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HELLENIC  ASSOCIATION   DERMATOLOGY-VENEREOLOGY

 

VASCULITIC SYNDROMES:

AN APPROACH TO THEIR MANAGEMENT

by G.Ch.Chaidemenos, MD

State Hospital for Skin and Venereal Diseases, Thessaloniki, Greece.

 

"Vasculitic syndromes" is an all-encompassing term comprising the conditions with vascular inflammation and implying different aetiologic factors but common clinical ana pathologic features. The unaware reader is much embarrassed because several specialties (i.e. dermatologists, dermatopathologists, rheumatologists) use radically different terminology and clinical taxonomy.

In order to prevent further confusion, the first disease to deal with in this chapter, is the vasculitis the dermatologist usually encounters in private office or mediCal Center Clinics. 

NECROTIZING VASCULITIS

Also called allergic, hypersensitivity or leukocytoclastic vasculitis or angiitis (from the Greek áăăĺßďí=lumen) is characterized clinically by palpable purpura often coupled or followed by urticarial, nodular or ulcerative lessons. Fibrinoid necrosis of small vessel walls and leukocytoclasis of the inflammatory cells, in and around the post capillary venular wall, is the histological hallmark of the syndrome.

The answer to the question "How should a patient with necrotizing vasculitis be managed?" is not an easy one. Well-experienced authorspropose the following sequence of therapy: Antihistamines, indomethacin plus antihistamines, colchicine, dapsone or hydroxychloroquine, systemic corticosteroids plus azathioprinel1. This approach indicates the relative risk-factors of each treatment modality and what is the best sequence to follow from an idealistic point of view. In every day practice however, dermatologists use much more easily oral corticosteroids, at least for their suppressing effect on the constitutional symptoms.

The management of necrotizing vasculitis should be bidirectional: symptomatic and aetiologic. Simple bed rest usually suffices and allows the faster resolution of the lesions . The use of prednisone is considered when progression of skin involvement continues despite bed rest, and/or internal organ, especially renal, involvement appears, or severe serum-like manifestations, e.g. fever and arthralgias persist. Initial doses of 60-80 mg, but sometimes as low as 20 mg of oral prednisone, are given daily in a single morning or divided doses. This therapy may relieve from serum-sickness like symptoms but does not hasten the elimination of immune-complexes1. Maintenance therapy may be required for several weeks because recurrences are common. Alternate-day corticosteroid therapy carries a low likelyhood of side effects, but is considered suboptimal for the treatment of immune complex mediated diseases, such as vasculitis2.

The second line of management should be directed to the correction of the associated, causally linked with the vasculitic syndrome, disorders: inflections, immunologic or neoplastic. An exogenous antigen, bacterial or viral and drugs are implicated at almost equal percentages in the aetiology of 22% of all cases of necrotizing vasculitis3. By treating the infection or stopping the incriminating drug, a rapid resolution of the disease is expected. Indeed, the removal of chronic dental abscesses and the treatment of chronic infeetions, such as pyelonephritis, effect favourably the vasculitis4. However, the cause of the latter is not simply a single factor, and the infectious or toxic exogenous antigen may only initiate the whole cascade of events leading to vessel injury; it is therefore a rational approach to act to these events, especially when the course of vascuiitis is subacute or chronic.

Antihistamznes, considered as possibly beneficial by blocking the histamine-induced endothelial gaps, have constantly been proved unsuccessful5. Nonsteroidal antiinflammatory drugs may relieve from serum sickness like symptoms but do not influence the skin lesions2. Colchicin in doses of 0.6 mg one to three times daily, may improve some cases but diarrhea may lead to dosage reduction and neutropenia to its interruption . The drug is usually effective in the first week after initiation of therapy but the disease quite often relapses when colchicine is stopped6. The mode of action is probably at the level of inflammatory changes, because colchicine inhibitis polymorphonuclear leukocyte chemotaxis, blocks lysosomal formation and stabilizes lysosomal membranes. Sulfones and retinoids have also been used successfully but mainly -like the above mentionned regimens- in uncontrolled series of patients7. Doses of 104-150 mg/day of Dapsone have the preference of the authors8, but even very low regimens (25 mg/day) administered for some weeks, may cure subacute forms of leukocytoclastic vasculitis9. Azathioprine and cyclophosphamide apparently have to place in the treatment of mild cutaneous necrotizing vasculitis. However, azathioprine may be reserved as an alternative regimen in severe disease11.

Oral pentoxifylline, a drug with multiple effects, including antithrombotic and inhibitory to the inflammatory action of interleukin and cachectin, clear chronic leukocytoclastic vasculitis lesions actinq either as a monotherapy or as a steroid sparing agent; doses of 400 mg three times daily for several weeks usually suffice, but one should be aware of a possible clinical worsening in the first few weeks of therapy, due to increased local blood supply and decreased platelet adhesiveness12.

An open trial evaluating the efficacy of Cyelosporin-A in the treatment of recalcitrant; chronic, recurrent vasculitis was promising, since most of the patients improved in the first 24 hours . It seems that Cyclosporin A acts mainly through the reduction/impairment of y-interferon13.

High dose pooled immunoglobulin improved seven patients with systemic vasculitis14. One patient with intractable systemic disease was treated with monoelonal antibodies and remained disease free one year after therapy15; it is suggested that more rational therapeutic approach for cutaneous vasculitis is the one expected from anti-idiotypic antibodies, cytokine inhibitors or antagonists and monoclonal antibodies against leukocyte and endothelial adhesion molecules16.

Since the most common mechanism of disease in necrotizing vaseulitis is the immune-complex mediated damage to vessel wall, every effort to remove circulating immune complexes by apheresis or by an efficient reticuloendothelial system could be of benefit. Indeed, seven out of eight patients with chronic and refractory to aggressive corticosteroid therapy leukocytoclastic vasculitis, experienced considerable relief from their symptoms after intermittent courses of plasma exchange17; additionally, diets with reduced contents of macromolecular antigens i.e. those restricting from meat and allowing rice, fruits and vegetables, led to the regression of purpura and laboratory parameters in 24 controlled patients suffering from mixed cryoglobulinemia of essential origin, acting possibly by restoring a saturated mononuclear phagocytic system18.

Occasionally hepatitis C is associated with necrotizing vasculitis or even systemic forms of the disease19. In these patients, immunosuppressants are usually of no value; instead, plasma exchange or interferon in low doses improve most cases20.

The careful evaluation of the patients with necrotizing vasculitis will reveal an autoimmune disorder in one third of cases3. Especially when infarctive or widespread ecchymotic lesions exist, a search for lupus anticoagulant or cryoprotein will help to elucidate and manage the underlying disorder.

Cryogolobulins are found in almost 3% of all cases of vasculitis: when they are monoclonal, a purpura of the exposed surfaces of the body appears after cold exposure; in the mixed type, an investigation for Systemic Lupus Erythematosus, Szogren's syndrome or Rheumatoid arthritis must be made and appropriate therapy initiated. The safety of modern y-globulin intravenous preparations make their use a promising mode of therapy, especially for those patients with disease refractory to other treatment modalities; doses of 0.4gr/kg/day for 4 days may suffice21.

The herglobulinemic purpura of Waldenstrom is usually diagnosed when a woman with extensive, recurring purpura, appearing like "pepper" dots, manifests abnormal serum protein electrophoresis. When the disease is primary, and this is the rule, the course is chronic and benign requiring only bed rest. Although chlorambucil, and much more rarily prednisone, may temporarily reduce skin lesions, therapy as a whole is considered disappointing and unwarranted22.

HENOCH - SCHONZEIN PURPURA (Rheumatoid purpura) is a clinical subset of necrotizing vasculitis characterized by:

a) its predominance in children less than 7 years of age,

b) the appearance of lesions in the extensor surfaces of the extremities and buttock, and the frequent Koebnerization in the form of linear purpura on the legs (fig.1), and mainly by:

c) the concurrence of arthralgias and abdominal pain and

d) the demonstration of IgA immune complexes in the walls of papillary dermal vessels.

Since the prognosis of the syndrome is good and its course is self limited, only supportive measures are required23. Interruption of suspected as provoking the disease drugs, such as ampicillin, penicillin, chlorpromanin etc., is considered as beneficial24. Glycocorticoids and other aggressive therapy should be considered only in the cases that progressive renal disease appears25; some authors however consider that corticosteroids may only alleviate from the symptoms and can not substantially alter the course of purpura and nephropathy26.

Eighty to 90% of pediatric cases of Henoch-Schonlein purpura, suffer from or have a recent history of upper respiratory streptococcal infection and its appropriate treatment may improve the vasculitic syndrome27. Some authors consider plasma exchange as the treatment of choice for the rare, severe, progressive cases23. Dapsone in doses of 100 mg/day for three months permitted the rapid and permanent resolution of cutaneodigestive symptoms. The reduction of complement deposits and diminution of IgA synthesis may be some, specifically beneficial for Henoch-Schonlein purpura, aspects of the multifactorial action of dapsone. In the occasional patient with severe abdominal symptoms and decreased level of factor XIII activity (a transglutaminase catalysing cross-linking of fibrin, thus helping in normal hemostasis), replacement therapy with heat treated, placenta derived factor XIII concentrate is considered a harmless and first-line treatment modality29.

Acute hemmorrhagic edema of childhood is probably related to Henoch-Schonlein purpura, and appears during the winter months in the form of painful, edematous, usually target-like, petechiae and ecchymoses at the head and perineal region of infants and young children. No therapy is required because the patient recovers completely. Sometimes oral prednisone (1-1.5 mg/kg/day) may be administered in a rapidly decreasing schedule of 10-15 days total treatment; recurrences may necessitate an investigation for a latent infection, usually from group A â-hemolytic streptococci, and appropriate treatment30.

URTICARIAL VASCULITIS is another variant of necrotizing angiitis. Urticarial lesions accompanied by a burning sensation rather than pruritus, remain more than 24 hours and subside leaving residual hyperpigmentation. The course of the syndrome lasts from a few weeks to several years and depends on the nature of the associated disorders .

It seems that there are two extremes in the spectrum of the course of Urticarial Vasculitis31. The benign pole comprises the cases that are not associated with other clinical or biological signs; it is quite reasonable to consider these cases as responsive to antihistamines, since they represent 20% of chronic idiopathic urticaria32. At the other end of the spectrum there is the"hypocomplernentemic urticarial vasculitis" (Mc Duffie syndrome)33, which is usually associated with renal, ocular, digestive or neurologic manifestations. Its corticoresistance speaks in favor of the differentiation from Systemic Lupus Erythematosus; however its relationship to the latter has not so far been elucidated. High doses of corticosteroids are usually required; colchicine may be added as a steroid sparing agent because doses of prednisone below, 30-40 mg/day are usually followed by disease exacerbation31. Sometimes hydroxychloroquine in low doses (200 mg/day) may be used as an adjunct or alternative therapy 34.

As a consequence of the diversity of the course of urticarial vasculitis, no one treatment is considered as universally effective. Antihistamines and non steroidal antiinflammatory drugs, especially indomethacin35, have almost 50% probability of achieving control of the disease36. Occasionally dapsone for hypocomplementemic disease37 and colchicine (0.5 mg/day) for recalcitrant urticarial vasculitis38 may be required. Corticosteroids in doses of 10-60 mg/day will be administered in the occasional patient with obstructive pneumonopathy, arthropathy, or glomerulonephritis. Plasmapheresis may be considered in the particular cases that do not respond to conventional measures39, 40. Phenoxymethyl penicillin 50 mg/kg/day for one month, cured a patient with urticarial vasculitis representing a manifestation of Lyme disease 41.

Schnitzler's syndrome, associating chronic non-pruritic urticaria with leukocytoclastic vasculitis, 'flush, bone pains with hyperostosis, intermittent fever and macroglobulinemia, is usually benign but long follow-up, is necessary because lymphoproliferative disorders may develop42. An adequate treatment has been found. High corticosteroid doses may transiently effect beneficially at the urticaria, and non steroidal antiinflammatory drugs may alleviate from bone pains 43.

LIVEDOID VASCULITIS

Also called segmental hyalinizing vasculitis and vasculitis of atrophie blanche or, rarely; livedo reticularis with ulcers and summer or winter ulcerating, is quite easily diagnosed after a careful clinical inspection: atrophic stellate ivory-white scarring with surrounding punctate telangiectasias are intermingled with small painful ulcers and hyperpigmentation in the lower legs and feet, usually of a middle-aged woman (Fig.2) .

How should a patient with livedo vasculitis be managed? At first a thorough examination to rule out toxic, inectious and especially immunologic (Irconnective tissue disease) cause or abnormalities of coagulation, is indicated. The following tests may be instructed: Erythrocyte sedimentation rate, platelet count, liver and renal functions, serum markers for hepatitisB, rheumatoidfactor, antinuclear antibodies, VDRL, TPHA, anticardiolipin antibodies, activated partial thromboplastin time, CH50, C3 and C4 levels, serum fibrinogen, cryoglobulin, cold agglutinins and immunoelectrophoresis.

Supportive measures with bed rest and antiseptic dressings are instructed, but a systemic therapy is usually required because the course of the disease is chronic with recurrences.

Nicotinic acid in doses of 2gr/day may be tried but it seldom exhibits a beneficial effect. Nifedipine in doses of 30 mg/day combined with heparinotherapy permits the rapid healing of ulcers but there is no effect on erythematous netlike lesions44. Fibrinolytic therapy using phenphormin and ethylestrenol was abandonned because of the life threatening side effect of lactic aeidosis that phenphormin may proroke.

The combined use of antithrombotics with different mode of action is promising45. Aspirin, a cyclooxygenase inhibitor, at low doses such as 40 to 80 mg/day inhibits the production of the thrombus forming mediator thromboxare ; dipyridamole, administered in doses of 150-225 mg/day, stimulates the release of prostaglandin , an inhibitor to aggregation of platelets, and inhibits the biosynthesis of thromboxane; ticlopidine (200mg/day) interferes with platelet aggregation, by raising ademylate cyclase activity and improves blood flow in.microcirczlation. However, this combined regimen seems to heal only the ulcers and has no effect to livedo status45. The use of oraly aspirin and dipyridam, for several weeks seems to be equally beneficial for the patients46.

Pentoxifylline, a xanthine derivative that increases blood flow through the microcirculation, primary by increasing erythrocyte flexibility and reducing blood viscocity, in doses of 400 mg two or three times daily heals the ulcers and improves symptomatology in a few weeks to two months period47. A patient with the clinical picture of livedo vasculitis and histological of capillary thrombosis, apparently due to protein C system deficiency, failed to improve with colchicine, aspirin, dipyridamole and low-molecular-weight heparin but responded to low doses (50-75 mg/day) of dapsone48.

NODULAR VASCULITIS

This vasculitic process of arteries and veins of the panniculus, is manifested by recurrent nodules that are more easily felt than seen, appear smaller, harder, more painful and persistent than those of erythema nodosum, have a tendency for necrosis and scarring exacerbating during cold weather, and are located asymmetrically on the lateral or posterior legs of a woman over 40. years of age.

Supportive treatment with avoidance of cold, overeating and immobility combined or not with an antiinflammatory regimen, usually improve the conditionl. Our experience and that of other authors49 are in favor of the use of potassium iodide: oral doses of 300 mg three times daily bring about a prompt relief from the symptoms and resolve completely the lesions in a period of two weeks. Its mode of actzon to vasculitic process has not been elucidated: it may act immunosuppressively, mediated by beparin release or, more probably, to the myeloperoxydase system of polymorphonuclear cells. An alternative therapeutic modality is given with an oral gold compound (auranofin) with antiinfectious, antiproliferative, anti-inflammatory and immunomodulatory effect and beneficial action to nodular vasculitis, when administered in doses of 3 mg three times daily for at least two months50.

A peculiar form of nodular vasczuitis is that of erythema nodosum leprosum: Manifested clinically with crops of nodules and, rarely, ulcers to the extremities, face and trunc, is usually encountered during therapy of a patient with Lepromatous Zeprosy or rarely at his first presentation. In addition to regular antileprosy chemotherapy, cortĂcosteroid treatment for a period of two months may be required51.

RHEUMATOID VASCUZITIS

Management of rheumatoid vascuzilitis is guided by the assessment of disease activity. This is primarily evaluated by the clinical appearance and the measurement of levels of IgG rheumatoid factor, complement and antiendothelial cell antibodies52. Digital, often periungual, transient, recurrent, smaller than 1 mm microinfarctions, are considered as isolated digital vasculitis and usually require only the treatment of uncomplicated rheumatoid arthritis. Perhaps, much more attention should be paid for an appropriate nutrition, restriction of smoking and control of blood pressure53.

Special and even aggressive therapy is under consideration when skin ulcers, purpura, petechiae and digital tip gangrene appear. Glycocorticoids, immunosuppressants or D-penicillamine are usually cited as the drugs of choice. It should be mentionned however, that D-Penicillamine is the least effective and prednisone be used with caution, because high oral doses (0.5 to 1.0 mg/kg/day) are required and disease exacerbation follows a rapid decrease of this dosage 53. In uncontrolled series, cyclophosphamide54 or methotrexate, orally or intramuscularly in doses of 10-l5 mg/weekly55, improved severe rheumatoid vasculitis. In particular cases, moderate doses of dapsone administered as monotherapy of in association with colchicine, could be useful 56.

PUSTURAR VASCUZITIS is a clinical term that has not yet passed the test of time: it unifies the cases appearing with pustules on purpuric bases and includes idiopathic disease, bowell associated dermatitis - arthritis syndrome, Behcet's disease, gonococcemia, chronic menningococcemia and acute generalised pustural bacterid2, 4, 57. Systemic antibiotics are the treatment of choice. They act either by diminishing antigens in circulating immune complexes, after the suppression of bowel flora, or by suppressing neutrophil migration. Whatever their mode of action, tetracycline, metronidazole or erythromycin improve and even cure most of the patients2, 57, 58. When the disease is refractory to the above regimen, thalidomide may be considered 59; however, colchicine may be a more rational approach in the cases that are not associated with infections 60.

BEHCET’S DISEASE is a chronic, multiorgan, inflammatory vasculitic process that dermatologists are quite often asked to diagnose and manage . The most common clinical finding, recurrent aphthous stomatitis, is accompanied or followed by genital aphthous ulceratious, aseptic skin pustules and/or erythema nodosum, and specifically by uveitis, cerebrospinal. fluid pleocytosis and meningoencephalitis or angriographically proved angiitis.

In acute vasculitic phases affecting more than just mucocutaneous sites, prednisone is administered to rapidly rgduce the inflammation. Corticosteroid treatment plus alkylating agents are also indicated when large vessel arteritis appears61. Since sudden death from arterial disease may occur in steroid monotherapy, 80 mg of aspirin daily are simultaneously used to prevent thromboses62.

As soon as the acute inflammatory phase subsides, corticosteroids should be lowered to maintenance dose. Ocular and neurological lesions do not signigicantly respond to prednisone61, so that other regimens are proposed. Dapsone is usually effective in maintaining the suppression of the disease63, but colchicine is the drug of choice and administered in doses of 0. 6 mg two to three times daily, is preferred to azathioprine or methotrexate for the treatment of mucocutaneous lesions64.

Ocular and extraocular manifestations of Behcet's disease may be controlled by azathioprine in doses of 2.5mg/kg/day65. Chlorambucil in doses of O.1mg/kg/day is considered as the drug of choice when postezior uvatis for meningoencephalitis occur66. When the condition is under control, a decrease to 2-4 mg daily is usually required for several years to maintain remission and finally the disease seems to enter an inactive phase. Neutropenia, sterility and leucemic hazard are the major drawbacks of therapy with chlozambucil, especially when high doses. are administered. Because of these side effects, some authors suggest oral prednisone and azathioprine be used first67. When chlorambucil is not effective or tolerated, cyclosporine, a cyclic undecapeptide that suppresses T helper/inducer lymphocytes, is administered in doses of 5-6 mg/kg/day61. Although this regimen is considered especially efficacious for ocular attacks and acting rapidly an eye and neurological signs, prompt disease exacerbation follows the interruption of cyclosporine61, 68.

SWEET'S SYNDROME

Acute febrile neutro hilic dermat sis is characterized by one or more plum-coloured, painful nodules with a "mountain" relief pattern, appearing in an acutely ill patient (Fig. 3). Cortic'osteroids in doses of 30-80 mg daily relieve from the constitutional symptoms and hasten the resolution of skin lesions; treatment must continue for several days because a rapid decrease to a level below 10-15 mg/day is usually followed by a disease recurrence69.

Alternative treatment modalities for this self-limited but recurring disease have been reported with: Potassium iodide70, indomethacine71, dapsone72, colchicine73, oral isotretinoin74 and tetracycline75.

PYODERMA GANGRENOSUM is a condition manifested initially by non- specific, usually pustural cutaneous lesions, and later by the characteristic superficial bullous or necrotic and ulcerative, non infective lesions with the raised, paiful, undermined, bluish edge that spreads slowly peripherally to leave a cribriform atrophic scar (Fig.4). When the disease is extensive and a high rate of activity exists, high oral ( 1-3 mgl kg/day)76 or intravenously administered corticosteroids are required. The pulse methylprednisolone therapy in "bolus" of 750 mg - 1 gr in 150 ml of 5 % dextrose, as an infusion of one hour for 3 to 5 days, arrests the progression of the disease but carries the hazards of electrolyte imbalances and cardiac arrythmias 77.

Salazopyrine in doses of 4 - 6 gr daily78 and dapsone79 (100 - 300 mg/day) may benefit the less acute forms of the disease or be ,used as an adjunctive to corticosteroids therapy. The results obtained with dapsone in an uncontrolled series of our patients were excellent and maintenance treatment with low doses (25-75 mg/day) seemed to keep the disease permanently suppressed.

Clofazimine in doses of 200-400 mg1 and cyclosporine in doses of 5-10 mg/kg/day for several months 80, may improve same patients unresponsive to conventional therapy. Azathioprine81 or cyclophosphamide may be used as a monotherapy or as a steroid sparing agent, when corticosteroids are reduced after the initial suppression of the disease82. Sometimes a combined regimen of oral steroids, oral chlorambucil 2 gm/day and pulse methylprednisolone 1 gm/daily may be required83 or an experimentally immunosuppressive Ágent, FK 506, may be tried in recalcitrant disease84.

When the course of the disease is subacute, minocycline 100 mg b.i.d. is indicated85. Topical antiseptic measures are a regular adjuvant but aggressive debridement may flare the lesions. Since pyoderma gangrenosum is associated, at a percentage of almost 80%, with other conditions such as rheumatoid arthritis, ulcerative colitis and Crohn' s disease, it is rationale to manage the underlying disorder and expect the cutaneous lesions to improve1.

RELAPSING POLYCHONDRITIS is a clinical complex expressed by multiorganic cartilaginous involvement, especially auricular, with characteristic sparing of ear lobule, nasal, with a saddle nose, and laryngotracheal cartilage, airway with an obstruction. Clinically heterogenous cutaneous lesions may appear in 25%, and biopsy proved leukocytociastic vasculitis is found in 5 -14% of patients.

The disease is very rare and consequently treatment formulations are lacking. Nonsteroidal anti-inflammatory drugs are claimed as efficacious; however, the disease usually has a poor prognosis and aggressive therapy especially with corticosteroids is indicated86, 87. Combined regimen with dapsone, oral prednisone and cytoxic drugs may at times be required; when administration of systemic steroids is not allowed, dapsone (100 - 200 mg/day) together with colchicine (1mg/day), chloroquine (500 mg/day) and a non steroidal antiinflammatory agent may prove useful88.

COGAN'S SYNDROME is a very rare condition manifested by interstitial, non syphilitic Keratitis, audiovestibular symptoms and constitutional non specific findings in a teenager or young adult. Special topical measures for the cutaneous lesions, that appear in 10% of patients and are polymorphous, are usually not required; ophthalmologic signs however may necessitate topical glucocorticoids.

Systemic steroids (1 - 2 mg/Kg/day) is the mainstay of treatment and are indicated for vertigo, vomiting, ataxia, tinnitus and for the prevention of deafness89. The serious manifestations of systemic vasculitis and aortic insufficiency may be life threatening and immunosuppressive drugs (cyclophosphamide, azathio-prine, cyclosporine) combined with corticosteroids may be tried in recalcitrant cases90.

ERYTHEMA ELEVATUM DIUTINUM with the characteristic, symmetrical, asymptomatic, deep purple papular lessons on the extensor surfaces of forearms, hands and fingers, is very rare and very difficult to manage. Daspone in doses over 100 mg/day is the treatment of choice but prompt recurrences follow its interruption91. Niacinamide has been reported to suppress the disease92. Corticosteroids are not effective; however, 20mg/day of oral prednisone combined with 100mg/day of cyclophosphamide cured a patient who concomitantly sufferedfrom polychondritis93.

GRANULOMA FACIALE

As soon as the diagnosis is made by the clinical appearance of persistent, asymptomatic, reddish facial modules with exaggerated follicular openings (fig.5) and the histological picture of granulomatous and leukocytoclastic vasculitis, an informatin to the patients about the bening though chronic nature of the disease must follow. The resistance of the disease to therapy is notorious. Surgical excision and dermabrasion may be considered, but recurrences or appearance of new lesions nearby, are usual. Intralesional triamcinolone or cryotherapy may help some patients94. Dapsone has repeatedly been reported as efficacious94, 95, but two of our patients failed to respond to moderate doses of the drug. Clofazimine 300mg/daily for three months, improved the lesions in one patient and no recurrence was reported after a 15- month follow-up96. Electrocoagulation, C02 or Argon Laser therapy may temporarily ameliorate some patients97. For these reasons, a therapy is usually proposed.

MALIGNANT ATROPHIC PAPULOSIS (DEGO'S DISEASE) is a very rare, “lethal cutaneous and gastrointestinal arterioral thrombotic” syndrome characterized by asymptomatic papules with porcelain white center and livid, telangiectatic border, associated with abdominal cramps and vomiting.

There is no effective treatment. Phenylbutazone has been claimed as inducing a remission and anticoagulants may alter the progression of the disease. Aspirin 500mg twice daily and dipyridamole 50mg three times daily, seemed to improve some patients99 but did not help others.

POLYARTERITIS NODOSA (PAN)

True segmental panmural necrotizing vasculitis, mainly of small and medium sized muscural arteries, comprise the pathologic spectrum of the disease that is clinically characterized by general symptoms - fever, fatigue, weight loss - and multiorgan - especially renal, arthritic, peripheral nerve and gut -involvement; since nodules are nowadays exceptionally found, the term "nodosa" may be omitt.ed from the head title of the disease .

Oral Prednisone in a single or divided daily doses ranging from 40-60 mg and in the severe cases 60-120mg, is considered as the most appropriate management of the disease100, 101. As soon as the clinical status improves and erythrocyte sedimentation rate returns to normal, a reduction of 5-lOmg every one to two weeks is instructed. When a level of l5mg per day is reahed, the tapering of prednisone is much more slower at the rate of 1mg every several weeks. Even at this low dose maintenance therapy, alternate-day prednisone administration is not encouraged, because of the high probability of disease exacerbation100.

Cytotoxic drugs may be used for their steroid-sparing effect and in the particular cases the disease is progressing despite the high doses of corticosteroids. Cyclophosphamide in oral doses of l-2mg/kg/day is preferred to azathioprine, mainly because of its rapid onset of action101. lytopenia, gonadal dysfunction, secondary maligiancy and bladder toxicity may appear however as potential side effects of cyclo-phosphamide : it has been reported that 15 % of patients suffer from hemorrhagic cystitis after an average time of 38 months and ingestion of 101gr of the drugl02; bladder carcinoma seems to occur in 3% of patientsl02 while the concomitant use of cyclophosphamide and prednisone exceeding l5mg/day predispose to systemic life-threatening infectionl03.

Therefore, azathioprine may be selected, especially when the condition of the patient permits a delay of some months for the drug to exert its full action. Some authors believe that cytotoxic drugs shall be reduced together with the prednisone, because their hematologic toxic effects increase when the latter is tapered101. However, the cytotoxic action on white cell lineage already exists, and is simply unveiled at the time the corticosteroids are decreased and their enchancing, compensatory to neutrophils action is diminished. On the other hand, neutropenia is not a prerequisite for cytutoxic drugs to induce systemic or opportunistic infections104.

Glucocorticoids, though considered the drug of choise for PAN, may actually promote the process of vascular occlusion100. This may be explained by the differential action of steroids to prostaglandin formation by endothelial cells and platelets: A glucocorticoid - cellular cytoplasmic receptor complex, stimulates the cell nucleus to produce an inhibitory protein, lipocortin, which results in the inhibition of prostacyclin, leucotrienes and thromboxane;on the opposite, platelet lack nucleus and platelet thromboxane formation may be unaffected by glucocorticoids, thus permitting platelet aggregation and release of substances that cause vasospasm, further clot formation and finally progressive vascular occlusion. Therefore, it is a rational approach to administer concomitantly steroids and antiplatelet drugs, at least for the prevention and treatment of late complication of  PAN such as renal vascular hypertension, cerebral vascular and coronary artery disease100. Plasma exchange and pulse methylprednisolone have been advocated as efficacious, but the first carries the risk of rebound phenomenon and the second seems not superior to oral prednisone. Dapsone may occasionally help some patients105 and calcium channel blockers may probably be beneficial for others100.

MICROSCOPIC POLYARTERITIS is a systemic arteriolar vasculitis that primarily involves the Kidneys and occasionally necessitates the consultation of a dermatologist: skin lesions appearing in 30-40% of cases with the form of purpura, splinter hemorrhages and mainly esccharrotic leg ulcers, are usually combined with manifestations from other systems (microscopic hematuria, proteinuria, articular and neurologic signs), cutaneous leukocytoclastic vasculitis and specific antimyeloperoxidase antibodies. In a recent case report, azathioprine was proved superior to other treatment madalities106.

CUTANEOUS OLYARTERITIS NODOSA ( Livedo with modules )

The absence of general symtoms and the appearance of small, painful, subcutaneous, leg nodules that quickly regress so that they hardly are noticed by the physician, together with the presence of a "star-burst" appearing livedo, constitute the clinical spectrum of Cutaneous Polyarteritis nodosa. Since the purely cutaneous form represent only a small minority of 11 cases of PAN, the physician should proceed with caution to its management107. Indomethacin, aspirin, sulfapyridine, nicotinic acid, stanozolol may be used108; of critical importance however, for the decisian of further therapy remain the follow-up of the course of the disease, usually lasting a few months, and the evaluation for systemic involvement or other significant systemic disease.

Corticosterids in high dosages are usually required. Painful, resistnt ulcers are reported as responding to azathioprine109. Oral methotrexate, in doses of 5-20mg/weekly, dramatically improves the condition of some patients110.

 

Sneddon's Syndrome appearing with extensive livedo reticularis, cerebrovascular accidents and labile hypertension in young females, needs supportive and symptomatic therapeutic measures when it is associated with antiphospholipid antibodies, it may be considered as a subset of Antiphospholipid Syndrome112 and an analogous management be followed.

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

This syndrome represents a constellation of clinical signs and serologic findings: Recurrent venous and arterial thromboses, recurrent fetal loss and thrombocytopenia are associated with a raised IgG anticardiolipin antibody, or a Lupus anticoagulant test, to at least two occasions more than 8 weeks apart; at least one clinical feature and one serologic finding are required for the syndrome to be established113.

Dermatologists' advice is usually asked in front of a positive VDRL reaction and/or cutaneous lesions, that are present in 25 % of patients, in the form of gangrene, thrombophlebitis, hemorrhage, necrosis and mainly livedo reticularis and ulcers114. The management of the syndrome is a matter of controversy and personal decision; some general measures are cited below.

When anticardiolipin (ACL) or Lupus anticoagulant (LA) antibodies exist without cˇĂnical signs, the patient should better be observed regularly; when mild clinical ar even thrombotic events appear, one aspirin tab per day may suffice; when active or recurrent thrombotic lesions exist, anticaagulant therapy with heparin and, later, warfarin are indicated. Corticosteroid therapy is beneficial in cases of an ongoing systemic inflammation, expressed clinically and paraclinically with elevated sedimentation rate, a polyclonal gammopathy and anemia113.

Despite the side effect of corticosteroid therapy, an oral prednisone in doses up to 60 mg/day plus aspirin (75mg/day) offer successful outcome with live birhts in women with the syndrome, recurrent fetal loss and history of Lupus erythematosus115. Intravenous gamma globulin has been reported as efficacious for successful pregnancy outcome116, and this treatment modality seems promising for the near future. Some fruste forms of the syndrome presenting clinically with only cutaneous lesions of painful, ulcerating nodules, respond to alternate-day doses of prednisone117.

KAWASAKI SYNDROME also known as "mucocutaneous lymph node syndrome", is an acute systemic vasculitis that regresses without sequelae in 75-80% of children; however, serious complications including coronary aneyrysms, thrombosis and even death may be the final outcome in one fourth of patients.

Early diagnosis is mandatory because therapy is most efficacious when started within the first 10 days from the onset of illness: Aspirin, 80 to 100 mg/kg/day in four divided doses, are given with intravenously administered Ş-globulin, in a single dose of 2 grams/kg, in 10-12 hour infusion. On the fourteenth day of illness, aspirin is reduced in a single daily dose of 3-5 mg/kg and is interrupted at the sixth week from the onset of the disease, if no coronary artery abnormalities are detected by echocardiography118.

The antiinflammatory and antithrobotic effect of aspirin is well known. The mechanism of action of intravenous Ş-globulin is not clear. Blockade of the immunologic activation and/or of the inflammatory response directed at vascular surfaces, or saturation of Fc receptors on platelets or reticuloendothelial cells or simply an immunoregulatory effect are the plausible theories regarding the action of y-globulin119.

The echo - and ECG examinations should be made at least once weekly for the acute, subacute and convalescent phases of the disease until one month after the erythrocyte sedimentation rate returns to normal. If the results remain normal, ECG may be repeated every year thereafter.

GRANULOMATOUS VASCULITIS

WEGENER'S GRANULOMATOSIS (WG) is a necrotizing granulomatous angiitis that presents the classic ELK triad of ear, nose, throat (E) , lung (L) and kidney (K) involvement; its rapid and usually fatal outcome make the early recognition - before irreversitive organ involvement occurs - mandatory.

The clinical and laboratory evaluation of the patient determines the therapeutic approach. It is of critical importance to trace the early signs and symptoms of the "transformation" of a "limited" form to systemic disease: Joint, eye and especially skin involvement with extension of necrotic and ulcerative lesions, are associated with general symptoms such as weight loss, malaise and fever120. Paraclinical signs such as erythrocyte sedimentation rate, C-reactive protein and titer of c-ANCA (cytoplasmic - antineutrophil cytoplasmic antibodies)121 determine the activity of the disease.

When the disease is limited to the upper and/or lower respiratory tract, and the progression is slow, trimethoprim-sulfamethoxazole 160-180 mg b.i.d. is administered122. The vast majority of the patients respond to this regimen within 2 to 8 weeks. Since discontinuation of the drug may lead to disease relapse, low dose maintenance therapy is proposed122, 123.

When the progression of the disease is moderate, or slow with systemic involvement except kidney, oral prednisone 1mg/kg/day is added to the above regimen120. When the kidney is involved, the prognosis is poor and aggressive immunosuppressive therapy is instructed; the same management is indicated in case of rapid disease progression: Oral prednisone 1mg/kg/day plus cyclophosphamide 2mg/kglday constitute the most acceptable therapeutic regimenl24. Trimethoprim-sulfamethoxazole may be added at a later stage . The risk of opportunistic infections that is especially significant in WG1O4, may be lessened by a different treatment schedule, permitting the introduction of cyclophosphamide only at a later stage, when the dose of prednisone is decreased120. However, occasionally concomitant oral and even intravenous bolus administration of cyclophosphamide (0.5-1.0 g/m2, one dose/month) may be required if the disease progression is not halted by oral regimenl25.

Methotreatel26, chlorambucill27 or azathioprinel28 have been claimed as effective. Surgical interventions to eorrect or improve deformations provoked by the disease, may be managed by an otolaryngologist or plastic surgeon120.

CHURG - STRAUSS SYNDROME, also called the syndrome of "allergic granulomatosis and angiitis", differs from WG in that a) it is associated with a history of atopy, asthma, eosinophilia and much less likelyhood of renal damage, and b) it responds favourably to corticosteroid monotherapy129.

However, a recent report describes the inefficacy of 60mg daily of prednisone and the dramatic response of clinical, biochemic and hematologic manifestations to intravenous pulse cyclophosphamide, 750mg/m2 of body surface area130.

Some authors recommend pulse methylprednisolone as the first therapeutic choise131. Others, prefer simultaneous treatment with prednisone 60-l0Omg/day and cyclophosphamide to reduce or prevent irreversible major organ damage132. Chlorambucil and plasma exchange may occasionally be added133.

LYMPHOMATOID GRANULOMATOSIS is presented here because many classic textbooks of dermatology describe the condition under the title of Granulomatous Vasculitides. Nevertheless, the disease is considered a lymphoproliferative rather than granulomatous or vasculitic process120. The cutaneous lesions are protean, usually nodular, appear in 50 % of the patients and usually clear spontaneously. A combined therapy with prednisone 1mg/kg on alternate days plus cyclophosphamide (2mg/kg/day) may significantly improve the prognosis and, even prevent from the development of lymphoma134.

CUTANEOUS GRANULOMATOUS VASCULITIS is expressed clinically by nodules, papules or plaques, and corresponds to systemic granulomatosis in 20% of patients; the rest cases are associated with lymphoproliferative, autoimmune or inflammatory disorders. Management of the underlying disease, namely of the commonly encountered Rheumatoid arthritis and inflammatory bowel disease, influence the final prognosis. Prednisone may be administered in those patients who do not suffer from lymphoproliferative disorders135.

LARGE VESSEL ARTERITIS

TAKAYASU' S ARTERITIS This is an uncommon chronic vasculitis affecting primarily the aorta and its main branches. Corticosteroids in doses of 0.5 to 1.0 mg/kg/day improve the inflammatory manifestations of the disease, such as fever, arthritis and myocarditis136. In addition, they ameliorate the hemodynamic problems and lead to impressive favourable results such as the return of absent pulses and regression of carotid stenoses, after a therapy of several months. There are however some patients who do not respond to steroids and require cyclophosphamide for their treatment137.

In most cases, corticosteroids may be discontinued after a period of two years or so. The normalization of erythrocyte sedĂmentation rate and the adequate control of inflammation, are the cardinal indicators for the decision of drug interruption and initiation of surgical Vascular reconstruction138.

GIANT CELL TEMPORAL ARTERITIS, also known as Horton's disease, is a systemic vasculitis appearing usually in an elderly person with slowly deteriorating constitutional symptomatology of fever, unexplained increase of erythrocyte sedimentation rate, headache and jaw claudication, together with tenderness or decreased pulsation of the temporal arteries.

Corticosteroids are the mainstay, of therapy. Oral prednisone, 40-60 mg/day, is administered for a month and is followed by a reduction to the lowest possible dosage. Maintenance dose of 2.5 to 20 mg daily may be required for at least 24 months139; a dose of 5-7.5 mg/kg/day can be attained after a few months and in the majority of cases no therapy is required after one yearl40. The decision for a more or less rapid decrease of prednisone depends on the clinical course, the level of erythrocyte sedimentation rate and the age of the patient; side effects are significantly related to the cumulative dose of prednisone and the major complications are noted in those with a higher mean age141.

Adjuvant administration of azathioprine or cyclophosphamide seem efficacious but in uncontrolled series of patients140. Dapsone, in doses of 75-100 mg daily, is recommended at least as a steroid sparing agent142. Whatever the mode of therapy, physician must have in mind that giant-cell arteritis tends to subside on its own, and therefore is in need for aggressive treatment, at least after the time the risk of blindness passes away.

THROMBOANGIITIS OBLITERANS (BUERGER'S DISEASE) is an occlusive vasculitis of medium and small sized distal vessels of arms and legs. Dermatologists are increasingly facing with this disorder, by examining young to middle aged male patients with gangrene and ulceration, rubor, cold sensitivity, dysesthesias or rest pain of the toes and fingers .

The universal knowledge that the disease and its exacerbations occur in heavy smokers necessitate the complete abstinence from tobacco. Antibiotics are given in case of infection or superficial thrombophlebitis143. Anticoagulants, vasodilators, non steroidal antiinflammatory drugs, vascular by pass surgery do not help the patients144. Avoidance of trauma and of exposure to cold are beneficial145. Sympathectomy a may help some patients by reducing symptomatology and healing the ulcers143. Intraarterial of intravenous infusion of prostaglandin E1 (PGE1) may heal trophic ulcers144. Amputation is advised when gangrene exists for a period exceeding 2-3 weeks. As a whole, the guidelines followed for atherosclerosis are also applied in Buerger' s disease . It is conceivable that the term "Vasculitic syndromes" can be expanded by the inclusian of several, so far unclassified conditions that exhibit an histological relationship to vessels; in this case, the Chapter dedicated to their management would seem almost endless and this is not the scope of the writer. There are however some unclassified vasculitides that complicate systemic disease and merritt special care: The cutaneous gangrene that appears as a complication of chronic colitis, responds to corticosteroids rather than anticoagulants when it is attributed to thrombosis146, and cyclophosphamide when circulating cryoglobulins are the cause147. The cutaneous vasculitis specific to HIV infection, usually observed in stages II and III, clearly improves after oral zidovudine administration148.

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Dr George Ch. Chaidemenos

Dermatologist

State Hospital for Skin and Venereal Diseases, Thessaloniki, Greece