Are You Confident of the Diagnosis?
What to be alert for in the history
Vasculitis in the skin may follow a variety of illnesses such as infection, result from a drug sensitivity, represent a manifestation of a systemic illness or connective tissue disease, develop in malignancy or from other causes. Nonspecific or non-localizing antecedent illnesses may also be seen. A large number of patients (30% to 40%) have no preceding illness of consequence.
Characteristic findings on physical examination
Characteristic findings on physical examination most often are those of palpable purpura. The preferred location is in the lower extremities, especially about the ankles/dorsal feet and lower legs (Figure 1). The thighs, buttocks and upper extremities can be involved at times and less often the truncal areas in descending frequency. In general, dependent areas are more prone to develop skin lesions. Occasionally lesions may develop in areas of antecedent trauma or inflammation.
The patient often complains of burning or stinging in the skin lesions. Lower extremity edema may accompany or precede skin lesions. Ulceration can develop in more severe cases in the day or two after onset of clinical lesions. Neuropathic symptoms may also develop in more severe cases. Joint discomfort is not uncommon.
Expected results of diagnostic studies
The diagnosis requires the correlation of clinical findings together with a characteristic biopsy of a lesion of less than 3 days’ duration. The biopsy shows a combination of findings including inflammation in and through the blood vessel wall with spilling of inflammatory cells, mainly polymorphonuclear cells, into the the surrounding dermis along with red blood cell extravasation (leukocytoclastic vasculitis). Occasionally eosinophils are seen as well as lymphocytes and histiocytes (Figure 2).
Blood tests may be unremarkable in those patients with purely cutaneous vasculitis or there may be a slight elevation of the sedimentation rate. Most often patients are not highly febrile (<39° C) on presentation. Other tests may or may not be abnormal depending on the underlying cause of the process.
Diagnosis confirmation requires clinical and pathlogic correlation. Infection should always be considered in the differential diagnosis and appropriate workup and cultures may be needed. Examples include Rocky Mountain Spotted Fever or gonococcemia. Chronic hepatitis, particularly hepatitis C, can lead to vasculitis through formation of mixed cryoglobulins.
Henoch-Schonlein purpura (HSP) is a special subset of cutaneous vasculitis that often follows an upper respiratory infection and may be seen more often in the fall and early spring. Symptoms may include joint pain and abdominal pain and occasionally peripheral edema of the feet and occasionally scrotum. Biopsy for direct immunofluorescence (DIF) from a fresh lesion or just perilesional may help confirm the diagnosis of HSP by the demonstration of IgA immune complexes in the capillaries.
Renal disease is a possible consequence and evaluation for microscopic hematuria and proteinuria is always required. Renal dysfunction may follow the skin lesions by days or even weeks. Cutaneous vasculitis may also be the presentation for a systemic vascultis such as Wegener’s granulomatosis. In patients with lesions of a more urticarial quality but resolution over days and leaving a purpuric resdual, urticarial vasculitis (UV) is a consideration in the differential diagnosis.
Some patients with lupus erythematosus or connective tissue disease may present with urticarial vasculitis or with leukocytoclastic vasculitis. Biopsy for DIF is also helpful in these cases to confirm likelihood of lupus by granular basement membrane zone fluorescence. A thorough review of systems, careful medication review and examination are always warranted in vasculitis patients to rule out an underlying disorder.
Who is at Risk for Developing this Disease?
Cutaneous vasculitis is seen in all ages and both genders. It is more common in adults except for HSP, which is more common in children.
What is the Cause of the Disease?
Etiology of cutaneous vasculitis is related to the generation of immune complexes by various antigenic stimulants including medications, drugs, infection, tumor or others.
The pathophysiology of cutaneous vasculitis is thought to revolve around the actual deposition of immune complexes in blood vessels at risk in the skin. Blood vessels in the skin involved are most often in areas of slower flow and lower volume such as the capillaries and postcapillary venules. Other factors such as vasodilation or cooler temperatures may enhance immune complex deposition and influx of inflammatory cells and in turn efflux of red blood cells into the surrounding dermis.
Generation of cytokines and chemokines including tumor necrosis factor-alpha, interferon-gamma, interleukin-1, 4, 8 and others result in amplification of the inflammation. There may be direct damage to vessels by degranulation of eosinophils and polymorphonuclear cells. As a consequence, there is enhanced endothelial adhesion and local coagulation. Other immunologic responses include activation of lymphocytes, dermal dendrocytes and Langerhan cells. Eventually angiogenesis is stimulated as part of the healing response.
Systemic Implications and Complications
At least one third of patients will have no known or associated disorder.
Causes include drug reactions, infections including hepatitis, Streptococcus and other bacteria, infections of the urinary tract or prostate, upper respiratory tract and sinuses, solid tumors and hematologic malignancies, systemic inflammatory disorders such as Crohn’s disease, connective tissue diseases such as rheumatoid arthritis or lupus erythematosus and systemic vasculitis including Wegener’s granulomatosis or other antineutrophil-associated (ANCA) vasculitides.
A careful history and basic physical examination is essential including vital signs and blood pressure. Ask about any new medications. Screening tests should include complete blood count, erythrocyte sedimentation rate or C-reactive protein, urinalysis, creatinine, chest x-ray, liver function tests, stool guaiac, appropriate infectious disease workup depending on the history and examination. Confirmation is most often accomplished by skin biopsy and routine microscopy, Biopsy for DIF is very helpful if HSP, lupus or cryoglobulinemia are suspected or need to be ruled out.
Patients with hematuria or abnormal renal function as measured by creatinine or with acute onset of hypertension should be seen by a nephrologist.
Mild cases of cutaneous vasculitis without any associated disease may not require therapy and will resolve in a matter of days to weeks. If an underlying cause has likely been identified or is strongly suspected, then removal of that cause as much as possible is recommended, including stopping offending drugs, treating underlying infection, removal of tumor, etc.
Non-steroidal anti-inflammatory drugs may be of help in relieving skin discomfort or joint discomfort in milder cases with no associated disease. but I also use naproxen and ibuprofen as well in the recommended doses. Indomethacin has been utilized particularly for patients with more urticarial lesions with vasculitis but can be used in uncomplicated leukocytoclastic vasculitis as well, starting at 25mg per day and working up to 75mg/day as needed or as tolerated. Other alternatives for milder disease include naproxen or ibuprofen used in the recommended over-the-counter dosages.
For cases requiring additional treatment:
Colchicine may be a good option. Dose can start at 0.6mg/day and increased to 1.8mg/day (adults) as needed or as tolerated.
Dapsone is an often-used option for those with cutaneous disease. Dose range varies from 50mg/day to 150mg/day in adults.Standard precautions should be followed including a screening G6PD test, starting at a lower dose (25 to 50mg/day for adults) and frequent (weekly until target dose, then monthly for 3 months and eventually quarterly for maintenance). CBC is recommended. Reticulocyte counts or the methemoglobin need not be checked unless there is a problem with the Hgb dropping significantly (>1 to 2g).
Plaquenil may be of value in patients not responding to dapsone or colchicine or intolerant of those medications. Standard dose of 200 to 400mg/day (adults) is used; baseline eye examination and periodic eye (retinal) examinations (approximately yearly) are recommended.
Prednisone is still the most often used drug for those patients with more symptoms or more severe cutaneous disease. Dose is typically 0.5 to 1.0mg/kg/day until the skin improves and then slowly tapered over several weeks to months.
Azathioprine may be used as a solitary treatment or as a steroid-sparing drug in those patients requiring ongoing therapy after trials at steroid taper are not successful. Dose is most often 50 to 200mg/day (adults). A baseline thiopurine methyltransferase (TPMT) enzyme activity level is recommended as well as periodic following of CBC and liver function tests.
Mycophenolate mofetil is a good choice for patients requiring additional therapy above prednisone or in those where prednisone cannot be tapered. The adult dose is most often 500 to 2500mg/day divided twice daily.
Methotrexate has been reported to be effective as a steroid-sparing agent in some cases but is not used as often as azathioprine. Dose can range from 5 to 25mg/week. Adding folic acid 1mg/day is recommended as long as the patient remains on methotrexate.
Cyclosporin has been effective in patients either intolerant of prednisone or in those in whom prednisone cannot be used. It is used most often in the early state of disease and is tapered in weeks. Dose range in adults is 2.5 to 5mg/kg/day divided twice daily.
Intravenous immune globulin (IVIG) has been used in selected cases where the disease is severe and where infection or immune deficiency may be present. Precautions in the use of IVIG include checking for IGA deficiencies and making sure renal function is normal or infusion adjusted appropriately.
Plasmapheresis has been used in severe cases refractory to other treatments and in HSP and ANCA-associated vasculitis. Exchanges can vary from 2 to 3 up to 7 depending on response. This treatment is usually reserved for patients with more severe renal disease and may help restore renal function. It is almost always combined with other more standard therapies above.
Rituximab (375mg/m2) may be of value in severe cases and in cases associated with systemic vasculitides such as Wegener’s granulomatosis. It has been administered up to this point mainly as part of trials.
Hyperbaric oxygen (HBOT) is helpful in cases with refractory ulcers or infection—most often 20 to 30 treatments administered at 1.5 to 2.4 atmospheres (ATM) given daily or 5 days per week.
Optimal Therapeutic Approach for this Disease
Therapeutic decisions must be based on the results of a thorough investigation and workup. Those patients with purely cutaneous disease may not require systemic therapy beyond supportive care or over-the-counter nonsteroidal anti-inflammatory drugs. Topical care with corticosteroids such as triamcinolone cream 0.01% and wet compresses may have a role in mild uncomplicated disease.
Colchicine or dapsone are often used in cases that are mild, uncomplicated by systemic disease or in cases where a prednisone-sparing drug is needed.
Prednisone is a long-used drug for vasculitis and is inexpensive with a well known side effect profile. When used alone for several weeks, it is often well tolerated and not likely to generate signficant long-term side effects. Its effectiveness in some subsets of vasculitis such as HSP is not certain, but it is still a mainstay of therapy for vasculitis.
If cutaneous lesions develop with taper, consideration can be given to use of steroid sparing drugs inlcuding colchicine and dapsone.
Antimalarial therapy is not as reliable in inducing remission but can be used in patients with more of an urticarial subset of vasculitis or in those with connective tissue disease, such as lupus. It can be used alone or in combination with prednisone.
Cyclosporin is another option to use in the short term for patients requiring additional therapy above prednisone or in those patients where prednisone cannot be used without increased risk.
Azathioprine and mycophenolate mofetil are most often used in combination with prednisone in patients with more severe disease and can be continued for several months if need be. Their use may allow for tapering of the prednisone without reflare of the vasculitis. If it appears that long-term immunosuppressive therpay is needed, baseline negative PPD should be present and other tests such as quantiferon-gold can be done in those patients who have had BCG vaccination or in those in whom there is a question as to positivity of the PPD. Pneumocystis prophylaxis can be considered in those who are not allergic to sulfa or pentamidine.
Final decision about prophylaxis varies depending on other risk factors such as medication sensitivities, anticipated duration of immunosuppression and other co-morbidities.
Methotrexate does not have as long a track record as azathioprine or mycophenolate mofetil but could be considered if the two steroid-sparing agents are not effective or if methotrexate may have additional benefits, such as improvement of joint inflammation in arthritis.
IVIG is reserved for patients with severe or refractory disease or those with infection. It is very expensive and is not often used.
Plasmapheresis is another option used most often in those patients with other systemic involvement, such as renal involvment in HSP. It is also very expensive.
Hyperbaric oxygen may play a role in patients with severe ulcerations as a consequence of vasculitis. It requires many treatments over a period of weeks and is very expensive.
Rituximab is a newer option used in patients with associated systemic disease unresponsive to therapies above. It likely has a role in the treatment of Wegener’s granulomatosis or ANCA-associated diseases. It is also very expensive.
Therapy and monitoring depends entirely on the severity and extent of disease as assessed by body surface involvement, presence of ulceration, pain, neuropathy, joint pain or other systemic symptoms. Expensive or immunosuppressive medications other than prednisone are often not required in skin-only vasculitis and a rush to use these medications with only cutaneous disese is not needed.
Monitoring depends upon the drugs used in therapy and the severity of disease. Some forms of vasculitis, such as HSP, are notoriously slow to respond and may take several weeks to months to reach maximum improvement. Other forms of vasculitis not associated with any systemic disease may respond in days to weeks. Response to treatment may be assessed initially in days and should include a reduction in new lesion formation, pain or neuropathy. Patients need to be followed closely and at least weekly until response is assured and then less often.
Changes in therapy depend upon response, lack of it or finding of other organ involvement, such as renal.
Unusual Clinical Scenarios to Consider in Patient Management
Patients who are otherwise healthy coming into an episode of cutaneous vasculitis most often will tolerate the disease as well as most any of the treatments discussed above. Special circumstances include the presence of diabetes or other immune-suppressing premorbid conditions such as chronic lymphocytic leukemia (CLL). In these diseases nonsteroidal options may be. HSP is also known to recur, and renal abnormalities may present weeks to months after the initial episode of cutaneous vasculitis. Therefore, special scrutiny of general health issues, including presence of malignancy and assessment of renal function, are appropriate especially in adults with chronic (months) or recurrent disease.
Lack of response or worsening of skin lesions should result in reassessment of not only the therapy but also a search for a possible antigenic stimulus or another complicating disease such as secondary infection. Increasing immunosuppression in the face of infection or tumor may further mask these conditions and result in added morbidity if not recognized promptly.
A rare form of cutaneous vasculitis in children is known as acute hemorrhagic edema (AHE) of infancy. Most consider AHE to be in the spectrum of IgA vasculitis but differentiated by the young age of patient (most often 2 years or less), characteristic urticarial-like skin lesions of the feet or legs and face and no systemic complications. As is true with HSP, it is preceded by a viral or bacterial illness, but renal disease is not seen and the course is self-limited.
What is the Evidence?
Gibson, LE. “Cutaneous vasculitis update”. Dermatologic Clinics. vol. 19. 2001. pp. 603-15. (A review of the clinical presentations of cutaneous vasculitis based primarily on clinical and pathologic correlation. Tests helpful in the diagnosis are discussed including immunofluorescence.)
Fiorentino, D. “Cutaneous vasculitis”. J Am Acad Dermatol. vol. 48. 2003. pp. 311-40. (A review of the clinical presentations of vasculitis in the skin including the associated illnesses and evaluation. Treatment is discussed and tabulated according to type of vasculitis and also annotated as to the degree of evidence supporting each therapeutic option.)
Russell, JP, Gibson, LE. “Primary cutaneous small-vessel vasculitis: approach to diagnosis and treatment”. Int J Dermatol. vol. 45. 2006. pp. 3-13. (A review of primarily cutaneous leukocytoclastic vasculitis where no systemic disease is associated. Evaluations starting with simpler, broader and cost-effective tests are presented and tabulated. Therapy is discussed and placed in a table with annotation as to costs and common side effects for each.)
Chen, K-R, Carlson, JA. “Clinical approach to cutaneous vasculitis”. Am J Clin Dermatol. vol. 9. 2008. pp. 71-92. (A comprehensive review of cutaneous vasculitis and the various subtypes including cutaneous polyarteritis nodosa, urticarial vasculitis and others. Emphasis is given on the clinical and pathologic aspects of each disease and the differential diagnoses.)
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