CUTANEOUS VASCULITIS

IHAB YOUNIS,MD

ClassificationI- Small Vessel vasculitis 1- Cutaneous vasculitis

2- Henoch-Schoelein purpura

3- Urticarial vasculitis

4- Erythema elevatum diutinum

5-Granuloma faciale

6-Erythema induratum(Nodular vasculitis)

II- Large vessel vasculitis

Polyarteritis nodosa

III- Neutrophilic vascular reactions:

1- Sweet’s syndrome

2 - Behcet’s disease

3 - Erythema nodosum

4- Pyoderma gangrenosum

IV- Overlap:

Pityriasis lichenoides chronica

I- Small vessel vasculitis

1-Allergic vasculitis

Etiology• The exact mechanisms remain unknown

• Although immune complexes are involved

in the pathogenesis, other autoantibodies

such as antineutrophil cytoplasmic antibody, other inflammatory mediators and local factors that involve the endothelial cells

and adhesion molecules play an important role

1- Between one third and one half of the cases of cutaneous vasculitis are idiopathic

2-Drugs: almost all drugs are potential causes . However, The most common drugs are antibiotics, particularly beta-lactam drugs, nonsteroidal anti-inflammatory drugs, diuretics and foreign proteins such as streptokinase and those found in vaccines

3-Various infections may be associated:

– Upper respiratory tract infections and viral hepatitis are implicated most often

3-Foods or food additives may cause vasculitis.

4-Collagen vascular diseases ( rheumatoid arthritis, Sjögren syndrome & SLE in particular) account for 10-15% of vasculitis cases

5- Malignancy accounts for less than 1% of cases of cutaneous vasculitis

Diagram of histopathology

Perivascular infiltration of polymos with formation of nuclear dust (leukocytoclasis)

Fibrinoid necrosis of vessel walls

Extravasation of erythrocytes

Clinically• Palpable purpura is the most frequent:

– Lesions usually are round and 1-3 mm.– They may coalesce to form plaques, and in

some instances, they may ulcerate– Observed most often on the legs, but any

surface can be involved

• Ecchymosis may be seen

• Vesicles &hemorrhagic bullae and in severe cases necrotic areas & ulceration occur

• Patients may also experience systemic symptoms with fever, joint , pains and stomach upsets at any time during an attack

• The acute rash usually subsides within 2-3 weeks but may recur

Acute form

Palpable purpura

Subacuteform

Associations

• Renal

• Joint

• Gastrointestinal

• CNS

• Pulmonary

Investigations• It serves 2 purposes: The first is

determining the presence of systemic disease. The second is identifying an associated disorder, which aids in the prediction of the patient's prognosis.

• Although no routine has been established, testing for all adult patients includes complete blood cell count, erythrocyte sedimentation rate, urinalysis and blood chemistry panel

• Serologic studies, such as antinuclear antibody, ANCA, and rheumatoid factor, should be obtained in patients without an obvious cause of their disease

• In patients suggested to have lupus erythematosus or patients who have urticarial vasculitis, complement levels may be obtained

• In patients without otherwise identified disease, tests for paraproteins should include serum protein electrophoresis, cryoglobulins, and hepatitis C antibody

• Chest radiograph is part of the routine evaluation

Treatment• Elevation of the legs or compression stockings

may be useful• Patients with an identifiable cause should

receive treatment for that cause e.g. removal of a drug thought to be causing the vasculitis may result in rapid clearing of the process in as short as 2 weeks

• Patients with urticarial lesions may be treated with antihistamines, sometimes, a combination of these agents is needed to control the disease

• Some patients respond to nonsteroidal anti-inflammatory agents

• Anti-inflammatory agents : 1- Colchicine (Colmetidine) 0.5-0.6 mg PO

bid/tid Has effects against neutrophils -Adverse effects: Pregnancy category D , risk of renal

failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy and decreased sperm count may occur; dose-dependent GI upset is common

2-Dapsone: 150-200 PO qd(once/day) Precautions

-Perform weekly blood counts (first mo),

then perform WBC counts monthly (6

mo), then semiannually; discontinue if

significant reduction in platelets, WBC,

or RBC counts is seen

- Caution in G-6-PD deficiency (patients

receiving >200 mg/d)

• In severe cases or if visceral involvement is found, patients may require high doses of corticosteroids (1-2 mg/kg/d)

• In refractory cases, an immunosuppressive agent (eg,cyclophosphamide 1-2 mg/Kg/day, azathioprine 1-3 mg/Kg/d, methotrexate 10-25 mg/ week)

2-Henoch-Schonlein Purpura

• It was first described by Schönlein in 1837 and the manifestations of abdominal pain and nephritis were reported by Henoch in 1874

• The peak prevalence of HSP is in children aged 3-10 years

• In the Northern Hemisphere, the disease occurs mostly from November to January

Etiology• The etiology of HSP remains unknown

• However, IgA clearly plays a critical role in the immunopathogenesis of HSP, as evidenced by increased serum IgA , IgA-containing circulating immune complexes and IgA deposition in vessel walls resulting in elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin

• An antigen may stimulates the production

of IgA. Allergens may include:

- Foods -Insect bites - Cold exposure

- Drugs (eg, ampicillin, erythromycin,

penicillin)

- Infections (eg, Haemophilus,Mycoplasma,

Shigella, Salmonell, adenoviruses,

Epstein-Barr virus,parvoviruses,varicella)

-Vaccines such as cholera, measles

Clinically• HSP begins with a symmetrical

erythematous macular rash on the lower extremities that quickly evolves into palpable purpura

• The rash can initially be confined to malleolar skin, but it usually extends to the dorsal surface of the legs, the buttocks, and the ulnar side of the arms

• Within 12-24 hours, the macules evolve into palpable purpuric lesions that are dusky red and have a diameter of 0.5-2 cm• The lesions may coalesce into larger plaques that resemble ecchymoses

• GI manifestations occur in about 50% of cases and usually consist of colicky abdominal pain, melena, or bloody diarrhea. Hematemesis occurs less frequently

• Arthralgia occurs in 60-84% of cases, commonly affecting the knees and ankles

• The most serious complication of HSP is renal involvement. It occurs in 50% of older children but is only serious in approximately 10% of patients

• Heart: Vasculitis involving the myocardia can occu.

• Lungs: Vasculitis involving the lungs can occur, resulting in pulmonary hemorrhage

Investigations• No specific diagnostic laboratory markers exist• The plasma coagulation factor XIII is reduced in

about 50% of patients• Urinalysis reveals hematuria. Proteinuria may

also be found• CBC can show leukocytosis with eosinophilia

and a left shift. Thrombocytosis is present in 67% of cases

• Serum IgA levels are increased in about 50% of patients during the acute phase of illness

• The antistreptolysin O (ASO) titer is elevated in 30% of cases

Imaging Studies:

• Abdominal ultrasonography can be used if GI symptoms are present

• Chest radiography may help to determine the presence and extent of pulmonary hemorrhage

• To date, no form of therapy has been shown to appreciably shorten the duration of HSP; thus, treatment for most patients remains primarily supportive

• Corticosteroids may be considered for the following serious situations:

- Persistent nephrotic syndrome -Crescents in more than 50% of glomeruli

-Severe abdominal pain -Substantial GI hemorrhage -Severe soft tissue edema -Severe scrotal edema -Neurologic system involvement -Intrapulmonary hemorrhage

The following protocol is suggested: • Induction with 250-750 mg of IV

methylprednisolone every day for 3-7 days plus cyclophosphamide 100-200 mg/d PO

• Maintenance with prednisone 100-200 mg PO every other day, plus cyclophosphamide 100-200 mg/d PO 30-75 days

• Taper prednisone by approximately 25 mg/mo, while the cyclophosphamide dose remains constant

• Discontinue treatment after at least 6 mo by abruptly discontinuing cyclophosphamide and complete prednisone taper

3-Urticarial vasculitis

Etiology• It is strongly associated with connective

tissue diseases e.g. it is present in 20 % of patients with SLE

• Other associations include: physical urticarias, hepatitis, cance colon or drugs as AC inhibitors, fluoxetine, thiazides

• Immune complexes(circulating and deposited in vessel walls) can be found in 75% of cases

Clinically• Erythematous, indurated weals with

purpuric foci

• Weals tend to be of longer duration, often longer than 24 hours and tend to resolve with some residual pigmentation or ecchymosis. Patients experience more burning rather than itching

• Angioedema,livedoreticularis, nodules and bullae may be found

• Constitutional symptoms, GIT & respiratory symptoms, lymphadeopathy, glomerulonephritis & occular affection may be present

Urticarial vasculitis

Investigations

• ESR is elevated

• Look for hypocomplementemia

• Look for changes of associated signs

Treatment• Corticosteroids : 0.5-1.5 mg/kg/d PO initial; taper

as disease responds; if chronic use required, qod administration is safer

• Other drugs that are effective include:

- Dapsone 100-200 mg once daily

- Colchicine 0.6mg twice daiy

- Hydroxychloroquine (Alexoquine 250 mg)

200 mg once or twice daily• Oral antihistamines for angioedema

4- Erythema Elevatum Diutinum

Etiology• First described in 1888 by Hutchinson and

in 1889 by Bury • The pathophysiology of EED is not well

understood• Direct immunofluorescence shows

deposits of complement as well as IgG, IgM, IgA and fibrin around the damaged vessels

• Initiation of EED may occur via activation of cytokines such as interleukin 8, which causes selective recruitment of leukocytes to tissue sites

Clinically• Patients usually present with persistent, firm

lesions on the extensor surfaces of their skin, especially over the joints

• These lesions are most often nodules and round or oval plaques

• The color of the lesions progresses over time from yellow or pinkish to red, purple, or brown

• Lesions increase in number and size over time. They may also enlarge during the day and return to their previous size overnight

• The lesions can be completely asymptomatic, painful, or cause a sensation of burning or itching. These symptoms can be exacerbated by cold

• The lesions

usually feel firm

and are freely

movable over

the underlying

tissue

Investigations• The erythrocyte sedimentation rate in

patients with EED is often elevated

• Direct immunofluorescence study results show including deposits of complement, immunoglobulins (IgG, IgA, IgM) and fibrin intravascularly and perivascularly

Treatment• Dapsone 50-300 mg/d PO revolutionized

the treatment of patients with EED

• Systemic steroids generally have not been found to be effective

• Surgical excision of the lesions is sometimes performed to provide symptomatic relief

5-Granuloma Faciale

Etiology

• Lever and Leeper first recognized GF as a distinct entity in 1950

• Sun exposure may play a role

• Some cases are idiopathic

• A gamma interferon-mediated process has been suggested

Clinically

• Lesiona are usually asymptomatic • Solitary or, more commonly, multiple, soft,

elevated, and well-circumscribed papules, plaques, or nodules. They have a smooth surface with prominent follicular orifices (peau d'orange)

• Most commonly located over the face

• The size varies from a few millimeters to several centimeters in diameter

• The color varies from shades of dull red to brown, blue, and purple. Lesions may darken upon sun exposure

Histopathology

•Normal epidermis

•Grenz zone

•Polymorphs and a few other inflammatory cells are present

•Fibrin replacement of the vessel wall as well as perivascular fibrin deposition

Prominent

perivascular fibrous lamellae

Infiltrate contains eosinophils, leukocytes, plasma cells, lymphocytes, and a few histiocytes

Treatment• Surgical excision

• Dermabrasion

• Argon laser(Argon,CO2,Pulsed dye )

• Electrosurgery

• Cryotherapy

GF is notoriously resistant to treatment; therefore, many different medical therapies have been tried

• Topical & intralesional corticosteroid injections

• Intralesional gold injections• PUVA• Radiotherapy • Dapsone 25-200 mg/d PO

6-Erythema Induratum (Nodular Vasculitis)

• In 1861, Bazin gave the name erythema induratum to a nodular eruption that occurred on the lower legs of young women with tuberculosis

• In 1945, Montgomery et al, coined the term nodular vasculitis to describe nodules of the legs that showed histopathologic changes similar to those of erythema induratum

• Therefore, erythema induratum/nodular vasculitis complex is classified into 2 variants. Erythema induratum of Bazin type(related with TB) and nodular vasculitis or erythema induratum of Whitfield type. Bazin type is related with tuberculous origin, but Whitfield type is not

Etiology• M tuberculosis is the cause of erythema

induratum. Recently, hepatitis C virus has been suggested, but a direct relationship remains unclear

• The cause is unknown in cases of nodular vasculitis with a negative tuberculin skin test reaction

Clinically• A past or present history of TB at an

extracutaneous site(mostly pulmonary) occurs in about 50% of patients

• Crops of small, tender, erythematous nodules may be observed:

– Commons sites are the calves, although the shins are also sometimes involved

– The nodules are concentrated on the lower third of the legs, especially around the ankles

– Lesions may ulcerate with bluish borders, which may be precipitated by cold weather

Histopathology• Septal & lobular granulomatous

inflammation with neutrophilic vasculitis is characteristic and contrasts with erythema nodosum (primarily septal)

• Caseation-like necrosis may also be seen. The histologic features are not specific

Lymphoid infiltrate in the wall & around it

Nodules in the subcutis

Treatment• Antituberculous therapy(for erythema induratum

of Bazin): - Isoniazid (Isocid 200 tab) 5-10 mg/kg PO qd or divided bid; not to exceed 300 mg/d. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended - Rifampin (Rimactane300 cap) 10 mg/kg/d PO or

450-600 mg PO qd; not to exceed 600 mg qd - Ethambutol (Etibi 500 tab) 15-25 mg/kg PO qd - Pyrazinamide (PTB 500 tab) 15-30 mg/kg PO qd;

not to exceed 2 g/d

• Bed rest with systemic steroids • Potassium iodide is sometimes applied, with

high efficacy; however, this therapy requires caution when used in children or in patients with thyroid disease

- Dose:Liquid supersaturated potassium iodide 3 gtt tid in juice and increase by

1 gtt tid; not to exceed 15 gtt tid

II- Large vessel vasculitis

Polyarteritis Nodosa

Etiology• First described by Kussmaul and Maier in 1866• Approximately 30% patients with PAN are

positive for hepatitis B surface antigen– In these patients, hepatitis B antigen and circulating

hepatitis B antigen-antibody aggregate in the serum and in vascular lesions

– This finding suggests that PAN results from complexes of antibodies and exogenous antigen, such as hepatitis B antigen

Clinically

• Skin: About 40% of patients manifest dermatologic symptoms and signs including rash, purpura, nodules, cutaneous infarcts, livido reticularis, and Raynaud’s phenomenon

PAN

• Renal system: About 60% of patients with PAN have renal involvement. Ischemic changes in the glomeruli can cause renal failure or hypertension

• Musculoskeletal system: Symptoms manifest as arthritis, arthralgia, or myalgia

• Central nervous system: Transient symptoms of cerebral ischemia, including typical spells of transient monocular blindness, are the most commonly presenting

Investigations• No diagnostic serologic tests are available

• Positive Antineutrophil cytoplasmic antibody (ANCA) titers often are found; however, they are not diagnostic

• Leukocytosis, with neutrophil predominance

• ESR is almost always elevated

• Hypergammaglobulinemia is found in 30% of patients with PAN

• Arteriogram reveals microaneurysms in the small and medium-sized arteries of the kidneys and abdominal viscera

• EEG shows generalized slow wave activity during periods of encephalopathy or toxic delirium

•Prominent eosinophilic "fibrinoid"

necrosis involving the intima and media

•The lumen has been occluded by

granulation tissue

Treatment• Treatment may include a regimen of

prednisone (1 mg/kg/d) and cyclophosphamide (2 mg/kg/d). In general, patients respond better to combined therapy with immunosuppressants and corticosteroids than to steroids alone

• In contrast, for hepatitis B–related PAN, treatment consists of schemes that include plasmapheresis and antiviral agents

III- Neutrophilic vascular reactions

1- Acute Febrile Neutrophilic Dermatosis

(Sweet's syndrome)

Etiology Initially described in 1964 by Robert Sweet

I-Associated with a (malignant) neoplasm in 20-25% of the cases

– Leukemia

– Lymphoma

– Multiple myeloma

– Genitourinary cancers

II- Multiple infections :

- Streptococcal pneumonia is the most

commonly described infection.Other

bacterial infections include those due to

Salmonella ,Staphylococcus ,enterocolitica,

Entamoeba coli, Helicobacter pylori and TB

- Viral agents such as HIV, cytomegalovirus (CMV), hepatitis A, and hepatitis B

III - Multiple drugs have been reported to

cause Sweet syndrome: – Trimethoprim-sulfamethoxazole (Sutrim), all-

trans retinoic acid, and minocycline, which have all appeared in more than 1 case report

IV - Systemic disorders (15 %) :– The most commonly associated diseases are

Crohn disease, ulcerative colitis, Behçet disease, lupus erythematosus and rheumatoid arthritis

Clinically• Fever typically precedes the appearance

of each crop of lesions by several days to weeks

• Headache, malaise, and arthralgias are common

• Episodes of disease cluster in the spring and autumn

• Skin manifestations– Typical skin lesions are reddish blue or

violet(plum color) papules, plaques, or nodules. Lesions may be studded with pustules. Papules often coalesce into circinate plaques 2-10 cm in diameter

– Plaques can cause pain and burning, but they are not pruritic

– Ulcers and bullae are more common in malignancy-associated disease

• The face, neck, and extremities primarily are affected, characteristically in an asymmetric distribution. Lesions on the dorsum of the hand are not uncommon

• Lesions spontaneously resolve without scarring, or they resolve after treatment

• Sweet syndrome is known to cause pathergy (Köbner phenomenon), in which lesions occur at sites of minor trauma

• Mucosal lesions– Oral lesions can occur on the lips, buccal

mucosa, and/or tongue. These lesions most commonly appear as ulcers in Sweet syndrome patients with hematologic disorders

– Conjunctivitis and episcleritis may also occur

• Extracutaneous manifestations– Pulmonary manifestations are the most

common and may manifest as a chronic cough or pulmonary infiltrates on chest radiographs

– Other extracutaneous sites that have been reported include the bones, intestines, joints, pancreas, liver, heart, muscles, spleen, and kidneys

– Proteinuria, hematuria, and decreased creatinine clearance have been reported

Diagnostic criteria The presence of 2 major and 2 minor

clinical findings:

- Major criteria

• Abrupt onset of tender or painful erythematous plaques or nodules

• Predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis

- Minor criteria

• Preceding nonspecific respiratory or gastrointestinal tract infection or vaccination or associated with inflammatory disease, hemoproliferative disorders, solid malignant tumors, or pregnancy

• Periods of general malaise and fever (fever >38°C)

• Laboratory values during onset showing ESR >20 mm, positive C-reactive protein result, segmented nuclear neutrophils, bands >70% in peripheral blood smears, and leukocytosis (count >8000/mL) (meeting 3 of 4 of these values is necessary (

Investigations 1- A CBC count with differential must be ordered

to screen for underlying hematologic disorders:– Neutrophilia is typically present, but the

absence of neutrophilia in a patient who is neutropenic does not rule out Sweet syndrome

– Anemia and thrombocytopenia are common in patients with underlying malignancy

2-ESR is elevated in more than 90% of cases. This is, of course, a nonspecific manifestation of inflammation

3-Urinalysis may show proteinuria

4-If an underlying malignancy is suspected, the appropriate imaging modality should be used for early detection and treatment

Treatment

• In most cases, prednisone is extremely and rapidly effective, in doses of 40-80 mg qd(once daily) or divided bid/qid(4 times daily); taper slowly over 4-6 wk; qod(every other day) tapering may decrease adverse reactions

• For long-term management, numerous drugs may be helpful. They work by inhibiting neutrophil chemotaxis, but none have been shown to be better than corticosteroids– Indomethacin, colchicine and potassium

iodide were helpful in small series of patients– Dapsone, cyclosporine, etretinate,

pentoxifylline, and clofazimine also have been used, with anecdotal success

– Doxycycline, metronidazole, isotretinoin, methotrexate, cyclophosphamide, pulse doses of methylprednisolone& interferon alpha are also reportedly successful

– However, despite the initial excellent response, recurrences are common and generally develop as steroid use is being tapered. If the underlying disease flares, it may take longer to effectively taper therapy

– High-potency topical steroids (eg, clobetasol propionate 0.05%) or intralesional glucocorticoids (eg, triamcinolone acetonide 3.0-10 mg/mL) may also be useful in localized lesions

2- Behçet Disease

• Named in 1937 after the Turkish dermato- logist Hulusi Behçet who suggested the HSV as a causative agent in his first report

• Most prevalent (and more virulent) in the Mediterranean region, Middle East,and Far East, with an estimated prevalence of

1 case per 10,000 persons

• In Turkey, the male-to-female ratio was 16:1 among 427 patients

Etiology• Immunogenetics

– HLA-B51 or its B101 allele is significantly associated with BD

– The MICA allele which is thought to be in linkage with HLA-B51 has recently been shown to be significantly associated with BD (74%), compared with controls (45.6%) in Japan

• Viral and bacterial infection

- Herpes simplex virus DNA has been

detected in saliva, genital ulcers, and

intestinal ulcers

- Hypersensitivity to streptococcal

antigens plays an important role

• Immunological abnormalities :

- The Th1 cytokine interferon (IFN) level

is elevated in serum, in skin T cells,

and cerebrospinal fluid

- The Th2 cytokine IL-6 is also increased

in the serum of patients with BD

- Levels of TNF–alpha, TNF receptor 1,

IL-1, IL-8, IL-10 and IL-13 are elevated

• Endothelial and vascular dysfunctions:

- Antiendothelial cell antibodies show

significantly increased prevalence in BD

- T cells (mostly CD4 cells), B cells, and

neutrophils are infiltrated perivascularly

- The level of endothelin 1 & 2 is

increased in BD vascular involvement

- Endothelial cell–dependent vasodilator

function is significantly impaired

Clinically• Oral ulcers (70 %)

– Indistinguishable from common aphthae– Aphthae may be more extensive, more

painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore

– Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin

– They can appear singly or in crops, are located anywhere in the oral cavity

– They persist for 1-2 weeks, and subside without leaving scars

– The interval between recurrences ranges from weeks to months

• Genital manifestations– Genital ulcers resemble their oral

counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers

– In males, the ulcers usually occur on the scrotum, penis, and groin. In females, they occur on the vulva, vagina, groin, and cervix

– Ulcers have also been found in the urethral orifice and perianal area

– Orchiepididymitis is observed in 10.8% of men

• Cutaneous manifestations (58.6-97%)–Erythema nodosum–like lesions, which are

most common– Pseudofolliculitis–Erythema multiforme–like lesions–Acne-like lesions –Ulcers –Lesions resembling Sweet syndrome –Bullous necrotizing vasculitis–Pyoderma gangrenosum –Pathergy

Pathergy- An erythematous papule larger than 2 mm at the prick site 48 hours after the application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours

• Ocular manifestations

- Uveitis - Hypopyon and its

(ant&post) sequelae

- Cataracts - Glaucoma

- Synechiae - Retinal vasculitis

- Hemorrhag - Retinal detachment

• Neurologic manifestations (5-10%):usually occur later in the course of disease

- Meningoencephalitis

- Spastic paralysis and incontinence

- Personality changes

- Cranial nerve abnormalities:difficulty in

swallowing and deafness

• Vasculopathy

- Deep venous thrombophlebitis has been

described in about 10% of patients

- Noninflammatory vascular lesions

include arterial and venous occlusions,

varices, and aneurysms

• Arthritis and arthralgias occur in any pattern in as many as 60% of patients

• Gastrointestinal manifestations

• Renal manifestations(Glomerulonephritis and epididymitis) occur in about 10% of the patients

• International criteria for the classification of BD (1990) are as follows:– Recurrent oral ulceration at least 3 times/year + 2 of

the following: • Recurrent genital ulceration• Eye lesions - (1) Uveitisor (2) retinal vasculitis• Skin lesions - (1) Erythema nodosum–like

lesions, pseudo-folliculitis, and papulopustular lesions or (2) acneiform nodules in postadolescent patients not receiving corticosteroids

• Positive pathergy test

Investigations– C-reactive protein, ESR, leukocyte count, and

complement components and acute-phase reactants all may be elevated during an acute attack

– Elevations occasionally are found in IgA and immunoglobulin M (IgM) levels and immune complexes

– None of these findings is specific for the diagnosis of Behçet disease, but they can corroborate active disease

Histopathology

Mononuclear &neutrophilic infiltrate with RBCs extravasation without fibrin deposition

Treatment• Prednisone (Hostacorten)60 mg PO /d• Immunomodulators: - Colchicine 0.6 mg PO bid or tid - Dapsone 50-100 mg/d PO - Levamisole 150 mg PO twice a wk - Cyclosporine (Sandimmune, Neoral) 2.5-5 PO mg/kg/d in bid - Tacrolimus(Prograf) 0.15 mg/kg/d PO - Thalidomide (Thalomid) 100-300 mg/d PO

• Immunosuppressives

- Azathioprine (Imuran) 1-2 mg/kg/d (50-

200 mg) PO

- Cyclophosphamide (Cytoxan) 1-2

mg/kg/d PO

3- Erythema Nodosum

Etiology– Bacterial Infections:• Tuberculosis• Yersinia enterocolitica: A gram-negative

bacillus causes diarrhea and abdominal pain• Mycoplasma pneumoniae• Leprosy• Lymphogranuloma venereum• Campylobacter

-Fungal infections :• Coccidioidomycosis • Histoplasmosis• Blastomycosis

-Drugs: Sulfonamides and halide agents

• Gold and sulfonylureas

• Oral contraceptive pills are implicated in an increasing number of report

-Enteropathies: Ulcerative colitis and Crohn disease may trigger EN

-Hodgkin disease and lymphoma EN associated with non-Hodgkin lymphoma may precede the diagnosis of lymphoma by months

-Sarcoidosis: The most common cutaneous manifestation of sarcoidosis is EN. Lofgren syndrome involves: EN, hilar lymphadenopathy, fever, arthritis, and uveitis. This presentation has a good prognosis with complete resolution within several months in most patients

-Behçet disease is associated with EN

-Pregnancy: Some patients develop EN during pregnancy, most frequently during the second trimester

Clinically• The eruptive phase of EN begins with flulike

symptoms of fever and generalized aching and arthralgia occurs (in 50% of cases) and may precede or appear after the eruption

• Primary skin lesions: begin

as red tender nodules.

Lesion borders are poorly

defined and vary from 2-6 cm• During the first week, lesions

become tense, hard, and painful

• Distribution of skin lesions: lesions appear on the anterior leg; however, they may appear on any surface

• Color of skin lesions: Lesions change color in the second week from bright red to bluish or livid. As absorption progresses, the color gradually fades to a yellowish hue, resembling a bruise. This disappears in 1 or 2 weeks as the overlying skin desquamates

• Hilar lymph nodes: Hilar adenopathy may develop as part of the hypersensitivity reaction of EN. Bilateral hilar lymphadenopathy is associated with sarcoidosis, while unilateral changes may occur with infections and malignancy

• Most lesions in infection-induced EN heal within 7 weeks, but active disease may last up to 18 weeks. In contrast, 30% of idiopathic EN cases may last more than 6 months

Investigations• Throat culture to exclude strept infection

• ESR It is often very high

• Antistreptolysin titer is elevated in some patients with streptococcal disease, but normal values do not exclude infection

• Stool examination, since along with the appropriate history of gastrointestinal complaints, a stool examination can exclude infection by Yersinia, Salmonella, and Campylobacter organisms

• Chest radiographs to exclude sarcoidosis and tuberculosis and to document hilar adenopathy

• Intradermal skin tests can be used to exclude tuberculosis and coccidioidomycosis

Histopathology• Punch biopsies usually are not adequate.

Deep skin incisional biopsies are required as findings are localized to the subcutaneous

tissue

Treatment• Supersaturated potassium iodide liquid :

3 gtt tid in juice, increase by 1 gtt tid; not to exceed 15 gtt tid

• Mechanism of action in EN is unknown, but it is known to enhance response by potentiating neutrophil activity

• Prolonged use may result in hypothyroidism

• Relief may occur within 24 h. Most lesions completely subside within 10-14 d

• Potassium iodide is not effective for all patients with EN. Patients who receive medication shortly after the initial onset of EN respond more satisfactorily than patients with chronic EN

• Anti-inflammatory agents : Provide symptomatic relief for lesional tenderness, arthralgia & fever

- Aspirin (325-650 mg PO q4-6h ) - Indomethacin (Indocid25-50 mg PO bid/tid - Colchicine : 0.5-1.2 mg PO initially, followed by 0.5-0.6 q1-2h or 1-1.2 mg q2h until response is satisfactory. Reduces formation of uric acid crystals in affected joint, thereby reducing amount of acute inflammation and pain; also decreases uric acid levels in blood

4-Pyoderma Gangrenosum

Etiology• No specific causes of PG have been

identified, but trauma to the skin (pathergy) may induce new lesions

• Altered neutrophil chemotaxis, is believed to be involved

Clinically• Patients with PG usually describe the initial

lesion as a spider bite reaction, with a small, red papule or pustule changing into a larger ulcerative lesion, but they have no evidence that a spider actually caused the initial event

• Pain is the predominant historical complaint

• Arthralgias and malaise may often be present

Two main variants of PG exist:– Classic PG is characterized by a deep

ulceration with a violaceous border that overhangs the ulcer bed. These lesions of PG most commonly occur on the legs, but they may occur anywhere on the body

– Atypical PG has a vesiculopustular "juicy" component. This is usually only at the border, is erosive or superficially ulcerated, and most often occurs on the dorsal surface of the hands, the extensor parts of the forearms, or the face

Classical PG

Early PG treated by IL

Atypical PG

Atypical PG

Commonly associated diseases include:

• Ulcerative colitis or regional enteritis/Crohn disease

• A polyarthritis that is usually symmetric and may be either seronegative or seropositive

• Hematologic diseases such as leukemia

Investigations• Routine blood work to evaluate for an underlying

systemic illness: CBC; a comprehensive chemistry profile, including a liver function test; and a urinalysis

• A hepatitis profile should be performed to rule out hepatitis

• Serum and/or urine protein electrophoresis, and bone marrow aspiration should be performed if indicated to evaluate for hematologic malignancies

Treatment• Prednisone (Hostacorten) 0.5-2 mg/kg/d PO

• Immunosuppressives

- Cyclosporine (Sandimmune, Neoral) 3-5

mg/kg/d PO/IV,

- Azathioprine (Imuran) 1-2 mg/kg/d (50-

200 mg) PO

- Cyclophosphamide (Cytoxan) 1-2

mg/kg/d PO

-Tacrolimus (Prograf): Suppresses humoral immunity (T-lymphocyte). 0.05 mg/kg/d IV or 0.15-0.30 mg/kg/d PO divided bid

• Immunomodulators : These agents have effects on the activity of the immune system:

- Thalidomide (Thalomid):50-300 mg/d

PO qd

• Clofazimine (Lamprene) : 100 mg/d PO

qd mechanism of action is unknown

Prognosis• The prognosis of PG is generally good; however,

recurrences may occur, and residual scarring is common

• Many patients with PG improve with initial immunosuppressive therapy and require minimal care afterwards; however, many patients follow a refractory course and multiple therapies fail

• Some patients demonstrate pathergy, and, in such instances, protection of the skin from trauma may prevent a recurrence

Pityriasis Lichenoides

Types 1-Pityriasis lichenoides chronica (PLC):

The more common form

2-Pityriasis lichenoides et varioliformis

acuta (PLEVA) or Mucha-Habermann

disease

Etiology• Most cases of PLEVA cannot be attributed

to any one cause and are idiopathic

• Familial outbreaks, clustering of cases & comorbid symptoms have been used to support a hypersensitivity reaction to infectious agents, although clear causality is lacking

• The most commonly reported associated pathogens are Epstein-Barr virus (EBV), Toxoplasma gondii & human immuno-deficiency virus (HIV)

• some authors don not consider PLEVA as a type of vasculitis but a self-limited lymphoproliferative disease because:

- Fibrin is not present in the walls of vessels

- Thrombi are not found in the lumen

- CD30 cells, which are associated with

large cell lymphoma, have been identified

in the infiltrate of PLEVA

Clinically• PLEVA and PLC are not distinct diseases,

but rather, they are different manifesta-tions of the same process, although the process is accelerated in PLEVA

• PLC presents as small erythematous–to–reddish brown papules, although with increased numbers compared to PLEVA. A fine scale usually is found, although not initially, which has been likened to frosted glass. The eruption often is polymorphic, with lesions at different stages of evolution

• PLEVA presents acutely with 10-50 erythematous–to–reddish brown or purpuric round or ovoid lichenoid papules that are 5-15 mm in diameter. Many papules demonstrate a pseudovesicular summit evolving to a central necrosis and a hemorrhagic crust.

• PLEVA lesions may evolve into lesions of PLC

• Lesions may be distributed symmetrically or asymmetrically on the trunk, buttocks, and proximal extremities, with occasional acral involvement. Lesions may appear on the palms, soles, face, and scalp. Asymmetric or segmental nondermatomal presentations have been reported

• Erosions and hemorrhagic crusts may be found• Mucosal lesions consisting of irregular erythema

and superficial ulcerations on the buccal mucosa and palate have been reported

• Most lesions heal with postinflammatory changes, such as a transient or persistent leukoderma or hyperpigmentation

PLEVA

Investigations• Tailor the workup to each patient's

presentation to exclude a possible cause e.g.– EBV IgM/IgG viral antigen– Erythrocyte sedimentation rate– Hepatitis B & C surface antigen, antisurface

antibody, and anticore IgM– HIV screening– Rapid plasma reagin– Throat cultures– ELIZA for Toxoplasma

Wedge-shaped perivascular lymphocytic infilterate

- Parakeratosis

- Lymphocytes at holes inside keratinocytes

High power of the previous picture

Extravasation of RBCs into the epidermis

Few atypical lymphocytes (AL(

Treatment• Antibiotics :

- Tetracycline (Hostacyclin) 1-2 g PO

divided bid/qid

- Erythromycin (Erythrocin) 250 mg PO qid

• UV radiation, produce photoproducts resulting in suppression of both DNA synthesis and cell division

• Acitretin : 0.75-1 mg/kg/d PO in divided doses; increase at weekly intervals by 0.25 mg/kg/d up to 1.5 mg/kg/d; establish maintenance dose (0.5-0.75 mg/kg/d) after 8-10 wk of therapy

• Methotrexate 0.3 mg/kg/wk; not to exceed 20 mg: inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction