braun GS et al., 2007).Aggressive antiviral therapy with Peg-IFNα and ribavirin provide the best opportunity for improvement of HCV-associated cryoglobulinemic vasculitis (Langford CA, 2010;Saadoun D et al., 2008).Plasmapheresis is performed together with administration of corticosteroids and immunosuppressive drugs in order to prevent production of abnormal protein or to treat primary disease.But it is impractical for long-term treatment (Langford CA, 2010;Siami GA & Siami FS, 1999).Rituximab, a chimeric monoclonal anti-CD20 antibody, is suitable as a rescue therapy in resistant cryoglobulinemia associated with HCV (Ahmed MS & Wong CF, 2007).Immunosuppressive agents are typically applied in patients with severe disease symptoms such as membranoproliferative glomerulonephritis, severe peripheral or central nervous system neuropathy, severe cutaneous disease, and vasculitis involving vital organs such as the heart or gastrointestinal tract (Vassilopoulos D & Calabrese LH, 2002).Immunosuppressive agents such as cyclophosphamide, azathioprine, cyclosporine, melphalan, chlorambucil, and fludarabine are usually used together with corticosteroids (Vassilopoulos D & Calabrese LH, 2002).

Henoch-schönlein purpura
Henoch-Schönlein purpura is an acute, self-limited, systemic, small-vessel vasculitis.It predominantly affects children.Clinical presentation of Henoch-Schönlein purpura nephritis in adults is severe and the prognosis is relatively poor, worse than in children (Blanco R et al., 1997;Narchi H, 2005;Pillebout E et al., 2002).Therefore, more active treatment and careful follow up are needed in adults.The treatment is not required in many cases of Henoch-Schönlein purpura because Henoch-Schönlein purpura is typically characterized by its self-limiting condition (Langford CA, 2010).Treatment with systemic application of glucocorticoids to patients with severe gastrointestinal symptoms is strongly recommended (Gunasekaran TS et al., 2000;Leung SP, 2001;Reinehr T et al., 2000;Ronkainen J et al., 2006).Prednisone does not prevent the development of renal symptoms but treats them effectively (Ronkainen J et al. reported that renal symptoms resolved in 61% of the prednisone-treated patients 80-100 mg/kg/day, compared with 34% of the placebo-receiving patients) (Ronkainen J et al., 2006).Moreover, methylprednisolone pulse therapy is effective in patients at risk of progression of nephropathy, particularly in the cases that started therapy early during the course of the disease before the crescents became fibrous (Niaudet P & Habib R, 1998).The efficacy of immunosuppressive agents (e.g.cyclophosphamide, cyclosporin A), plasmapheresis, anticoagulant agents and antiplatelet agents is controversial.Glucocorticoids in combination with each of these treatments can be effective in patients with severe nephritis (Flynn JT et al., 2001;Hattori M et al., 1999;Kawasaki Y et al., 2004;Ronkainen J et al., 2003;Scharer K et al., 1999;Someya T et al., 2004;Tanaka H et al., 2003;Tarshish P et al., 2004;Wyatt RJ & Hogg RJ, 2001;Zaffanello M et al., 2007).Administration of Factor XIII, tonsillectomy, and dapsone may be useful for the patients with Henoch-Schönlein purpura, but the evidence concerning efficacy is insufficient.Factor XIII concentrate may contribute to abdominal pain relief in Henoch-Schönlein purpura patients (Shimomura N et al., 2005;Utani A et al., 1991).Tonsillectomy may be useful for alleviating Henoch-Schönlein purpura nephropathy (Hotta O et al., 1996;Inoue CN et al., 2007;Sugiyama H et al., 2005;Tomioka S et al., 1996).Dapsone therapy may be useful for improving purpura and arthritis (Hoffbrand BI, 1991;Iqbal H & Evans A, 2005;Ramelli GP & Bianchetti MG, 1997;Sarma PS, 1994;Shimomura N et al., 2005).

Kawasaki disease
Kawasaki disease is an acute multisystem vasculitis of infants and young children.This disease represents the primary cause of acquired heart disease (Barron KS et al., 1999).For patients in the acute stage of the disease, a single high-dose intravenous immunoglobulin (2 g/kg) in combination with high-dose aspirin (80-100 mg/kg/day) is given (Muta H et al., 2004;Rowley AH & Shulman ST, 2010;Terai M & Shulman ST, 1997).However, patients in Asia are often treated with 80-100 mg/kg/day, because it is believed that 80-100 mg/kg/day of aspirin is excessively toxic in Asian children (Rowley AH & Shulman ST, 2010).Whether it is an advantage to add corticosteroid to this combination therapy is controversial (Inoue Y et al., 2006;Jibiki T et al., 2004;Newburger JW et al., 2007).About 5-15% of Kawasaki disease patients do not respond to this therapy.A second 2 g/kg dose of intravenous immunoglobulin and a 3-day course of intravenous pulsed methylprednisolone (30 mg/kg/day) can be effective in nonresponders (Freeman AF & Shulman ST, 2004;Rowley AH & Shulman ST, 2010;Sundel RP et al., 1993).Administration of infliximab to these patients has been reported, but the efficacy is unclear (Burns JC et al., 2008;Burns JC et al., 2005).Low-dose aspirin (3-5 mg/kg/day) is given to the patients after the acute stage (Rowley AH & Shulman ST, 2010).In order to check the development of coronary aneurysms, an echocardiogram should be performed at 2, 6, and 8 weeks after illness onset (Langford CA, 2010).Close follow-up using ultrasonographic monitoring is needed for the patients with multiple aneurysms, giant aneurysms, or coronary artery obstruction.

Behçet disease
Behçet disease is a multisystem inflammatory disease with an unknown etiology that affects all types and sizes of blood vessels (Calamia KT & Kaklamanis PG, 2008;Langford CA, 2010;Yazici Y et al., 2010).Treatment of Behçet disease is adjusted depending on the type and severity of symptoms, sex, and age (Yazici Y et al., 2010).Colchicine, 1.0-2.0mg/day, can be effective for genital ulcers, erythema nodosum, and arthritis among women, although merely for arthritis in men (Yurdakul S et al., 2001).Azathioprine, 2.5 mg/kg/day, is able to prevent the progression of Behçet disease, particularly the eye disease (Yazici H et al., 1990).Cyclosporine is useful in treating ocular manifestations, oral aphthous ulcer, dermal lesions, and genital ulceration (Masuda K et al., 1989).Thalidomide, 100 mg/day, is effective for the oral and genital ulcers and papulopustular lesions (Hamuryudan V et al., 1998).Interferon alpha-2a improves the duration and pain of oral ulcers and the frequency of genital ulcers and papulopustular lesions (Alpsoy E et al., 2002).It was reported that tumor necrosis factor TNF α) antagonists, which are infliximab, etanercept, and adalimumab, improve symptoms in patients with eye, mucocutaneous, and gastrointestinal involvement, as well as neurological disease, and even pulmonary artery aneurysms (Sfikakis PP et al., 2007).Corticosteroids are widely used in the treatment of Behçet disease (Yazici Y et al., 2010).
Topical therapy, including glucocorticoids and sucralfate suspension, can be effective for aphthous lesions and mucocutaneous disease (Alpsoy E et al., 1999;Hatemi G et al., 2009).For patients in the early disease stages of pulmonary and peripheral arterial aneurysms, cyclophosphamide pulse therapy and corticosteroids are especially effective (Yazici Y et al., 2010).