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Small-vessel vasculitis: A review and case report

Posted on March 31, 2017 | Comments Off on Small-vessel vasculitis: A review and case report

by Kinna A. Patel, DPM1*

The Foot and Ankle Online Journal 10 (1): 1

Small-vessel vasculitis is responsible for a wide variety of diseases that affect vascular structures such as venules, capillaries, arteries, and arterioles with classic inflammation. The inflammation, in turn, can damage the affected organ, which can lead to a wide variety of signs and symptoms. The most commonly affected organ is the skin.  There are many causes of vasculitis, and in recent years, diagnosis has substantially progressed due to the discovery of more pertinent labs, as well as the use of biopsy techniques.  This review of small-vessel vasculitis will also present a case in the lower extremity with biopsy and treatment.

Keywords Vasculitis, ulcer, small-vessel vasculitis, cutaneous vasculitis, purpura, leg ulcer

ISSN 1941-6806
doi: 10.3827/faoj.2017.1001.0001

Department of Podiatric Medicine and Surgery. West Palm Beach, Florida.
* – Corresponding author: Kinna@temple.edu

The first historical accounts of vasculitis are of small-vessel vasculitis, especially forms associated with purpura [1]. The Latin term vasculitis may have derived from the Greek porphyra, describing the color produced by a mollusk (purpura lapillus) [1]. Small-vessel vasculitis accounts for a wide range of diseases that affect venules, capillaries, arteries, and arterioles with classic inflammation. It is important to note that small-vessel vasculitis may affect arteries, and thus the vascular distribution overlaps with that of the medium-sized-vessel and large-vessel vasculitides [2].  Excess leukocytes within the vessels lead to a loss of structural integrity and possible destruction [3]. Clinical presentation may vary widely, depending on the organs affected. Generally, the only organ involved is the skin, but it is possible for systemic involvement to occur also. Skin lesions may represent the initial sign of a systemic vasculitis [4]. Cutaneous small-vessel vasculitis is characterized by a spectrum of cutaneous lesions, but palpable purpura is most common [4].  

The etiology of small-vessel vasculitis is unknown in many cases but may be due to primary diseases such as microscopic polyarteritis and connective tissue disorders. Lotti, et al., reported  that systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, and Behcet’s disease are some common primary causes. Secondary causes to an underlying disorder, such as drug reaction, post viral syndromes, infection (bacterial, fungal, protozoan, or helminths), or malignancy, were also reported [1,3]. In addition, patients with hyperglobulinemic states and cryoglobulinemia may have small-vessel vasculitis and, occasionally, it is associated with bowel bypass syndrome, ulcerative colitis, cystic fibrosis, primary biliary cirrhosis, and HIV [4].  Still, as in all forms of vasculitis, most cases of small-vessel vasculitis are idiopathic (45-54%), due to medications (10-45%), or infections (10-36%) [1]. Drug-induced vasculitis usually develops within 7 to 21 days after treatment begins 1. Medications most commonly associated with small vessel vasculitis are insulin, penicillins, aminopenicillins, sulfonamides, allopurinol, retinoids, quinolones, hydantoins, propylthiouracil, pyrazolones, and diuretics. Foods, such as gluten and milk proteins, and chemicals such as insecticides, should also be considered as a cause.  Lotti, et al., states that small-vessel vasculitis occurs equally in both sexes and at all ages, and approximately 10% of affected patients are children. It is important as a clinician to think outside the box in diagnosing.

Cutaneous vasculitis may present as purpura, erythema, urticaria, nodule, bullae, or skin infarction leading to ulceration [5]. In the beginning stages, all patients have purpura, but the lesions might not be palpable. According to Gamarra, et al., as the process continues, the lesions, which range in size from pinpoint to several centimeters, may become papulonodular, vesicular, bulbous, pustular, or ulcerated as superficial infarctions occur. Occasionally, subcutaneous edema in the area of the vascular lesions can be observed [1]. Lesions occur in stages and while they may appear in other areas, they predominantly appear in the legs and ankles [1]. Lesions may be mildly pruritic or painful and subside within 3 or 4 weeks, leaving residual hyperpigmentation or atrophic scars [1,4]. Patients may describe “flu-like” symptoms, such as fever, malaise, arthralgias, and myalgias, although presentation can vary greatly. Although most cases of vasculitis are self-limiting, 10% of patient are likely to have recurrence of symptoms with new crops of lesions appearing for months or years [1,2,4].  

Since cutaneous ulceration is usually caused by small-sized to medium-vessel vasculitis, it is important to obtain a complete list of differential diagnoses for your patient and take a thorough history and clinical exam. Further studies must be performed to diagnose your patient appropriately. Laboratory testing consisting of serum creatinine, liver function test, urinalysis, complete blood count, antibody testing [including antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA)], hepatitis B and C serologies, immunoglobulins, as well as radiographs, are helpful in achieving a diagnosis. The current gold standard for diagnosis of vasculitis is biopsy of the affected vessel. The histopathologic examination of the biopsy will reveal angiocentric segmental inflammation, fibrinoid necrosis, and a neutrophilic infiltrate around the blood vessel walls with erythrocyte extravasations.  A positive biopsy supports the diagnosis, while a negative one does not necessarily exclude it [1].

Case Report

A 41-year-old male with an unremarkable past medical history presented to clinic for extremely sensitive, painful lesions of his bilateral lower extremities for 4 weeks (Figure 1). The patient was not currently on any medications, nor were there any noticeable changes to his daily routine.

Figure 1 Initial presentation of patient with extremely sensitive, painful lesions of his bilateral lower extremities outstanding for the duration of 4 weeks.

Physical examination revealed palpable purpura with several non-blanchable, pinpoint, erythematous lesions of the bilateral upper and lower extremities, as well as the abdominal region (Figures 2, 3). Among the lower extremity lesions were hemorrhagic vesicles of varying sizes, as well as pustular lesions, with various stages of ulceration present ranging from 0.5 cm to as large as 2.0 cm with areas of necrosis (Figure 4).

Figure 2 The lesions of his lower extremities were ulcerated with purulent drainage.

Figure 3 Palpable purpura with several non-blanchable, pinpoint, erythematous lesions of the bilateral upper and lower extremities, as well as the abdominal region.

Figure 4 Lower extremity lesions, hemorrhagic vesicles of varying sizes, as well as pustular lesions with various stages of ulceration were present ranging in a plethora of sizes from 0.5 cm to as large as 2.0 cm with areas of necrosis present.

The patient had initially seen his primary care doctor and the lesions were locally treated with mupirocin 2% ointment and dry sterile dressings. At follow-up, only mild improvement was noted and extensive laboratory work was ordered by the primary care physician. The many tests ordered include; a liver function test, hepatitis panel, rheumatoid factor, antinuclear antibody, and complete blood count with differentials, and the patient was referred to our clinic with the results. In our clinic, radiographs were performed, which were negative for any significant related pathology, and the lab work was reviewed and noted to be unremarkable.

A 3-mm punch biopsy was performed on a non-ulcerative lesion and sent for pathology. Local wound care was continued. The biopsy results revealed “small and medium-sized vessel vasculitis” with sections demonstrating a mixed inflammatory infiltrate with a predominance of neutrophils centered within the deep reticular dermis. Small muscular vessels exhibit neutrophils within their walls in concert with fibrin extravasation. The etiology of his condition was unknown, and the patient was started on oral prednisone 50 mg, twice daily, and tapered accordingly. The patient continued to have local wound care performed and his signs and symptoms greatly improved at each follow-up appointment.

Results

When possible, identification and removal of the causative agent are an effective approach to treatment [4]. This is occasionally followed by rapid clearance of the skin lesions, and no other treatment is necessary [4]. In many patients, small-vessel vasculitis will have a relatively benign, self-limited course, especially if the disease is limited to the skin; however, for the patients with aggressive disease, it is imperative to begin the appropriate treatment quickly [2]. Topical therapy, such as antibiotic ointments and corticosteroid creams, as well as routine debridement and local wound care may prove helpful to the patient. If localized edema is present, gradient support stockings can help with symptoms as well. Systemic treatment can include, but not limited to, systemic corticosteroids, non-steroidal anti-inflammatory medications, colchicines, dapsone, potassium iodide, antihistamines, fibrinolytic agents, aminocaproic acid, immunosuppressive agents, and monoclonal antibodies [4]. In our case, systemic corticosteroids were chosen due to the significant cutaneous ulcerations. Rebound is a serious problem with rapid reduction of the medication dose; therefore, if this therapy is selected, the authors recommend a gradual taper over 3 to 6 weeks [4].  

Discussion

Small-vessel vasculitis can present itself in a variety of ways. It is important to obtain a thorough medical history and physical examination, as well as obtain a list of any pre-existing and new medications the patient may had started. Obtaining a thorough family history may help in diagnosing connective tissue disorders that the patient himself may not have been diagnosed with yet. Extensive laboratory testing is an essential key to diagnosing small-vessel vasculitis in addition to a biopsy, which is the gold standard. Biopsies should be performed within 24-48 hours after the appearance of a vasculitic lesion to prevent the pathological characteristics of vasculitis from being lost [3]. Once biopsy results are reviewed, appropriate therapy should be started. Therapeutic approach requires elimination of the cause (drugs, chemicals, infections, food allergens) when possible and in patients where the etiology is unknown, local and systemic therapy is recommended [4]. The goal should be neither to over-treat a mild disease nor to under-treat a severe disease [2].

References

  1. Gamarra A, Matteson E, Restrepo J. Small vessel vasculitis. Revista Colombiana De Reumatologia. 14(3):187-205, 2007.
  2. Jennette J, Falk R: Small-vessel vasculitis. The New England Journal of Medicine. 337(21):1512-1523, 1997.
  3. Wagoner M, Creech C, Vlahovic T, et al: Idiopathic mixed small and medium vessel cutaneous vasculitis: A case report. The Foot and Ankle Online Journal. 7(1):5, 2014.
  4. Lotti T, Ghersetish I, Comacchi C, Jorizzo J, et al: Cutaneous small-vessel vasculitis. Journal of the American Academy of Dermatology.39(5):1, 1998.
  5. Mekkes J, Loots M, Van der wal A, Bos J, et al: Causes, investigation and treatment of leg ulceration. British Journal of Dermatology. 148:388-401,2003.
  6. Brogan P, Eleftheriou D, Dillon M, et al: Small vessel vasculitis. Pediatr Nephrol. 25:1025-1035, 2010.

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Idiopathic mixed small and medium vessel cutaneous vasculitis: A case report

Posted on March 31, 2014 | Comments Off on Idiopathic mixed small and medium vessel cutaneous vasculitis: A case report

by Matthew R. Wagoner, DPM1, Corine L. Creech, DPM1, Tracey C. Vlahovic, DPM2pdflrg

The Foot and Ankle Online Journal 7 (1): 5

Vasculitis is a rare, inflammatory condition of the blood vessels whereby excess leukocytes within the vessel leads to a loss of structural integrity, and possible destruction. This family of disorders can lead to varying degrees of organ and skin damage. Vasculitis may be due to primary disease or secondary due to an underlying disorder, drug reaction, or infection. In a large number of cases cutaneous vasculitis may present as an idiopathic condition and affect both small and medium sized vessels. We present a case of small and medium-vessel vasculitis on the lower extremity with cutaneous manifestations, without an identifiable cause.

Key Words: Vasculitis, leukocytoclastic cutaneous vasculitis, polyarteritis nodosa

ISSN 1941-6806
doi: 10.3827/faoj.2014.0701.0005

Address correspondence to:Matthew Wagoner, DPM Temple University School of Podiatric Medicine 148 N. 8th Street, Philadelphia, PA 19108
E-mail: mwagoner@temple.edu

Vasculitis is an inflammatory condition of the blood vessels whereby excess leukocytes within the vessel leads to a loss of structural integrity, and possible destruction. Cutaneous vasculitis may present with varying clinical manifestations and may be caused by systemic disease or secondarily due to an underlying disorder, drug reaction, or infection [1-2]. While numerous etiologies have been reported, a number of cases are idiopathic. Clinical, histopathologic, and laboratory evaluation are imperative to appropriately diagnose cutaneous vasculitis. Once confirmed though biopsy, treatment should begin with symptomatic management and treatment of any underlying disorder or causative agent. In more severe cases immunomodulatory medications or steroids.

Case Report

A 64-year old male with a medical history significant for hypertension and hypercholesterolemia presented with a three-week history of multiple painful lesions to his bilateral lower extremities. Physical examination revealed several non-blanchable, erythematous lesions with hemorrhagic vesicles, areas of necrosis, and palpable purpura. Initial treatment by his primary care physician consisted of mupirocin and methylprednisolone with continued worsening of lesions. The patient reported that he had recently begun taking HCTZ, simvastatin, and metoprolol, but the lesions had started before the onset of these medications.

An extensive serologic evaluation was completed which included rheumatoid factor, antinuclear antibody, anti-DS DNA, cryoglobulin, complement levels, hepatitis panel, HIV and various other studies. All laboratory studies were unremarkable. A chest x-ray was performed which was negative. The patient also underwent evaluation by numerous other specialists including rheumatology, gastroenterology, and vascular surgery.

Figure 1 Figure 2 Figure 3 Figure 4

Figure 1-4 Clinical appearance of lower extremities at initial presentation.

Figure 5

Figure 5 Patients back at initial presentation.

Biopsies were obtained and sent for histopathologic examination and immunofluorescence. Histopathology confirmed cutaneous leukocytoclastic vasculitis. Direct immunofluorescence revealed medium vessel disease.

Figure 6

Figure 6 Histopathology Slides revealing leukocytoclastic vasculitis.

Figure 7

Figure 7 Direct immunofluorescence revealing medium-sized vessel disease.

At our institution, the patient was started on prednisone 50 mg BID, and tapered accordingly. Local wound care was also initiated and included intermittent sharp debridement. Over a six-month period the wounds diminished in size, and went on to complete resolution. The patient continued to follow up once the taper was finished and to this date, has not had a recurrence.

Discussion

Primary systemic vasculitis is uncommon, accounting for only four percent of cases in patients with cutaneous vasculitis. Infections lead the secondary causes accounting for 23% of cases followed by medications (20%), connective tissue disease (12%) and malignancy (4%). It has been reported that no identifiable cause is present in 3-72% of patients [1].

Vasculitis varies and may be classified based on the size of the blood vessel involved. Small-sized blood vessels are less than less than 50 µm and include capillaries, postcapillary venules, and nonmuscular arterioles. They are found primarily in the superficial papillary dermis. Medium-sized blood vessels are between 50-150 µm in diameter and contain muscular walls. They are often found in the deep reticular dermis at the junction of the dermis and subcutaneous tissue [2].

Figure 8 (1) Figure 9 (1) Figure 10 (1)

Figures 8-10 Follow up at eight months.

Systemic vasculitis may be caused by a variety of disorders, and vary depending on the vessel size. Large vessel vasculitis includes Giant Cell Arteritis and Takayasu arteritis. Medium vessel vasculitis includes Polyarteritis Nodosa and Kawasaki disease while small vessel vasculitis includes Wegener granulomatosis, Churg-Strauss syndrome, Microscopic polyangiitis, and Henoch-Schonlein purpura [3]. Secondary cases of vasculitis include autoimmune disease, infection, malignancy, or drug reaction commonly from penicillins, sulfonamides, allopurinol, thiazides, quinolones, propylthiouracil and hydantoins [4].

Many clinical features are present in a patient with cutaneous vasculitis. Palpable purpura may be the first clinical sign of vasculitis, which results from extravasation of erythrocytes into the dermis [4]. Purpura does not blanch with pressure and may be found symmetrically along dependent regions. Petechiae may be found and present as non-blanchable non-palpable pinpoint macules. Digital necrosis and ulceration can result due to a decrease in vascular perfusion in the skin. Superficial ulceration is common in small vessel disease while deeper ulcerations are present in medium vessel disease [4]. Livedo reticularis, hemorrhagic bullae, and urticaria are other clinical features of cutaneous vasculitis. According to Ekenstam and Callen in a study of 82 patients diagnosed with cutaneous leukocytoclastic vasculitis, palpable purpura was present in 51 patients followed by urticarial-like lesions (17 patients), ulcerations (8 patients), vesiculobullous lesions (5 patients), erythematous plaques (5 patients), nodules (5 patients), livedo reticularis (3 patients), erythematous papules (1 patent), and necrosis (1 patient) [5]. The majority of patients only manifested one type of skin lesion. In 12 patients two or more types of skin lesions were present. The most common location of skin lesions was the lower legs.

If cutaneous vasculitis is suspected it is imperative to perform a biopsy to confirm the diagnosis. Two biopsies should be obtained and sent for both histopathologic and direct immunofluorescence. Biopsies should be performed within 24-48 hours after the appearance of a vasculitic lesion to prevent the pathological characteristics of vasculitis from being lost [2]. Next, it is imperative that biopsies be of the appropriate depth. The depth of the biopsy determines which vessels are being examined. If medium vessel vasculitis is suspected, the biopsy must include subcutaneous fat. An incisional biopsy should be employed if larger vessels are suspected. Lastly, the biopsy should be obtained from non-ulcerated sites or from the edges of the ulceration if possible.

Once cutaneous vasculitis has been confirmed through biopsy it is essential to determine the etiology, evaluate for systemic disease, identify any treatable cause, and remove any offending agent. A thorough history can establish if any medications, infections or systemic disease can account for vasculitis. A thorough physical exam should be performed followed by laboratory and radiological evaluation, and further diagnostic testing as indicated. If chronic or systemic vasculitis is suspected the following laboratory studies should be performed: complete blood count with differential, BUN/Creatinine, liver function panel, urinalysis, stool guaiac, hepatitis B and C virus serologies, cryoglobulins, precipitins, complement levels (CH50, C3, C4), ANCA, antinuclear antibody, and rheumatoid factor. Other tests to consider may include blood cultures and echocardiography if fever or heart murmur is present, and anti-streptolysin O titers in children [6].

Treatment of cutaneous vasculitis should start with the removal or treatment of the underlying cause. Any offending medications or causative agent should be removed, and any underlying systemic disorder should be treated. According to Carlson et al, treatment should be guided and based on the severity of disease [6]. Treatment should begin with management of symptoms and may include antihistamines, non-steroidal anti-inflammatory drugs, rest, and elevation, and avoiding cold exposure. For mild limited skin disease with persistent, recurrent, or symptomatic disease, dapsone and colchicine have been effective. For moderate to severe skin disease, with extensive or recurrent disease treatment may consist of methotrexate, azathioprine and or prednisone. Systemic vasculitis is treated with prednisone and may be combined with cyclophosphamide, azathioprine, cyclosporine, or mycophenolate mofetil. Other treatments may be based on the specific underlying disorder and may include TNF inhibitors, intravenous immunoglobulin, and plasmapheresis.

Conclusion

Cutaneous vasculitis is a rare condition that can be caused by a variety of different conditions and may present with varying degrees of clinical manifestations. If cutaneous vasculitis is suspected it is imperative to perform a biopsy to be sent for both histopathology and direct immunofluorescence. Once cutaneous vasculitis is suspected, treatment should be guided and based on the severity of the condition as well as any systemic disease.

References

1. Carlson JA, Ng BT, Chen KR. Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol. 2005;27 (6): 504-28. – [Pubmed].
2. Gonzalez-gay MA, Garcia-porrua C, Pujol RM. Clinical approach to cutaneous vasculitis. Curr Opin Rheumatol. 2005;17 (1): 56-61. – [Pubmed]
3. Watts RA, Scott DG. Recent developments in the classification and assessment of vasculitis. Best Pract Res Clin Rheumatol. 2009;23 (3): 429-43. – [Pubmed]
4. Xu LY, Esparza EM, Anadkat MJ et-al. Cutaneous manifestations of vasculitis. Semin Arthritis Rheum. 2009;38 (5): 348-60. – [Pubmed]
5. Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. Clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120 (4): 484-9. – [Pubmed]
6. Carlson JA, Cavaliere LF, Grant-kels JM. Cutaneous vasculitis: diagnosis and management. Clin Dermatol. 2006;24 (5): 414-29. – [Pubmed]

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