Rare connective tissue diseases more common in HAE: Study
Prevalence of diseases like lupus 5-10 times higher than in general population
Rare connective tissue diseases are more common among people with hereditary angioedema (HAE) than in the general population, according to the results of a new Italian study the researchers say is the first to seek to better understand disease prevalence among HAE patients.
Among the diseases investigated — which affect the tissues in the body that support and hold organs and joints together — were lupus, Sjögren’s disease, systemic sclerosis, and antiphospholipid syndrome, known as APS.
The researchers found that the prevalence of such diseases is about 5 to 10 times higher among individuals with HAE compared with people in the general population. Prevalence is the number of people in a population at a given time who have a specific disease.
The study, “Rare connective tissue diseases in patients with C1-inhibitor deficiency hereditary angioedema: first evidence on prevalence and distribution from a large Italian cohort study,” was published in the journal Frontiers in Immunology.
Researchers report scarce data on rare connective tissue diseases in HAE
In HAE, inherited mutations disrupt the production or function of the C1-inhibitor protein, known as C1-INH. This protein regulates the production of bradykinin, a signaling molecule that plays a key role in inflammation and blood pressure control. Without C1-INH, bradykinin is overproduced, causing fluid to leak out of blood vessels into surrounding tissues, and triggering swelling attacks.
C1-INH also suppresses the spontaneous activation of the complement system, a group of immune proteins that work sequentially to promote inflammation and kill and clear microbes from the body. It does so by blocking the formation of the C1 protein complex — the first step in activating the complement system.
As such, a lack of C1-INH can disrupt the balance of other complement system proteins, potentially predisposing HAE patients to develop certain autoimmune diseases. These include lupus, in which the immune system mistakenly attacks connective tissue and organs throughout the body, and systemic sclerosis (SSc), a chronic condition marked by thick and hardened skin.
However, few studies have explored the occurrence of rare connective tissue diseases like lupus or SSc in HAE. Other conditions with a lack of research on links to HAE are Sjögren’s disease, antiphospholipid syndrome, known as APS, and mixed connective tissue disease, or MCTD for short.
To investigate further, researchers across Italy came together to examine data from 855 HAE patients, ages 15 and older, who had enrolled in the Italian Network for Hereditary and Acquired Angioedema registry.
“We [are] evaluating for the first time prevalence and distribution of [rare connective tissue diseases] … in a large Italian cohort of C1INH-HAE patients,” the researchers wrote.
Nearly all participants (87.2%) were diagnosed with HAE type 1, which is marked by a lack of C1-INH production, as opposed to the faulty C1-INH as seen in HAE type 2. Most (85.9%) had a family history of the disease. About 1 in 3 patients (35%) were receiving preventive HAE therapy. Overall, 6 of every 10 patients (60.6%) were women.
Among the HAE patients, 18 (2.1%) were diagnosed with a rare connective tissue disease, most of whom were women (77.8%). Two-thirds of these patients were receiving preventive HAE therapy, which was significantly more than the overall study population, “supporting the idea of a bidirectional link between [HAE] and autoimmunity,” according to the researchers.
Lupus is most common co-occurring disease found in HAE patients
The rare connective tissue diseases diagnosed alongside HAE were lupus, found in eight patients; Sjögren’s disease, seen in four patients; APS, seen in three patients; SSc, diagnosed in two patients; and MCTD, found in one patient.
The eight cases of lupus among the total number of HAE patients corresponded to a prevalence of 0.94%, which compares with an estimated worldwide prevalence of 0.04%. That’s a difference of nearly 24 times, according to the researchers.
Likewise, the prevalence of APS was markedly higher in these HAE patients compared with the overall estimated prevalence (0.35% vs. 0.05%). This also was true for SSc (0.23% vs. 0.023%). The prevalence of Sjögren’s in this study was similar to the overall prevalence (0.47% vs. 0.4%), the data showed.
Of the eight lupus cases, all but two occurred in women. Two HAE-lupus patients also had other co-existing autoimmune disorders. In most cases, lupus presented as skin inflammation, followed by kidney involvement or low blood cell counts. All of those affected received immunosuppressants, leading to stable remission for at least a year at the time of this study.
We provide the first evidence of distribution of [rare connective tissue diseases] in a large cohort of adult Italian patients with [HAE], documenting that the prevalence of [rare connective tissue diseases] — SLE, APS, and SSc — is approximately 5 to 10 times higher in [HAE] patients compared to the general population as reported in the literature.
The four HAE patients with Sjögren’s disease were women, and two carried spontaneously occurring HAE-causing mutations, as opposed to inherited mutations. All showed characteristic signs of Sjögren’s, including dry eyes and dry mouth. Two of them also had joint arthritis and peripheral neuropathy, or damage to nerves outside the brain and spinal cord.
All three HAE patients with APS showed common signs of the disease, including persistent evidence of lupus anticoagulant — an antibody that increases the risk of blood clots — and recurrent blood clots in veins. All took vitamin K antagonists, which are blood thinners; two were on preventive C1-INH replacement therapy.
Of the two SSc cases, one was a man with limited skin involvement. He had skin thickening on the fingers, spider veins, and Raynaud’s phenomenon, in which the narrowing of blood vessels in the fingers and toes leads to numbness in response to cold temperatures or stress. A woman with SSc had more diffuse involvement, with Raynaud’s phenomenon, skin thickening of the fingers, finger sores known as digital ulcers, and lung disease. Both patients were on long-term preventive HAE treatment at the time of the study.
The single MCTD case was a woman with swollen fingers, Raynaud’s phenomenon, joint pain, and pulmonary arterial hypertension. She received immunosuppressants and was on preventive HAE treatment at the time of the study.
“We provide the first evidence of distribution of [rare connective tissue diseases] in a large cohort of adult Italian patients with [HAE], documenting that the prevalence of [rare connective tissue diseases] — SLE, APS, and SSc — is approximately 5 to 10 times higher in [HAE] patients compared to the general population as reported in the literature,” the researchers wrote.
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