Hypocomplementemic Urticarial Vasculitis Syndrome: An Overview

Introduction:

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare type of vasculitis that affects the whole body. It is characterized by recurrent and chronic hives (urticaria) and low levels of complement proteins in the blood (hypocomplementemia). The exact cause of HUVS is not fully understood, but it seems to involve immune complex-mediated injury, similar to another condition called systemic lupus erythematosus or SLE (a chronic autoimmune disease that affects various organs and tissues in the body). There is a resemblance between HUVS and SLE in terms of symptoms and test results, leading to questions about whether they are distinct diseases or related.

What Is Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)?

Hypocomplementemic urticarial vasculitis syndrome (HUVS), also known as McDuffie syndrome, is an uncommon condition that was initially reported by McDuffie in 1973. It commonly occurs in people between their 40s and 50s, and it is more prevalent in females, with about 8 females affected for every 1 male. HUVS can affect different parts of the body, leading to symptoms such as skin vasculitis (a condition characterized by inflammation of the blood vessels in the skin), swelling (angioedema), stomach problems, lung issues, joint pain, kidney problems, eye inflammation (uveitis), and central nervous system involvement. Lung involvement is seen in about 20 to 50 percent of cases and is the main cause of serious health issues in HUVS. Around 90 to 100 percent of patients have increased levels of anti-C1q antibodies. HUVS may occur alone or alongside other autoimmune conditions, like systemic lupus erythematosus (SLE). HUVS and SLE have similar symptoms and characteristics. Studies have found that 7 to 8 percent of SLE patients also have HUVS, and 54 percent of HUVS patients may be diagnosed with SLE later on.

What Are the Clinical Features of Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)?

The major clinical features of HUVS include:

• Chronic Urticaria (Hives): The most common and characteristic symptom of HUVS is chronic urticaria. Individuals with HUVS experience itchy, raised welts on the skin that resemble hives. These lesions persist for more than 24 hours and may recur frequently. The hives in HUVS are typically larger and more persistent than typical hives seen in other conditions.

• Vasculitis: In addition to chronic urticaria, HUVS is associated with vasculitis, which is the inflammation of blood vessels. Vasculitis in HUVS typically involves small blood vessels, leading to skin manifestations like purpura (reddish-purple discolorations), petechiae (small red or purple spots), and skin ulcerations.

• Joint Involvement: Many individuals with HUVS experience joint pain and swelling. The joint inflammation can be quite debilitating and may lead to joint deformities in severe cases.

• Low Complement Levels: One of the distinguishing features of HUVS is the presence of low complement protein levels in the blood. Specifically, complement proteins C1q, C3, and C4 are reduced in HUVS patients, which is why the condition is termed hypocomplementemia.

• Elevated Anti-c1q Antibody Levels: A majority of HUVS patients have elevated levels of anti-C1q antibody, which binds to the C1q's collagen domain and causes immune complexes to deposit on the vascular lumina (channels within blood vessels). By activating the complement pathway as a result of this immune complex deposition, the endothelium (a single layer of cells lining the interior surface of blood vessels) and nearby tissues are damaged.

• Ocular Symptoms: Some individuals with HUVS may experience ocular symptoms, including conjunctivitis (inflammation of the outer layer of the eye) or uveitis (inflammation of the middle layer of the eye). These eye conditions can be painful and affect vision if not promptly managed.

• Fever and Fatigue: Patients with HUVS may experience recurrent episodes of fever and fatigue, which are often associated with disease flares and systemic inflammation.

• Systemic Involvement: HUVS can involve various internal organs, leading to systemic symptoms.

  1. Kidney involvement is relatively common, and it can lead to kidney dysfunction and impairment. The presenting features include blood in the urine and mild proteinuria (slightly high levels of protein in the urine). HUVS usually causes mild, non-progressive renal disease, but some patients may quickly advance to end-stage renal disease.

  2. Respiratory symptoms, such as shortness of breath or cough, may occur due to lung inflammation.

  3. Gastrointestinal involvement may result in diarrhea, abdominal pain or discomfort, nausea, and vomiting.

  4. Asthma (a persistent respiratory condition with airway inflammation) and moderate to severe chronic obstructive pulmonary disease (COPD, a progressive lung disorder that hinders airflow and results in breathing difficulties) are two manifestations present in cases with pulmonary involvement.

  5. In some cases, HUVS can affect the central nervous system, but this is not very common. When it does occur, it may manifest as conditions like pseudotumor cerebri (increased pressure in the brain), cranial nerve problems, or aseptic meningitis (inflammation of the membranes around the brain and spinal cord).

What Is the Diagnosis for Hypocomplementemic Urticarial Vasculitis Syndrome?

The diagnostic process begins with a thorough clinical evaluation by a healthcare professional, typically a rheumatologist or dermatologist. The doctor will take a detailed medical history, including a review of the patient's symptoms, their duration, and any potential triggers or exacerbating factors. A physical examination will be conducted to assess the skin, joints, and any other affected organs or systems. The characteristic features of HUVS, such as chronic urticaria, joint inflammation, and skin purpura, may be observed during this examination. HUVS shares some clinical features with other autoimmune and vasculitic disorders, such as systemic lupus erythematosus (SLE). Therefore, it is essential to rule out these conditions through additional laboratory tests and clinical evaluations. The other diagnostic methods include:

1. Laboratory Tests: Several laboratory tests are essential in diagnosing HUVS. The most significant feature of HUVS is the presence of low complement levels in the blood, specifically C1q, C3, and C4. Testing for complement levels is a critical diagnostic marker for HUVS.

2. Inflammatory Markers: Blood tests to measure markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), can help assess the degree of inflammation in the body.

3. Skin Biopsy: In some cases, a skin biopsy may be performed to aid in the diagnosis of HUVS. A tiny sample of the affected portion of skin is taken, and it is examined under a microscope. The presence of leukocytoclastic vasculitis (inflammatory cells surrounding blood vessels) is a characteristic finding in HUVS.

4. Organ Function Tests: Since HUVS can involve various internal organs, organ function tests may be conducted to assess the health of the kidneys, lungs, and other affected systems.

How Can Hypocomplementemic Urticarial Vasculitis Syndrome Be Managed?

There is no specific treatment established for HUVS, and various therapies have been attempted without a clear consensus on an effective regimen. Individualized treatment decisions are necessary for HUVS, depending on the patient's clinical condition.

• Patients with normal serum complement levels during a urticarial vasculitis (UV) attack usually have a self-limited disease and may require minimal therapy.

• Antihistamines are the preferred treatment for UV, with only cutaneous lesions. They help control itching but may be insufficient since they act late in the inflammation process and do not affect the immune complex formation, leaving the disease course unchanged. This drug may offer temporary relief in HUVS, but as the disease progresses, its effectiveness may diminish.

• Nonsteroidal anti-inflammatory agents can be used for joint pain relief in HUVS.

• Severe cases of HUVS, especially those involving the lungs or other organs, may necessitate specific treatments targeted at those organs and periods of intense immunosuppression.

• Serious HUVS cases with significant organ involvement may require high doses of glucocorticoids and cytotoxic agents like Cyclophosphamide, Cyclosporine A, Azathioprine, Mycophenolate mofetil, or Methotrexate, either alone or in combination with Prednisolone, for long-term control of the disease.

• Some HUVS cases respond to treatments commonly used in systemic lupus erythematosus (SLE), such as low-dose Prednisone, Dapsone, Hydroxychloroquine, or other immunomodulatory agents.

• If lesions are resistant to other treatments, options like Colchicine and Rituximab may be considered.

• In certain cases with rapid deterioration of kidney function or crescentic glomerulonephritis, plasmapheresis and intravenous immunoglobulin (IVIG) have been proposed as alternative treatment options.

Conclusion:

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune condition with various symptoms. Chronic hives, blood vessel inflammation (vasculitis), and low complement levels in the blood are some unique features that help distinguish it from other illnesses. Because it is uncommon, diagnosing HUVS can be challenging, but early detection is essential to prevent organ damage and improve the lives of those affected. Researchers are working on understanding HUVS better, hoping to find more effective treatments and better outcomes for those suffering from this condition.