|Ahead of print publication
Hypocomplementemic urticarial vasculitis syndrome: A disease with many faces
Ankit Agrawal1, Sangeetha Pabolu2, Shirisha Ale1, Yesenia Galan1
1 Division of Internal Medicine, Rutgers Robert Wood Johnson Medical School, Saint Peter's University Hospital, New Brunswick, New Jersey, USA
2 Division of Rheumatology, Rutgers Robert Wood Johnson Medical School, Saint Peter's University Hospital, New Brunswick, New Jersey, USA
Apt 6R, 10 Landing Lane, New Brunswick, New Jersey 08901
Source of Support: None, Conflict of Interest: None
Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disease process where the exact pathogenesis is not known. It is an independent immunological condition affecting multiple organ systems. Major manifestations include chronic urticarial vasculitis (UV) with complement deficiency and demonstration of serum C1q antibodies. We describe a case of a 60-year-old male who presented with a generalized rash and was eventually diagnosed with HUVS. Usually, HUVS and systemic lupus erythematosus (SLE) have overlapping features, and our case was unique as our patient did not have any SLE manifestations. This article emphasizes the importance of comprehensive review of systemic manifestations accompanying UV. Although rare, it raises the awareness among the physicians about its clinical presentation and diagnostic approach and also predicts the prognosis of the same.
Keywords: Autoimmunity, hypocomplementemia, McDuffie syndrome, urticarial vasculitis
| Introduction|| |
Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune clinical condition involving 6 or more months of urticaria with hypocomplementemia and vasculitis in the presence of systemic findings such as arthralgias or arthritis, mild glomerulonephritis, uveitis or episcleritis, and recurrent abdominal pain. The exact pathophysiology is unknown but is believed to be deposition of immune complexes in the vessel wall. Here, we describe a case of a 60-year-old male who presented with a generalized rash and was eventually diagnosed with HUVS.
| Case Report|| |
A 60-year old male with a history of 40 pack-years smoking, emphysema, and pulmonary hypertension presented to the emergency department (ED) with the complaints of diffuse body rash. He reported the rash to be persistent for 10 months, which was nonpruritic. It was associated with intermittent eye redness and pain, intermittent bilateral knee pain, and proximal muscle weakness. Vital signs on presentation were within the normal limits. Physical examination showed diffused urticarial rash in the arms, torso, and the back [Figure 1]a and [Figure 1] b. The patient was given intravenous (IV) steroid in the ED, following which he developed shortness of breath and started wheezing. He was transferred to intensive care unit (ICU) due to acute hypoxia. Computed tomography scan of the chest was obtained which revealed centrilobular emphysema and mediastinal lymphadenopathy. The patient was treated with bronchodilator nebulization. A steroid challenge with 10 mg of IV methylprednisolone was conducted in the ICU after stabilization under close observation following which a new rash developed in the neck within 15 min without any signs or and symptoms of airway compromise. It was considered as an allergic response. Laboratory investigations revealed low complement levels (C3 level of 30 mg/dL with a reference range of 88–165 mg/dL and C4 levels of <8 mg/dL with a reference range of 14–44 mg/dL) with normal anti-centromere antibodies, anti-Scl-70 antibodies, antinuclear antibodies (ANAs), and anti-Jo1 antibodies. In addition, human immunodeficiency virus fourth-generation screening, hepatitis B, and hepatitis C panel were nonreactive. C1q precipitin test by immunodiffusion was positive with levels of >200 mcg Eq/mL and undetectable serum C1q levels (reference range 5.0–8.6 mg/dL). Punch biopsy of the cutaneous rash was obtained which showed dermal infiltration with leukocytoclastic involving small- and medium-sized vessels with vessel wall confirming leukocytoclastic vasculitis [Figure 2]. Given the clinical presentation and the biochemical investigations, a diagnosis of HUVS was considered. Given the allergic response to steroids, mycophenolate mofetil 500 mg two times a day was initiated, and the patient tolerated it well. The patient is doing well on follow-up with significant improvement in the rash, arthralgias, and muscle weakness.
|Figure 2: Black arrow depicting dermal infiltration with leukocytoclastic involving small- and medium-sized vessels confirming leukocytoclastic vasculitis|
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| Discussion|| |
HUVS, also known as McDuffie syndrome, is an extremely rare autoimmune condition that was first described by McDuffie et al., in 1973. The incidence for inpatient chronic urticaria ranges from 2% to 20% diagnosed with urticarial vasculitis (UV). It is present in 7%–8% of systemic lupus erythematosus (SLE) patients, and 54% of HUVS patients are diagnosed with SLE during follow-up. It occurs mainly in young female population with female to male ratio of 8:1. Based on the level of complements and presence or absence of specific systemic signs, UV encompasses three distinct clinical entities:
- Normocomplementemic UV: It is an idiopathic benign hypersensitivity vasculitis and can be viewed as a manifestation of leukocytoclastic angiitis
- Hypocomplementemic urticarial vasculitis: There are two types of this entity. Primary, usually not associated with any systemic involvement and secondary, which is associated with systemic inflammation. The latter has overlapping features with SLE such as hypocomplementemia and presence of autoantibodies
- HUVS: It is the severe form of UV with multiorgan manifestation.
Pathogenesis of HUVS is believed to be the deposition of immune complexes in the vessel wall. Although the exact mechanism of this autoimmune phenomenon is not well delineated, a collagen-like region on C1q has been implicated to be the antigenic target for the autoantibody C1q precipitin. Genetic factors also play an important role in the pathogenesis. Mutations in DNASE1L3 have been associated with familial form of HUVS and HUVS associated with SLE.
HUVS involves multiorgan system. Urticarial wheal is a prominent dermatological finding. Arthralgias or arthritis is a common systemic manifestation in patients, with HUVS accompanying the cutaneous picture. Joint pain is usually transient and has a migratory pattern involving feet, ankles, knees, hands, and elbows. Renal involvement is noted in 14% of the patients and is manifested in the form of proteinuria and hematuria. Proliferative glomerulonephritis, crescentic glomerulonephritis, membranoproliferative, and tubulointerstitial nephritis are few renal pathologies seen in HUVS. Pulmonary involvement is seen in 20% of patients with HUVS and is manifested the form of cough, dyspnea, hemoptysis, asthma, or chronic obstructive lung disorder. The disease process is believed to cause vasculitis in the lung tissue leading to pulmonary destruction. Cross-reactivity between anti-C1q antibodies and surfactant apoproteins is a contributing factor toward the lung involvement. Affecting the gastrointestinal system, it usually causes recurrent abdominal pain, nausea, vomiting, or diarrhea. Episcleritis, uveitis, and conjunctivitis are common ophthalmological findings. Cardiac involvement is rare, and central nervous system disease is manifested in the form of pseudotumor cerebri (most common), cranial nerve palsies, or peripheral neuropathies.
Laboratory investigations usually show elevated erythrocyte sedimentation rate, hypocomplementemia (low C1q, C3, C4), and anti-C1q antibodies. Punch biopsy of the skin lesions is the cornerstone in making the diagnosis of HUVS by demonstrating the evidence of leukocytoclastic vasculitis. Direct immunofluorescence (DIF) should also be obtained which usually reveals perivascular or basement membrane deposits of immunoglobulins or complements. Unfortunately, in our case, the sample obtained was dry. An attempt to restore it in saline was made, but it was not successful, and hence, DIF could not be performed. The diagnostic criteria of HUVS was established by Schwartz et al., in 1982, which includes two major criteria (recurrent urticaria for 6 or more months and hypocomplementemia) and at least two minor criteria (venulitis on skin biopsy, arthralgias or arthritis, glomerulonephritis, ocular inflammation, recurrent abdominal pain, and positive C1q-p test by immunofluorescence with decreased C1q level). Criteria for exclusion from the diagnosis include cryoglobulinemia (cryocrit, >1%), elevated titer of anti-double stranded DNA antibodies, anti-smith antibodies, hepatitis B virus antigenemia, congenital complement defect or C1 esterase level deficiency, and a high titer of ANAs; however, 50% of patients have positive ANA in serum. The exact titers of antibodies to exclude from the diagnostic protocol has not been welldefined.
The treatment of HUVS depends on the severity of the condition and it is individualized. In patients with mild disease with only cutaneous manifestations, drug of choice for treatment is an antihistamine. They control the itching but do not alter the disease course. Nonsteroidal anti-inflammatory agents (NSAIDs) provide symptomatic relief in arthralgias. Mild-to-moderate disease (no end-organ damage) not responding to antihistamine and NSAIDs are treated with systemic glucocorticoids. It can be used with or without dapsone. Another alternative to consider is hydroxychloroquine. Severe systemic disease with life-threatening manifestation and end-organ damage are treated with a combination of systemic glucocorticoids and either mycophenolate mofetil, methotrexate, azathioprine, or cyclosporine. IV immunoglobulin and plasmapheresis are considered in cases of crescentic glomerulonephritis and rapid decline in renal function. Our case was challenging as the patient developed an allergic response to steroid treatment. We were left with steroid-sparing agents. Long-standing history of rash with systemic signs was the only clue to start with, which was a clinical challenge. Combining the biochemical investigations and skin biopsy results finally confirmed our diagnosis of HUVS. Here, we also review previously reported cases of HUVS as per [Table 1].
|Table 1: Review of previously reported cases of hypocomplementemic urticarial vasculitis syndrome|
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| Conclusion|| |
HUVS is a rare complicated condition with an unpredictable outcome. HUVS and SLE have overlapping features, and patients with HUVS should always be examined for SLE and vice versa. Our patient did not meet the diagnostic criteria for SLE. Pulmonary involvement is the most common cause of morbidity and mortality in HUVS, and cigarette smoking is a strong risk factor for the development of lung disease in HUVS. Degree of hypocomplementemia and severity of clinical signs and symptoms parallel the severity of the disease, hence depicting a poorer prognosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]