Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment.

The treatment strategies used for HAE-nC1INH are similar to those of HAE-C1INH and include the use of on-demand treatment (ODT), short-term prophylaxis (STP), and long-term prophylaxis (LTP) [ 8 – 13 ]. Until now, little is known about the outcomes of treatment in patients with HAE-nC1INH. There are no data from controlled clinical trials, and the limited information available comes from case reports and small case series. Since HAE-nC1INH is a group of conditions that are similar in clinical manifestation but differ in their pathogenesis, differences in treatment responses across the different subtypes of HAE-nC1INH must be expected. As for HAE-FXII treatments and outcomes, the use of icatibant and plasma-derived C1INH as ODT has been reported to be effective in most of the reported attacks although a significant number also derived little benefit [ 114 – 123 ]. Published information on the use of STP, in HAE-FXII, is limited to less than 10 patients (9 of which were pre-delivery), and all received plasma-derived C1INH, which was interpreted to be effective [ 117 , 123 , 124 ]. As for LTP, progestins, tranexamic acid, androgens, and lanadelumab have been used and reported to be effective in most cases [ 115 , 117 , 118 , 120 , 121 , 123 , 125 – 127 ]. In HAE-PLG, icatibant and plasma-derived C1INH have been used for ODT and reported to be efficacious in most cases [ 30 , 128 – 131 ]. Tranexamic acid and androgens are the most used LTP treatments in HAE-PLG as of now, and both were effective in the majority of cases reported [ 30 , 128 , 129 , 132 , 133 ]. The information on the use and outcomes of any treatments in other types of HAE-nC1INH is very limited, with few published reports [ 32 , 33 , 35 , 36 , 54 , 76 , 87 , 91 , 134 ]. Limited data is available concerning therapy for HAE-CPN1 and HAE-DAB2IP. In the families with CPN1 variants, LTP with tranexamic acid was tried and effective in seven symptomatic subjects and ODT with icatibant was effective in five subjects [ 36 ]. In the report describing the DAB2IP variant, four subjects received icatibant for ODT with good responses [ 35 ]. To obtain more information on the outcomes of treatment across the different subtypes of HAE-nC1INH, the HCT survey was developed and distributed to all international angioedema experts invited to the HAEA/HAEi-sponsored 2023 HAE-nC1INH symposium (see supplemental material). This survey provided information on 594 patients with HAE-nC1INH from 15 countries. For those countries with genetic testing available (all with the exception of New Zealand), the total numbers of patients for each HAE-nC1INH subtype were as follows: HAE-FXII, 337; HAE-PLG, 52; HAE-KNG1, 2; HAE-ANGPT1, 1; HAE-MYOF, 6; HAE-HS3OST6, 0; and HAE-UNK, 196. Of note, variants of CPN and DAB2IP were not identified at the symposium, and therefore, HAE-nC1INH with these mutations were not differentiated from HAE-UNK. All participating countries had access to and utilized modern ODT, i.e., intravenous plasma-derived or recombinant C1INH, ecallantide, and/or icatibant. STP use was reported in eight countries (Brazil, Israel, France, Japan, Netherlands, New Zealand, Spain, and the US). The predominant LTP treatment was the antifibrinolytic tranexamic acid. Progestins, plasma-derived C1INH, and lanadelumab were used substantially less frequently than antifibrinolytics. Berotralstat and attenuated androgens were used in a relatively small percentage of patients. The use of LTP was reported in all but three participating countries (China, Hungary, Italy). All but one country (New Zealand) had access to a modern prophylactic therapy, i.e., berotralstat, intravenous, or subcutaneous plasma-derived or recombinant C1INH, or lanadelumab. Berotralstat was available in all but five countries (Australia, Brazil, China, Israel, and New Zealand). Intravenous plasma–derived C1INH was available in all but three countries (Israel, Japan, and New Zealand). Subcutaneous plasma–derived C1INH was available in all but four countries (China, France, Israel, and New Zealand). Lanadelumab was available in all countries except New Zealand. The participating global experts ranked their assessments of the effectiveness for ODT and LTP therapies available to them that they used for each type of HAE. Assessments were made using a 5-point Likert scale from worsening to highly effective (see online supplement). For HAE-FXII (Fig.  2 ), the ODT efficacy of icatibant was assessed for 153 subjects and reported as high in 81.0%, moderate in 11.8%, mild in 2.6%, and no change in 4.6%. Plasma-derived C1INH ODT assessments were included for 97 patients, with 37.1% reporting high efficacy, 47.4% moderate efficacy, 6.2% mild efficacy, and 8.3% no change. As LTP therapy, intravenous plasma-derived C1INH was reported as moderately efficacious for two of two patients. Lanadelumab treatment of nine patients was assessed as highly efficacious in six, moderately in two, and non-effective in one. Attenuated androgens, used by three patients from a single center, were assessed as moderately effective. Antifibrinolytics efficacy, in 40 patients, was reported as high in 77.5% and mild in 22.5%. In 19 patients, progestin treatment was assessed as moderately efficacious in 94.7% and highly efficacious in 5.3%. No use of subcutaneous plasma-derived C1INH or berotralstat was reported. Fig. 2 Treatment efficacy for HAE-FXII from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-FXII patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-FXII patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response Treatment efficacy for HAE-FXII from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-FXII patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-FXII patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response For HAE-PLG (Fig.  3 ), ODT with icatibant was used by 19 patients and reported as highly and moderately effective in 78.9% and 21.1% of patients, respectively. Plasma-derived C1INH was used in three patients of whom one reported moderate and two mild efficacy. LTP therapy with subcutaneous C1INH was assessed as moderately effective in one of one patient. Lanadelumab treatment of seven patients was assessed as moderately effective in three and as mildly effective in two patients. Two patients were reported to show worsening with treatment. Antifibrinolytics, used in 12 subjects, were assessed as highly efficacious in all cases. Intravenous plasma-derived C1INH, berotralstat, attenuated androgens, and progestin use was not reported. Fig. 3 Pretreatment efficacy for HAE-PLG from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-PLG patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-PLG patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response Pretreatment efficacy for HAE-PLG from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-PLG patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-PLG patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response For HAE-ANGPT1, outcomes of ODTs in three patients were reported, with icatibant as mildly efficacious in two and plasma-derived C1INH as mildly efficacious in one. LTP therapy with antifibrinolytics and progestin each assessed as mildly effective for one patient each. HAE-MYOF treatment outcomes for five patients were reported by one participant, with on demand icatibant and plasma-derived C1INH each mildly effective for one subject and berotralstat moderately effective in three subjects. There were no reports of treatment outcomes for HAE-KNG or HAE-HS3OST6. For HAE-UNK (Fig.  4 ), the ODT efficacy of icatibant, used by 85 patients, was reported as high, moderate, and mild in 16.5%, 78.8%, and 4.7%, respectively. Plasma-derived C1INH, for ODT in 62 patients, was assessed as moderately effective in 16.1%, having mild efficacy in 74.2%, and not effective in 9.7%. Ecallantide was rated as highly efficacious for a single patient. As for LTP, subcutaneous plasma-derived C1INH was used by 25 patients, with efficacy reported as moderate and mild for 8% and 92%, respectively. Lanadelumab in 10 patients was assessed as moderately efficacious in seven and mildly efficacious in three. Berotralstat, in all 11 patients reported, was mildly effective. Attenuated androgens were used by six patients and were moderately effective, mildly effective, and non-effective in two each. The efficacy of antifibrinolytics, in 37 patients, was moderate in 13.5% and mild in 86.5%. Progestin treatment, in 15 patients, was assessed as mildly efficacious in 40% and non-effective in 60%. Fig. 4 Treatment efficacy for HAE-UNK from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-UNK patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-UNK patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response Treatment efficacy for HAE-UNK from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-UNK patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-UNK patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response Information available on the treatment of patients with HAE-nC1INH remains limited highlighting the need for further investigations. These should include real-world studies making use of registries, patient-reported outcome measures, and multicenter approaches with high patient numbers. Clinical trials, while challenging in rare diseases, should be performed to assess the efficacy of existing and emerging treatment options. The results of our HCT survey are in line with published observations, and they complement this information. Together, they suggest that plasma-derived C1INH and icatibant are both broadly used and effective ODTs in HAE-XII, HAE-PLG, and HAE-UNK. Ecallantide and recombinant C1INH, although perceived as effective, have only rarely been used by the clinicians surveyed. While it is counterintuitive that ODT with C1INH would be effective for diseases defined by normal C1INH levels, cleavage of C1INH to an inactive form during attacks has been documented [ 135 , 136 ]. This finding has been interpreted as the explanation for the effectiveness of C1INH for ODT. Information regarding STP outcomes in HAE-nC1INH is insufficient from the HCT survey and the literature to provide treatment recommendations. It is reasonable to consider the same approach as adopted for HAE-C1INH with treating physicians exercising clinical judgement. In all cases, it is recommended that ODT be made available for all patients. Similar to HAE-C1INH, disease severity can be increased with estrogen exposure in HAE-nC1INH, in particular for HAE-XII. Given the negative disease impact, discontinuation of exogenous estrogen is recommended whenever possible [ 120 ]. In contrast to HAE-C1INH, progestin treatment has been effective in case series of HAE-FXII patients demonstrating a significant reduction in attacks [ 58 , 120 ]. Similarly, all of the 29 HAE-XII patients in the HCT survey had moderate or better efficacy of progestin treatment. Taken together, LTP with progestin may be considered for HAE-FXII patients. LTP with attenuated androgens in HAE-nC1INH, in the literature [ 120 ] and the HCT survey, is reported for only a limited number of patients with inconsistent efficacy. Given the known risk of side effects and inconsistent evidence of benefit, no recommendation can be made for their use in HAE-nC1INH. LTP with antifibrinolytics appears to benefit patients with HAE-nC1INH, based on reports from the literature [ 52 , 58 , 120 ] as well as our HCT survey. Outcomes were particularly encouraging for HAE-PLG, where for all 12 of the patients, it was assessed as highly efficacious. A case series comparing antifibrinolytic and progestin therapy in HAE-PLG subjects found the former to be more effective [ 54 , 58 ]. Results of the HCT survey provide additional evidence supporting the use of antifibrinolytics for LTP treatment in patients with HAE-PLG. As of now, there are still very limited data on the use of lanadelumab for LTP in HAE-nC1INH. In the literature and in our HCT survey, the majority of the HAE-FXII patients who used it experienced high efficacy [ 115 ]. Patients with HAE-PLG, however, showed a much more mixed response to lanadelumab, with some patients experiencing moderate efficacy and others worsening. This may reflect that attacks in HAE-PLG relate to kinin generation directly from kininogen cleavage by plasmin, bypassing plasma kallikrein within the contact cascade [ 38 ]. HCT survey patients with HAE-UNK showed high efficacy of lanadelumab LTP in 70% and mild efficacy in 30%. Based on the currently available information, lanadelumab may be considered as an option for LTP in HAE-FXII and HAE-UNK, and it may help some patients with HAE-PLG. The information on LTP with plasma-derived C1INH or berotralstat is limited; however, outcomes in HAE-nC1INH patients when treated were mostly favorable [ 120 , 137 ].

The ability to unambiguously diagnose HAE-nC1INH currently relies on excluding other causes and identifying any underlying mutation; however, clinicians may not have access to gene sequencing. Many if not most patients with possible HAE-nC1INH do not have a demonstrated pathologic mutation. Even without an identified mutation, a presumptive diagnosis of HAE-nC1INH made by an expert physician is sufficient. Since these patients are at risk of serious morbidity and mortality, treatment needs to be available even for a presumptive diagnosis of HAE-nC1INH. The inability to make definitive diagnoses severely limits our ability to conduct clinical trials to elucidate treatment options. Thus, we recommend that concerted efforts be made to validate accurate biomarkers that can improve diagnosis and treatment of these patients. Since HAE-nC1INH is a rare disease, national or international registries will be essential for learning more about the natural history and response to treatment [ 138 ]. The introduction of new techniques into genetic testing has increased the number of genes identified, and biorepositories create the means for analysis of recently identified genes in stored DNA samples of the patients [ 138 , 139 ].

Angioedema is defined as intermittent, localized, and self-limited swelling of the subcutaneous and/or submucosal tissue. Multiple sites may be involved. It may occur in isolation, accompanied by hives (also known as wheals) or as part of a systemic allergic reaction. Angioedema may occur at any age developing spontaneously or in response to a triggering factor. Symptoms may persist for a few hours or may last days, resolving spontaneously or after treatment. All types of angioedema present with relatively similar signs and symptoms although there are differences between the various forms. The proximate cause of all angioedema is attributed to increased vascular endothelial permeability [ 1 , 2 ]. The underlying mechanisms, while heterogeneous and complex, ultimately result in enhanced vascular permeability leading to tissue swelling. Angioedema may result from mediators associated with mast cell activity; excess production of bradykinin due to either activation of the kallikrein-kinin system (KKS) or direct cleavage of kininogens by non- contact system proteases; reduced catabolism of bradykinin, as in some types of drug-induced angioedema; or intrinsic dysfunction of the vascular endothelium [ 3 , 4 ]. Hereditary angioedema (HAE) has been recognized for almost 150 years [ 5 ]. In 1963, Donaldson reported that HAE patients were characterized by decreased plasma levels of C1INH [ 6 ], a type of HAE now known as HAE-C1INH. Over the last two decades, new types of apparent non-mast cell mediated angioedema with normal quantity and activity of C1INH were described, in some cases with proven genetic pathogenic variants co-segregating with family and individual angioedema expression [ 4 , 7 ]. While several clinical guidelines and practice parameters regarding this new type of HAE have been published [ 8 – 13 ], substantial progress has been made encompassing diagnostic criteria, pathophysiology, and treatment outcomes. In the summer of 2023, HAE International (HAEi) and the US HAE Association (HAEA) enlisted 31 HAE with normal C1INH (HAE-nC1INH) global experts to synthesize our current knowledge in the area in order to present a best practice approach to the diagnosis and management of HAE-nC1INH. Preliminary drafts of the findings were presented and discussed in a symposium held on September 1, 2023 in Munich, Germany. The current manuscript reflects four rounds of revisions of these original drafts. Given the paucity of high-level evidence, all recommendations in this paper are based on expert opinion.