**3. Henoch-Schonlein Purpura**

**2.3. Treatment of non-HCV mixed cryoglobulaenimic syndrome**

ANCA – associated vasculitis [8].

222 Updates in the Diagnosis and Treatment of Vasculitis

**2.4. Special considerations**

up to 10% of patients [26].

correlate with response to treatment [27].

**2.5. Prognosis**

commonly are associated with cryoglobulinaemia.

According to current EULAR recommendations, patients presenting with mixed cryoglobu‐ linaemic syndrome non-related to HCV or other disorder should be treated as patients with

Although rare, cases associated to hepatitis B virus (HBV) have been documented. Antiviral therapy with lamivudine or entecavir has led to remission in isolated case reports. Myelo‐ proliferative diseases and most commonly B cell lymphoma may also be the cause of mixed cryoglobulinaemia. Prompt diagnosis and appropriate treatments should be applied. Among autoimmune diseases, Sjogren's syndrome and systemic lupus erythematosus most

**Patients with end Stage Renal Disease.** Patients are treated with hemodialysis or peritoneal dialysis. Survival is comparable with with that of end stage renal diseases. Kidney trans‐ plantation can be performed. High rate of relapse has been recorded (up to 70%). However, recurrent disease does not lead to graft loss and thus relapse risk does not forbid transplan‐ tation in patients with end stage renal disease. Another concern in cases of HCV-related dis‐ ease is that robust immunosuppression following transplantation may exacerbate HCV

**Cancer Risk.** B-cell lymphoma has been reported in up to 25% of patients with mixed cryo‐ globulinaemic syndrome. Patients are usually diagnosed within 10 years. Low levels of gamma globulins may predate neoplastic transformation. Standard chemotherapy in combi‐ nation with rituximab is usually required. HCV infection increases the B-cell lymphoma risk by 20-30% and is associated with increased frequency of liver cancer, which is diagnosed in

Most studies have examined glomerulonephritis (GN) where 10-year survival rate was re‐ ported to be 30-50%. However, therapeutic progress substantially improved prognosis since 10-year survival has recently been raised to almost 80%. Male gender, HCV infection, high cryocrit, low C3 and raised serum creatinine at baseline are considered bad prognostic fac‐ tors. Intestinal ischaemia and alveolar haemorrhage have high mortality rates (>80%). In pa‐ tients with HCV infection, carriers of genotype 2 and 3 along with early virological response have the best outcome. Of interest, changes of cryocrit level do not seem to correlate with clinical activity. It would be interesting, however, to examine whether the degree of solubili‐ ty at 37°C or a decline in the temperature at which the cryoproteins precipitate might better

infection. Fortunately, this has proven to be the exception rather than the rule [25].

Prognosis mainly depends on whether vital organ(s) are involved.

Henoch-Schönlein purpura (HSP) is the most common vasculitis syndrome of childhood, al‐ though is also well described in adults. Clinical features include palpable non-thrombocyto‐ penic purpura, particularly over the buttocks and lower extremities, arthritis (or arthralgia) affecting primarily large joints, diffuse abdominal pain and renal involvement with micro‐ scopic or gross haematuria, and/or proteinuria. There are also reports on the involvement of other organs, including lungs, brain and testes. Generally, it is a benign disorder that fol‐ lows an intercurrent illness, usually an upper respiratory tract infection.

HSP is an immune complex-mediated small vessel vasculitis. Serologic studies document elevated levels of IgA and activation of the alternate pathway of the complement system. The characteristic histopathologic finding of HSP is leukocytoclastic vasculitis with IgA de‐ posits with affected vessels.

Although prognosis is excellent in children with HSP, a small minority of patients develop long-term complications, and primarily renal disease. In adults, the risk of significant renal disease is increased. Management of HSP includes supportive care to ameliorate acute symptoms, as well as targeted treatment to decrease the risk of complications (usually due to gastrointestinal complications) and to prevent chronic renal insufficiency. Targeted treat‐ ment is summarized in Table 4.

#### **3.1. Supportive management**

Treatment of HSP is primarily supportive and includes adequate hydration and sympto‐ matic relief of pain. Edema of the lower extremities and buttocks is improved with bed rest and/or elevating the affected area. Acetaminophen and non-steroidal anti-inflamma‐ tory drugs (NSAIDs) help with mild rash and arthritis. However, NSAIDs should be used cautiously in elderly persons due to increased risk of renal impairment and gastro‐ intestinal bleeding.

#### **3.2. Targeted treatment**

#### *3.2.1. Glucocorticosteroids*

**Oral steroids.** Oral steroids are used in patients with painful cutaneous edema, severe rash, scrotal and testicular involvement, renal involvement and abdominal pain [28]. There is some supportive evidence for the use of corticosteroids in severe abdominal pain. In a sys‐ temic review that included three randomized trials and 12 retrospective studies, predniso‐ lone at a dose of 1 mg/Kg/day for two weeks or 2 mg/Kg/day for one week may decrease the intensity and duration of abdominal pain and may decrease the frequency of bowel intus‐ susceptions and thus surgical interventions [29-31] .

Renal involvement is a common finding in HSP. Although the prognosis of HSP is excellent in children, persistent renal disease can cause long-term morbidity. This risk of significant renal disease is greater in adults with HSP [32]

However, it is not clear if corticosteroids decrease the likelihood of renal disease [29;30;32-39]. A meta-analysis suggested that early use of corticosteroids reduced the odds of developing persistent renal disease [29]. However, concerns are raised over the validity of this analysis, which included studies with different treatment protocols and follow-up time [36]. A more recent meta-analysis of four randomized controlled trials showed no significant difference in the risk of persistent renal disease at 6 and 12 months in children treated with prednisone for 2-4 weeks after initial presentation compared with placebo or supportive treatment [34]. Thus there are no convincing data to support the routine use of oral steroids as a measure to prevent renal disease in patients with uncomplicated HSP.

dipyridamole, in 14 children with severe HSP nephritis, followed for 7.5 years, resulted in a

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225

In adults, adding CyP to steroids provided no benefit in a 12-month, open-label trial of 54

Cyclosporin A (CsA) is an effective immunosuppressive agent used for different immune-

In a randomized study of of 24 children with nephrotic-range proteinuria or crescenting HSP nephritis, CsA was more efficacious compared to IV pulses of methylprednisolone [44]. In two retrospective studies by the same group, CsA plus steroids was found to be beneficial in HSP children with nephrotic syndrome [45,46]. In a retrospective study of 29 children with nephrotic-range proteinuria treated with CsA plus steroids, 23 achieved stable remis‐ sion, while 6 patients became CsA-dependent [47]. In a clinical trial with a mean follow-up of 6 years all patients responded to CsA therapy (plus ACE inhibitors), however some pa‐

CsA plus steroids, either as initial treatment or after other immunosuppressive drugs in a small case series of 5 adult patients with HSP with nephrotic-range proteinuria showed beneficial effects on proteinuria and preservation of renal function, after a follow-up pe‐

Overall, despite the data reporting proteinuria reduction by CsA in patients with HSP neph‐ ritis, this treatment is not supported by RCTs and cautiousness should be exercised for po‐

Azathioprine is used in combination with steroids mostly in children with crescent HSP

Azathioprine plus steroids showed beneficial effects in a clinical trial of 21 children with severe HSP GN. Treatment with either oral or intravenous (IV) corticosteroids led to comparable outcome [50]. Retrospective studies also support the use of combination of azathioprine with steroids for the treatment of severe HSP nephritis in children [51]. Ear‐ ly treatment with azathioprine plus steroids prevented progression of chronic kidney dis‐ ease [52]. The combination was effective in improving histopathological changes [53]; however, 2 of the 10 patients treated with azathioprine showed definite tubulointerstitial

Mycophenolate mofetil (MMF) appears to be a promising therapeutic agent in many auto‐

immune diseases such as lupus nephritis, vasculitis and in IgA nephropathy.

significant improvement of histological grade of nephritis [42].

patients with severe HSP GN [43].

mediated glomerular diseases [32].

tients developed CsA- dependent nephritis [48].

*3.2.3. Cyclosporin A*

riod of 5 years [49].

*3.2.4. Azathioprine*

nephritis [32].

tential nephrotoxicity of CsA.

nephritis at followup biopsy [54].

*3.2.5. Mycophenolate mofetil*

**High dose steroids.** Steroid treatment with high intravenous doses (pulses) and/or long term oral administration are the treatment of choice in acute HSP glomerulonephritis in chil‐ dren [32]. Methylprednisolone pulse therapy was evaluated in a prospective study with 38 children with severe HSP nephritis, defined as nephrotic syndrome at presentation and/or 50% or more crescentic glomeruli on biopsy [37]. Clinical recovery was achieved in 20 chil‐ dren. Renal biopsy in these children showed a significant decrease of the activity index with a decrease or disappearance of IgA deposits.

Steroids can be used alone or in combination with immunosuppressive agents (i.e., cyclo‐ sporin A, cyclophosphamide, mycophenolate mofetil, and azathioprine) [32].

#### *3.2.2. Cyclophosphamide*

Cyclophosphamide (CyP) is widely used in the treatment for the majority of vasculitides. In HSP, CyP has been used mainly for rapidly progressive glomerulonephritis (GN), while case reports of successful management of pulmonary hemorrhage also exist [33].

In a randomized controlled trial, 56 children with severe HSP nephritis were treated with oral cyclophosphamide (90mg/m2 /day) without steroids for 42 days. At final follow-up, 48.2% of children had full recovery, 39.3% had persistent abnormalities and 12.5% ended up with end-stage renal failure or death. No patient with crescents in 50% or more of glomeruli went on to full recovery. The authors concluded that CyP had no significant efficacy [39].

The combination of CyP with steroids has provided better outcome. In a retrospective study, high dose corticosteroids plus oral CyP (2mg/kg/day for 12 weeks) significantly reduced proteinuria in children with HSP GN [35]. Oral prednisolone (1.5 mg/kg/day) combined with an 8-week course of CyP (2 mg/kg/day) in 9 children with severe HSP nephritis, result‐ ed in remission of proteinuria in 7 children [38]. Triple therapy with oral CyP (2.5mg/kg/ day), methylprednizolone (30 mg/kg/day [maximum 1g/day], for 3 days), and intravenous urokinase (5000 U/kg/day [max 180.000], for 7 days) reduced protein excretion and mesan‐ gial IgA deposition compared with the group that received the same therapeutic combina‐ tion without CyP [40]. In another study, combined therapy with intravenous pulse methylprednisolone (for 3 days), oral CyP (for 2 months), oral dipyridamole (for 6 months) and oral prednisolone (for 3 months) resulted in normalization of glomerular filtration rate in all but 1 patient [41]. Combined therapy with prednisolone, CyP, heparin/warfarin, and dipyridamole, in 14 children with severe HSP nephritis, followed for 7.5 years, resulted in a significant improvement of histological grade of nephritis [42].

In adults, adding CyP to steroids provided no benefit in a 12-month, open-label trial of 54 patients with severe HSP GN [43].

#### *3.2.3. Cyclosporin A*

However, it is not clear if corticosteroids decrease the likelihood of renal disease [29;30;32-39]. A meta-analysis suggested that early use of corticosteroids reduced the odds of developing persistent renal disease [29]. However, concerns are raised over the validity of this analysis, which included studies with different treatment protocols and follow-up time [36]. A more recent meta-analysis of four randomized controlled trials showed no significant difference in the risk of persistent renal disease at 6 and 12 months in children treated with prednisone for 2-4 weeks after initial presentation compared with placebo or supportive treatment [34]. Thus there are no convincing data to support the routine use of oral steroids

**High dose steroids.** Steroid treatment with high intravenous doses (pulses) and/or long term oral administration are the treatment of choice in acute HSP glomerulonephritis in chil‐ dren [32]. Methylprednisolone pulse therapy was evaluated in a prospective study with 38 children with severe HSP nephritis, defined as nephrotic syndrome at presentation and/or 50% or more crescentic glomeruli on biopsy [37]. Clinical recovery was achieved in 20 chil‐ dren. Renal biopsy in these children showed a significant decrease of the activity index with

Steroids can be used alone or in combination with immunosuppressive agents (i.e., cyclo‐

Cyclophosphamide (CyP) is widely used in the treatment for the majority of vasculitides. In HSP, CyP has been used mainly for rapidly progressive glomerulonephritis (GN), while

In a randomized controlled trial, 56 children with severe HSP nephritis were treated with

48.2% of children had full recovery, 39.3% had persistent abnormalities and 12.5% ended up with end-stage renal failure or death. No patient with crescents in 50% or more of glomeruli went on to full recovery. The authors concluded that CyP had no significant efficacy [39].

The combination of CyP with steroids has provided better outcome. In a retrospective study, high dose corticosteroids plus oral CyP (2mg/kg/day for 12 weeks) significantly reduced proteinuria in children with HSP GN [35]. Oral prednisolone (1.5 mg/kg/day) combined with an 8-week course of CyP (2 mg/kg/day) in 9 children with severe HSP nephritis, result‐ ed in remission of proteinuria in 7 children [38]. Triple therapy with oral CyP (2.5mg/kg/ day), methylprednizolone (30 mg/kg/day [maximum 1g/day], for 3 days), and intravenous urokinase (5000 U/kg/day [max 180.000], for 7 days) reduced protein excretion and mesan‐ gial IgA deposition compared with the group that received the same therapeutic combina‐ tion without CyP [40]. In another study, combined therapy with intravenous pulse methylprednisolone (for 3 days), oral CyP (for 2 months), oral dipyridamole (for 6 months) and oral prednisolone (for 3 months) resulted in normalization of glomerular filtration rate in all but 1 patient [41]. Combined therapy with prednisolone, CyP, heparin/warfarin, and

/day) without steroids for 42 days. At final follow-up,

as a measure to prevent renal disease in patients with uncomplicated HSP.

sporin A, cyclophosphamide, mycophenolate mofetil, and azathioprine) [32].

case reports of successful management of pulmonary hemorrhage also exist [33].

a decrease or disappearance of IgA deposits.

224 Updates in the Diagnosis and Treatment of Vasculitis

*3.2.2. Cyclophosphamide*

oral cyclophosphamide (90mg/m2

Cyclosporin A (CsA) is an effective immunosuppressive agent used for different immunemediated glomerular diseases [32].

In a randomized study of of 24 children with nephrotic-range proteinuria or crescenting HSP nephritis, CsA was more efficacious compared to IV pulses of methylprednisolone [44]. In two retrospective studies by the same group, CsA plus steroids was found to be beneficial in HSP children with nephrotic syndrome [45,46]. In a retrospective study of 29 children with nephrotic-range proteinuria treated with CsA plus steroids, 23 achieved stable remis‐ sion, while 6 patients became CsA-dependent [47]. In a clinical trial with a mean follow-up of 6 years all patients responded to CsA therapy (plus ACE inhibitors), however some pa‐ tients developed CsA- dependent nephritis [48].

CsA plus steroids, either as initial treatment or after other immunosuppressive drugs in a small case series of 5 adult patients with HSP with nephrotic-range proteinuria showed beneficial effects on proteinuria and preservation of renal function, after a follow-up pe‐ riod of 5 years [49].

Overall, despite the data reporting proteinuria reduction by CsA in patients with HSP neph‐ ritis, this treatment is not supported by RCTs and cautiousness should be exercised for po‐ tential nephrotoxicity of CsA.

#### *3.2.4. Azathioprine*

Azathioprine is used in combination with steroids mostly in children with crescent HSP nephritis [32].

Azathioprine plus steroids showed beneficial effects in a clinical trial of 21 children with severe HSP GN. Treatment with either oral or intravenous (IV) corticosteroids led to comparable outcome [50]. Retrospective studies also support the use of combination of azathioprine with steroids for the treatment of severe HSP nephritis in children [51]. Ear‐ ly treatment with azathioprine plus steroids prevented progression of chronic kidney dis‐ ease [52]. The combination was effective in improving histopathological changes [53]; however, 2 of the 10 patients treated with azathioprine showed definite tubulointerstitial nephritis at followup biopsy [54].

#### *3.2.5. Mycophenolate mofetil*

Mycophenolate mofetil (MMF) appears to be a promising therapeutic agent in many auto‐ immune diseases such as lupus nephritis, vasculitis and in IgA nephropathy.

There is limited evidence to support the use of MMF in HSP. Case reports [55-57] suggest a beneficial effect of MMF on HSP with complications. In six children in whom steroid thera‐ py has failed, MMF was able to control complications and to sustain disease remission. MMF was well tolerated [58]. More recently, MMF along with ACE inhibitors reduced pro‐ tein excretion and improved renal function in 12 children with HSP and nephrotic range proteinuria, who failed steroid treatment (20-25mg/kg/day) [59].

**3.4. Emergencies**

urgent surgical consultation.

Acetaminophen, NSAIDs

IV pulse steroids plus Immunosuppression

Patients with HSP may present with severe abdominal pain, gastrointestinal (GI) bleeding and renal insufficiency. Up to 50% of patients with HSP and GI manifestations have occult bleeding, but major hemorrhage occurs in only 5% and intussusceptions in 2% [74]. Other manifestations may include bowel infract, perforation and pancreatitis, which may require

**Medication Indication Comments**

Arthritis, rash (mild)

scrotal and testicular involvement, renal involvement and abdominal symptoms

syndrome

Rapidly progressive glomerulonephritis, pulmonary hemorrhage

pulmonary and gastrointestinal hemorrhage, cerebral hemorrhage

Cutaneous vasculitis is a vasculitis confined to the dermis and is not a single disease. In fact, only less than 30% of cutaneous vasculitis can be defined as idiopathic. All other cases are systemic vasculitides, vasculitis associated with other rheumatic diseases (sys‐

Oral steroids painful cutaneous edema, severe rash,

IV pulse steroids Nephrotic range proteinuria, nephritic

Plasma exchange Refractory HSP nephritis

ACE inhibitors Proteinuria

**Table 4.** Medications used in the treatment of HSP

**4. Idiopatic cutaneous vasculitis**

Precautions: renal insufficiency and GI bleeding (for NSAIDs)

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Steroids may shorten the duration of abdominal pain and the risk of surgical interventions In few RCTs, short-course of oral prednisone does not prevent persistent renal disease

CyP : no supporting RCT; serious side effects Azathioprine: no RCTs, cases of tubulointerstitial nephritis CsA: no RCTs, potential nephrotoxicity MMF: limited data Rituximab: limited data

#### *3.2.6. Rituximab*

The efficacy of rituximab (RTX) in chronic HSP has been suggested by a case report. Three pediatric patients were treated with RTX for severe refractory chronic Henoch-Schönlein purpura, characterized mainly by neurologic and gastroenterological symptoms resistant to steroids and CyP. All 3 patients responded to 1 or 2 courses of RTX without serious adverse events [60]. In another case report one patient with moderate nephritis and severe skin HSP responded to RTX [61].

#### *3.2.7. Plasma exchange*

The addition of plasma exchange to common immunosuppressives and steroids have shown efficacy in patients with HSP and severe of extra-renal manifestations (alveolar and cerebral hemorrhage, haemorrhagic pancolitis, extensive vasculitic leg ulcers) [62-64]. Plasma ex‐ change has also been used as sole treatment in patients with severe HSP nephritis with en‐ couraging results [65,66].

#### *3.2.8. Intravenous immunoglobulin*

The clinical use of intravenous immunoglobulin (IVIg) has been extended beyond antibodydeficiency syndromes, to a wide variety of clinical conditions, such as neuroimmunological diseases, and systemic autoimmune diseases. Kawasaki disease was the first primary vascu‐ litis in which IVIg had become the standard treatment of care. IVIg has also shown benefi‐ cial effects in patients with ANCA-associated vasculitis (AAV) refractory to standard therapy with prednisone and CyP [67]. In HSP, IVIg inhibited disease progression in isolat‐ ed case reports [68,69].

#### **3.3. Additional treatments**

From a pathophysiological point of view, the removal of any source of chronic bacterial challenge, which may trigger HSP episodes, should theoretically be beneficial [70]. This is the reason why there are reports about tonsillectomy and periodontal therapy in children with HSP [71-73]. However, the therapeutic contribution of such approaches are difficult to evaluate since are commonly used in combination with other therapies.

Antithrombotic prophylaxis with warfarin, dipyridamole, and acetylsalicylic acid has been used along with immunosuppressive agents by several authors [70]. ACE inhibitors have been shown to be efficacious in reducing proteinuria and should be added at any level of proteinuria.

#### **3.4. Emergencies**

There is limited evidence to support the use of MMF in HSP. Case reports [55-57] suggest a beneficial effect of MMF on HSP with complications. In six children in whom steroid thera‐ py has failed, MMF was able to control complications and to sustain disease remission. MMF was well tolerated [58]. More recently, MMF along with ACE inhibitors reduced pro‐ tein excretion and improved renal function in 12 children with HSP and nephrotic range

The efficacy of rituximab (RTX) in chronic HSP has been suggested by a case report. Three pediatric patients were treated with RTX for severe refractory chronic Henoch-Schönlein purpura, characterized mainly by neurologic and gastroenterological symptoms resistant to steroids and CyP. All 3 patients responded to 1 or 2 courses of RTX without serious adverse events [60]. In another case report one patient with moderate nephritis and severe skin HSP

The addition of plasma exchange to common immunosuppressives and steroids have shown efficacy in patients with HSP and severe of extra-renal manifestations (alveolar and cerebral hemorrhage, haemorrhagic pancolitis, extensive vasculitic leg ulcers) [62-64]. Plasma ex‐ change has also been used as sole treatment in patients with severe HSP nephritis with en‐

The clinical use of intravenous immunoglobulin (IVIg) has been extended beyond antibodydeficiency syndromes, to a wide variety of clinical conditions, such as neuroimmunological diseases, and systemic autoimmune diseases. Kawasaki disease was the first primary vascu‐ litis in which IVIg had become the standard treatment of care. IVIg has also shown benefi‐ cial effects in patients with ANCA-associated vasculitis (AAV) refractory to standard therapy with prednisone and CyP [67]. In HSP, IVIg inhibited disease progression in isolat‐

From a pathophysiological point of view, the removal of any source of chronic bacterial challenge, which may trigger HSP episodes, should theoretically be beneficial [70]. This is the reason why there are reports about tonsillectomy and periodontal therapy in children with HSP [71-73]. However, the therapeutic contribution of such approaches are difficult to

Antithrombotic prophylaxis with warfarin, dipyridamole, and acetylsalicylic acid has been used along with immunosuppressive agents by several authors [70]. ACE inhibitors have been shown to be efficacious in reducing proteinuria and should be added at any

evaluate since are commonly used in combination with other therapies.

proteinuria, who failed steroid treatment (20-25mg/kg/day) [59].

*3.2.6. Rituximab*

226 Updates in the Diagnosis and Treatment of Vasculitis

responded to RTX [61].

*3.2.7. Plasma exchange*

couraging results [65,66].

ed case reports [68,69].

level of proteinuria.

**3.3. Additional treatments**

*3.2.8. Intravenous immunoglobulin*

Patients with HSP may present with severe abdominal pain, gastrointestinal (GI) bleeding and renal insufficiency. Up to 50% of patients with HSP and GI manifestations have occult bleeding, but major hemorrhage occurs in only 5% and intussusceptions in 2% [74]. Other manifestations may include bowel infract, perforation and pancreatitis, which may require urgent surgical consultation.


**Table 4.** Medications used in the treatment of HSP

#### **4. Idiopatic cutaneous vasculitis**

Cutaneous vasculitis is a vasculitis confined to the dermis and is not a single disease. In fact, only less than 30% of cutaneous vasculitis can be defined as idiopathic. All other cases are systemic vasculitides, vasculitis associated with other rheumatic diseases (sys‐ temic lupus erythematosus, rheumatoid arthritis), or vasculitis induced by malignancy, infection or medication/toxin. Therefore, one should search carefully for extracutaneous manifestations of vasculitis and obtain a detailed medical history. Also mimics of vascu‐ litis, such as antiphospolipid syndrome, should be ruled out. Even idiopathic cutaneous vasculitis is not a single entity. An international consensus conference defined cutaneous leukocytoclastic angiitis as isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis [1]. This definition is controversial, since it requires biop‐ sy for diagnosis and even biopsy is not diagnostic. Other terms used under the umbrella of idiopathic cutaneous vasculitis include hypersensitivity vasculitis, and urticarial vascu‐ litis [75]. There are few points to consider in diagnosing cutaneous leukocytoclastic angii‐ tis (CLA). First, CLA manifests with palpable purpura. On biopsy, cutaneous leukocytoclastic angiitis is characterized by leukocytoclastic vasculitis in upper to middle dermis (where small vessles are located), whereas necrotizing vasculitis in lower dermis and subcutaneous fat involves medium-sized vessels associated with cutaneous polyar‐ teritis nodosa and other systemic vasculitides. Serum ANCA tests by immunofluores‐ cence, with ELISA for MPO and PR3 to exclude ANCA-associated vasculitis, serum cryoglobulin test, to exclude cryoglobulinaemic vasculitis, and immunofluorescence for IgA deposits on skin biopsy, to exclude Henoch-Schonlein purpura, are necessary labora‐ tory tests in diagnosing cutaneous leukocytoclastic angiitis.

NSAIDs or antihistamines usually relieve symptoms, such as pruritus and burning sensa‐ tion. For persistent disease, colchicine is considered a drug of first choice [77]. Colchicine is effective in 50% of patients with cutaneous leukocytoclastic vasculitis within 2 weeks, although in a randomized controlled trial colchicine (0.5 mg twice daily) for a month was no more efficacious than topical emollients [78]. Patients with chronic cutaneous venulitis are usually resistant to treatment. Dapsone (100-200 mg daily) may be very ef‐ fective in leukocytoclastic vasculitis and urticarial vasculitis. Dapsone appears to have synergistic effects with colchicine or pentoxifylline [79]. HCQ is more often used in urti‐ carial vasculitis associated with connective tissue diseases. Prednisolone, at the initial dose of 0.5-1 mg/Kg/day for 2 weeks with rapid tapering, can be very effective in acute severe episodes. However, Idiopathic Cutaneous Small Vessel Vasculitis can be active for 10 years and prednisolone monotherapy is not recommended for chronic use. In difficult to treat cases, azathioprine may be used with low-dose prednisolone. Other medications

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Urticarial vasculitis(UV) is characterized by persistent (greater than 24 hours) urticarial skin lesions and leukocytoclastic vasculitis on histology. It is associated with low serum comple‐ ment (hypocomplementaemic urticarial vasculitis, HUV) or normal serum complement lev‐ els (normocomplementaemic urticarial vasculitis, NUV). HUV is usually a systemic disease and associated with systemic lupus erythematosus (SLE) with autoantibodies against C1q. NUV is usually confined to the skin and rarely associated with SLE. Nearly 50% of patients

Treatment of UV is based on manifestations. For mild skin lesions antihistamines, colchi‐ cines, dapsone, HCQ and prednisolone are used. The addition of reserpine (0.3-0.4 mg/day) to antihistamines may improve UV symptoms [80]. For extracutaneous disease or chronic necrotizing skin lesions prednisolone is used, often in association with azathioprine, myco‐ phenolate mofetil (MMF), CsA, or CyP. IVIg and plasmapheresis have been used in difficult to treat urticarial vasculitis [76]. Rituximab, a monoclonal antibody against CD20, present on mature B cells, was successfully tried in a patient with UV with angioedema unresponsive

In mild cases, colchicine or NSAIDs may suffice. In moderate to severe cases, prednisolone is administered at an initial dose of 1 mg/kg/day, usually in conjunction with HCQ, dap‐ sone, methotrexate, azathioprine, CyP, or intravenous immunoglobulin [81]. Mizoribine, an inhibitor of inosine monophosphate and guanosine monophosphate synthetase, which in‐ hibits T and B cell proliferation, is also efficacious. Warfarin or clopidogrel are helpful adju‐

that have been used include CsA (2.5-5 mg/kg/day, in two doses).

with idiopathic UV have autoantibodies against IgE or IgE receptor.

to prednisolone, CsA and plasmapheresis [8].

**4.2. Cutaneous polyarteritis nodosa**

vant treatment [82].

**4.1. Urticarial vasculitis**

Treatment of idiopathic cutaneous vasculitis depends on the severity of lesions and the extent of cutaneous involvement. For example, purpura is a manifestation of superficial dermal small vessel vasculitis with no serious consequences. Therefore any treatment should be with few if any side effects. However, it should be reminded that what initial‐ ly appears to be isolated cutaneous vasculitis may be the presenting feature of an under‐ lying disease, such as lymphoma or systemic vasculitis. Therefore, vigilance is required. Nodulal lesions and ulcers are caused by medium-sized vessels and suggest cutaneous polyarteritis nodosa or other systemic vasculitides Therefore, more intense treatment is required. It should be mentioned that there are no randomized controlled trials and treatment of idiopathic cutaneous vasculitis is based on case reports or small case series.

When cutaneous vasculitis is associated with a systemic disease one should treat the sys‐ temic disease. Also, any inciting agent, either drug or infective agent, should be re‐ moved. For instance, any infectious trigger should be treated with antibiotics. If food allergen is suspected, allergy testing is recommended, and if positive, elimination of the relevant food is tried, since low-antigen diet prevents recurrences of palpable purpura [76]. Drugs that are used with variable efficacy in idiopathic cutaneous vasculitis include non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines (such as doxepin, lorata‐ dine, and cetirizine), colchicine, hydroxychloroquine (HCQ), dapsone, and prednisolone. However, no drug is universally efficacious. Colchicine inhibits neutrophil chemotaxis. Dapsone inhibits the alternative pathway of complement, and suppresses neutrophil che‐ motaxis. Hydroxychloroquine inhibits lysosomal enzyme release. The idiopathic leukocy‐ toclastic cutaneous small vessel vasculitis is often self-limited and does not require specific treatment. Leg elevation, avoidance of excessive standing, and administration of NSAIDs or antihistamines usually relieve symptoms, such as pruritus and burning sensa‐ tion. For persistent disease, colchicine is considered a drug of first choice [77]. Colchicine is effective in 50% of patients with cutaneous leukocytoclastic vasculitis within 2 weeks, although in a randomized controlled trial colchicine (0.5 mg twice daily) for a month was no more efficacious than topical emollients [78]. Patients with chronic cutaneous venulitis are usually resistant to treatment. Dapsone (100-200 mg daily) may be very ef‐ fective in leukocytoclastic vasculitis and urticarial vasculitis. Dapsone appears to have synergistic effects with colchicine or pentoxifylline [79]. HCQ is more often used in urti‐ carial vasculitis associated with connective tissue diseases. Prednisolone, at the initial dose of 0.5-1 mg/Kg/day for 2 weeks with rapid tapering, can be very effective in acute severe episodes. However, Idiopathic Cutaneous Small Vessel Vasculitis can be active for 10 years and prednisolone monotherapy is not recommended for chronic use. In difficult to treat cases, azathioprine may be used with low-dose prednisolone. Other medications that have been used include CsA (2.5-5 mg/kg/day, in two doses).

#### **4.1. Urticarial vasculitis**

temic lupus erythematosus, rheumatoid arthritis), or vasculitis induced by malignancy, infection or medication/toxin. Therefore, one should search carefully for extracutaneous manifestations of vasculitis and obtain a detailed medical history. Also mimics of vascu‐ litis, such as antiphospolipid syndrome, should be ruled out. Even idiopathic cutaneous vasculitis is not a single entity. An international consensus conference defined cutaneous leukocytoclastic angiitis as isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis [1]. This definition is controversial, since it requires biop‐ sy for diagnosis and even biopsy is not diagnostic. Other terms used under the umbrella of idiopathic cutaneous vasculitis include hypersensitivity vasculitis, and urticarial vascu‐ litis [75]. There are few points to consider in diagnosing cutaneous leukocytoclastic angii‐ tis (CLA). First, CLA manifests with palpable purpura. On biopsy, cutaneous leukocytoclastic angiitis is characterized by leukocytoclastic vasculitis in upper to middle dermis (where small vessles are located), whereas necrotizing vasculitis in lower dermis and subcutaneous fat involves medium-sized vessels associated with cutaneous polyar‐ teritis nodosa and other systemic vasculitides. Serum ANCA tests by immunofluores‐ cence, with ELISA for MPO and PR3 to exclude ANCA-associated vasculitis, serum cryoglobulin test, to exclude cryoglobulinaemic vasculitis, and immunofluorescence for IgA deposits on skin biopsy, to exclude Henoch-Schonlein purpura, are necessary labora‐

Treatment of idiopathic cutaneous vasculitis depends on the severity of lesions and the extent of cutaneous involvement. For example, purpura is a manifestation of superficial dermal small vessel vasculitis with no serious consequences. Therefore any treatment should be with few if any side effects. However, it should be reminded that what initial‐ ly appears to be isolated cutaneous vasculitis may be the presenting feature of an under‐ lying disease, such as lymphoma or systemic vasculitis. Therefore, vigilance is required. Nodulal lesions and ulcers are caused by medium-sized vessels and suggest cutaneous polyarteritis nodosa or other systemic vasculitides Therefore, more intense treatment is required. It should be mentioned that there are no randomized controlled trials and treatment of idiopathic cutaneous vasculitis is based on case reports or small case series. When cutaneous vasculitis is associated with a systemic disease one should treat the sys‐ temic disease. Also, any inciting agent, either drug or infective agent, should be re‐ moved. For instance, any infectious trigger should be treated with antibiotics. If food allergen is suspected, allergy testing is recommended, and if positive, elimination of the relevant food is tried, since low-antigen diet prevents recurrences of palpable purpura [76]. Drugs that are used with variable efficacy in idiopathic cutaneous vasculitis include non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines (such as doxepin, lorata‐ dine, and cetirizine), colchicine, hydroxychloroquine (HCQ), dapsone, and prednisolone. However, no drug is universally efficacious. Colchicine inhibits neutrophil chemotaxis. Dapsone inhibits the alternative pathway of complement, and suppresses neutrophil che‐ motaxis. Hydroxychloroquine inhibits lysosomal enzyme release. The idiopathic leukocy‐ toclastic cutaneous small vessel vasculitis is often self-limited and does not require specific treatment. Leg elevation, avoidance of excessive standing, and administration of

tory tests in diagnosing cutaneous leukocytoclastic angiitis.

228 Updates in the Diagnosis and Treatment of Vasculitis

Urticarial vasculitis(UV) is characterized by persistent (greater than 24 hours) urticarial skin lesions and leukocytoclastic vasculitis on histology. It is associated with low serum comple‐ ment (hypocomplementaemic urticarial vasculitis, HUV) or normal serum complement lev‐ els (normocomplementaemic urticarial vasculitis, NUV). HUV is usually a systemic disease and associated with systemic lupus erythematosus (SLE) with autoantibodies against C1q. NUV is usually confined to the skin and rarely associated with SLE. Nearly 50% of patients with idiopathic UV have autoantibodies against IgE or IgE receptor.

Treatment of UV is based on manifestations. For mild skin lesions antihistamines, colchi‐ cines, dapsone, HCQ and prednisolone are used. The addition of reserpine (0.3-0.4 mg/day) to antihistamines may improve UV symptoms [80]. For extracutaneous disease or chronic necrotizing skin lesions prednisolone is used, often in association with azathioprine, myco‐ phenolate mofetil (MMF), CsA, or CyP. IVIg and plasmapheresis have been used in difficult to treat urticarial vasculitis [76]. Rituximab, a monoclonal antibody against CD20, present on mature B cells, was successfully tried in a patient with UV with angioedema unresponsive to prednisolone, CsA and plasmapheresis [8].

#### **4.2. Cutaneous polyarteritis nodosa**

In mild cases, colchicine or NSAIDs may suffice. In moderate to severe cases, prednisolone is administered at an initial dose of 1 mg/kg/day, usually in conjunction with HCQ, dap‐ sone, methotrexate, azathioprine, CyP, or intravenous immunoglobulin [81]. Mizoribine, an inhibitor of inosine monophosphate and guanosine monophosphate synthetase, which in‐ hibits T and B cell proliferation, is also efficacious. Warfarin or clopidogrel are helpful adju‐ vant treatment [82].
