Are You Confident of the Diagnosis?
What you should be alert for in the history
Patients present primarily with urticarial or hive-like lesions. As opposed to simple urticaria, these lesions tend to be more persistent (greater than 24 hours in duration each) and may leave a small purpuric residual (Figure 1). Although itch may be part of the symptomology, burning or stinging of the skin is also often reported. Any portion of the anatomy may be affected but the truncal area and proximal extremities are common sites for involvement.
Abdominal pain, chest pain or joint pain may be reported especially in those patients with the hypocomplementemic variant. At times the patient’s complaints may be very simliar to those seen in lupus or connective tissue disease. Hypocomplementemic urticarial vasculitis (HUV) is more common in women but can be seen in both genders and represents about 15% of patients with urticarial vasculities (UV).
Characteristic findings on physical examination
These include raised, edematous hive-like lesions. Vesicles are usually absent. Small areas of purpura or bruise may be left after resolution of the skin lesions. Some patients may also have associated angioedema.
Expected results of diagnostic studies
The diagnosis requires careful clinical and pathological correlation. Biopsy should be taken from a fresh lesion of less than 24 or 48 hours duration if possible.
Routine microscopy shows changes of urticarial tissue reaction with dilated lymphatics and dermal edema but subtle blood vessel damage may be seen as well as mild extravasation of red blood cells into the adjacent dermis. Many eosinophils surround the blood vessels or at times neutrophils may predominate. Patients with depressed complement levels (HUV) tend to have an infiltrate that is more neutrophilic than eosinophilic (Figure 2).
Evaluation of patients should be similar if not identical to those who have other forms of cutaneous vasculitis. Screening for lupus (ANA) and complement levels (total [CH50] and C4) are helpful. Underlying causes of UV in patients with normal complement include drug hypersensitivity, infection, malignancy and other systemic inflammatory diseases.
Patients with depressed complement have features that closely mimic lupus erythematosus and may be ANA positive. They tend to have joint pain, and may have fever and chest and/or abdominal pain. In these patients, biopsy for direct immunofluorescence (DIF) may be helpful in that it shows granular basement membrane zone inflammation with C3 or IgM. These patients may be at risk for emphysema long term and chest X-ray and pulmonary evaluation is essential. Renal disease is more likely a complication in those with positive basement membrane zone findings on DIF.
Diagnosis confirmation is accomplished by combining the clinical features of the lesions together with a biopsy of a fresher lesion for routine microscopy. In those patients demonstrating more of a neutrophilic pattern on microscopy, screening with an ANA and for complement levels will determine if they have HUV. Biopsy for DIF is also helpful in confirming patients with HUV. Differentiation from chronic recurrent urticaria or from lupus erythematosus requires a thorough physical examination, biopsies as noted above and laboratory tests.
Associated systemic disorders in UV are similar to those seen in leukocytoclastic vasculitis and include drug hypersensitivity, infections (including viral, bacterial or parasitic infestation), malignancy and other systemic diseases.
Initial workup must start with a thorough history and review of systems including travel history and history of tobacco use. Over the counter drug use must be assessed and dietary flares of disease may be relevant in UV. Initial labs or tests should include a CBC with differential count, IgE level, ESR, CRP, chest x-ray, and urinalysis with microscopic examination.
Additional tests may include pulmonary function tests in those with a tobacco history or with asthmatic symptoms or history. Complement levels including total (CH50) and C4 will help separate out those patients with HUV.
In HUV patients additional workup should include ANA testing and other tests as appropriate based on the history and review of systems focusing on connective tissue diseases. Renal function should be carefully assessed especially in those with HUV and positive basement membrane zone fluorescence on DIF.
Who is at Risk for Developing this Disease?
UV can be seen at any age but similar to cutaneous vasculitis tends to be seen more often in adults and in the 4th or 5th decade. HUV is more commonly seen in women but not exclusively.
What is the Cause of the Disease?
The etiology of UV is similar to that of other forms of cutaneous vasculitis in that antigenic stimulation can be derived from a number of sources or illnesses including infection, both viral and bacterial, drug hypersensitivity, tumors, systemic inflammatory diseases, connective tissue disease and other disorders. HUV overlaps in many ways with lupus erythematosus and may share many symptoms and signs.
Similar to other cutaneous vasculitic syndromes, the pathophysiology is thought to be related to the generation of immune complexes in a vulnerable host. Deposition of these immune complexes results in a cascade of inflammatory events eventuating in blood vessel damage. IgE levels may or may not be increased in these patients but in some patients with UV the pathophysiology may overlap with that of urticaria.
HUV is thought to be more closely related to the generation of autoantibodies (Anti-C1q) to an initial collagenous portion of complement. Mast cell degranulation plays a role in the proinflammatory cascade as well as TNF-alpha release. Eosinophil degranulation further stimulates inflammation and may result in direct vascular damage as well. T-lymphocyte regulation is most likely involved as it is with other forms of cutaneous vasculitis.
Systemic Implications and Complications
Aside from the well known association with lupus and risk of renal involvement, patients with long standing UV have been known to to develop emphysema. Rare reports of cardiac valvular dysfunction have surfaced in HUV cases with or without deforming arthritis. Ocular inflammation can also rarely develop.
Treatment of UV requires that a thorough workup has been done or is underway and if an underlying cause can be identified, that it is eliminated or minimized. Over the counter drugs or dietary flares may be identified in the case of UV (not likely HUV) and if so, these items must be eliminated if possible.
Principles of therapy are similar to and may overlap often with that of both idiopathic chronic urticaria or with leukocytoclastic vasculitis. HUV may be more difficult to manage and tends to be chronic. In most instances HUV will require systemic corticosteroid treatment together with steroid-sparing medications.
Most often more traditional ’sedating’ H1 class such as hydroxyzine in doses of 25 to 100 mg daily in adults and titrated up from 25 mg, or combination H1/H2 antihistamines such as Sinequan, in doses of 25 to 100 mg, in adults and titrated from 25 mg as tolerated or as needed.
Non-steroidal anti-inflammatory drugs
Some synergy with antihistamines may be gained by adding medications such as indomethacin (25 to 75 mg daily in adults), or colchicine in doses of 0.6 to 1.8 mg per day for adults as needed or tolerated. Gastrointestinal intolerance may limit usefulness or dose.
Antimalarials can be used, predominantly but not exclusively hydroxychloroquine, in doses of 200 to 400 mg daily in adults. This treatment may be of more value in HUV either alone or in conjunction with prednisone therapy. Concurrent use of tobacco lessens efficacy.
Use dapsone as a solo therapy or in conjunction with prednisone. The dose starts at 25 or 50 mg daily in an otherwise healthy, non-anemic adult with baseline G6PD. The dose may be increased to 100-150 mg daily as required.
Prednisone is the mainstay of therapy for adults with more severe disease or symptoms and who are unresponsive to other more conservative therapy. It is most often used alone initially and then with another steroid-sparing drug as needed. Prednisone has the best track record in reducing or eliminating symptoms and signs of UV and also HUV. The dose is variable depending on the severity of disease but it is often higher in HUV and can range from 10 mg per day in an adult to 1 mg/kg daily.
Azathioprine can be used as a steroid sparing agent especially in those with HUV. It may not be required in UV. The dose is variable and can range from 50 to 250 mg daily in adults with a normal thiopurine methyl transferase test (TPMT).
Mycophenolate mofetil is gaining in popularity as a steroid sparing agent. Its cost has been greatly reduced by generic availability and levels can be monitored. The dose is quite variable and can range from 500 to 2,500 mg daily in an adult.
Cyclosporin may be considered as a steroid alternative if needed. The dose is quite variable and can range from 2.0 to 5.0 mg/kg daily in adults. Trough levels can be measured and renal function and blood pressure should be monitored.
Other uncommonly reported treatments include:
Plasmapheresis (one to seven plasma exchanges)
Interferon alpha (especially in hepatitis infected patients), most often used in combination with other therapies above.
Cyclophosphamide use is limited to the most severe or recalcitrant cases (100 to 200 mg daily in adults)
Intravenous immune globulin (IVIG) has been rarely used in very severe and recalcitrant cases
Optimal Therapeutic Approach for this Disease
The first step in management is to search diligently for an underlying cause to eliminate it if possible and to make sure patients with HUV have been identified. In those patients with UV, even subtle infections such as ’silent’ dental abscesses can cause or perpetuate disease and every reasonable ’stone’ must be overturned prior to treatment and during therapy to make sure an underlying cause has been eliminated.
In patients who are highly uncomfortable, prednisone is the most effective drug in bringing the process under control and allowing for comfort of the patient. This is particularly true with HUV. If therapy extends into weeks and if taper of prednisone is met with increased symptoms, then the process of selecting a steroid-sparing drug should be initiated.
For patients with milder disease, a combination of antihistamines and non-steroidal antiinflammatory drugs may suffice. In those with more severe disease, consideration could be given to dapsone or colchicine. Especially those with HUV, success may be had with antimalarial treatment.
In more resistant cases, mycophenolate mofetil or azathioprine should be considered. In patients requiring long term treatment with immunosuppressive therapy, consideration should be given to checking a PPD, chest x-ray or quantiferon-gold as deemed appropriate.
Once the diagnosis has been confirmed, it is essential patients are identified if possible as having HUV. At times repeat complement levels must be done to correctly identify these patients. HUV tends to require prednisone in the beginning and can be chronic and more challenging to manage. Patients need to be followed carefully until the disease is quiet and then depending on the medications used, monitoring then follows.
In those patients requiring several months of therapy or in those with continued symptoms suggestive of a connective tissue disease, periodic re-evaluation for lupus should be undertaken with appropriate laboratory and serologic tests.
Patients on corticosteroids should have considerations for monitoring for diabetes if treatment lasts longer than a few weeks and also for loss of bone calcium as well. Standard precautions regarding baseline eye examinations for antimalarial use apply as well as recheck approximately annually if the drug is continued. Dapsone will result in a modest reduction in hemoglobin (1 to 2 grams) even in those with normal G6PD levels.
Unusual Clinical Scenarios to Consider in Patient Management
UV can be very challenging for both the patient and the treating physician if no underlying cause is found. Close follow-up is often required and treatments may extend from months to even years. Secondary infection in patients treated with corticosteroids or immune suppressants should always be considered. Diabetes, premature cataract formation, hypertension and bone calcium loss are the most common complications of long term corticosteroid use and need to be treated and/or monitored.
Attempts at steroid weaning and substitution of suitable steroid-sparing agents are always to be considered in patients requiring more than a month or two of therapy. In the long-term, patients with HUV may develop pulmonary complications including emphysema. Monitoring of cardiac and pulmonary function is needed in this group of patients and strict avoidance of tobacco is important.
What is the Evidence?
Mehregan, DR, Hall, MJ, Gibson, LE. “Urticarial vasculitis: a histopathologic and clinical review of 72 cases”. J Am Acad of Dermatol. vol. 26. 1992. pp. 441-448. (A large case series review outlining the clinical presentation, associated illnesses and percentage of patients with depressed complement. Treatments are discussed.)
Davis, MDP, Daoud, MS, Kirby, B, Gibson, LE, Rogers, RS. “Clinicopathologic correlation of hypocomplementemic and normocomplementemic urticarial vasculitis”. J Am Acad Dermatol. vol. 38. 1998. pp. 899-905. (A large updated case series from the same institution as the study above. Emphasis on clinical and microscopic and immunopathologic findings.)
Wisnieski, JJ. “Urticarial vasculitis”. Current Opinion in Rheumatology. vol. 12. 2000. pp. 24-31. (A discussion of the pathophysiology of the disease and the commonalities and differences between hypocomplementemic urticarial vasculitis and lupus erythematosus.)
Houser, SL, Askenase, PW, Palazzo, E, Bloch, KJ. “Valvular heart disease in patients with hypocomplementemic urticarial vasculitis syndrome associated with Jaccoud’s arthropathy”. Cardiovasc Pathol. vol. 11. 2002. pp. 210-216. (One of the publications documenting that valvular heart disease can be seen in more severe cases of urticarial vasculitis with or without deforming arthritis.)
Russell, JP, Gibson, LE. “Primary cutaneous small vessel vasculitis: approach to diagnosis and treatment”. Int J Dermatol. vol. 45. 2006. pp. 3-13. (This manuscript focuses on cutaneous vasculitis not associated with significant systemic disease. Various treatments are discussed and tabulated starting with the simplest and least expensive and proceeding to more complicated, expensive or higher risk therapies.)
Peroni, A, Colato, C, Zanoni, G, Girolomoni, G. “Urticarial lesions: If not urticaria, what else? The differential diagnosis of urticaria. Part II. Systemic diseases”. J Am Acad Dermatol. vol. 62. 2010. pp. 557-570. (A very thorough discussion of the differential diagnosis of urticarial eruptions with a focus on urticarial vasculitis. Differential diagnosis and therapy are discussed.)
Ghazanfar, MN, Thomsen, SF. “Omalizumab for Urticarial Vasculitis: Case Report and Review of the Literature”. Case Rep Dermatol Med.. vol. 2015. 2015. pp. 576893(Case report and review of additional cases of urticarial vasculitis was treated with anti-IgE monoclonal antibodies. A larger and ideally randomized double blind trial is still needed but this may be a helpful therapeutic to try in refractory patients.)
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