Novel findings	Recommendations
Clinical presentation
All symptomatic patients present with dermatitis, angioedema or both.
Fasciitis is a common and debilitating complication that may be mistaken for angioedema.	In presence of episodic pain and stiffening in extremities, perform MRI (with gadolinium) and/or muscle biopsy to detect fasciitis.
Diagnosis
A significant proportion of patients have very small subsets of CD3−CD4+ T cells that may be overlooked by routine lymphocyte phenotyping and TCR gene rearrangement studies.	Adapt flow cytometry methodology for patients being investigated for HES variants: use of an enlarged staining panel (including markers such as CD2, CD5, CD45RO, CD95) and acquisition of a large number of CD4+ T cells.
Treatment
60% of oral corticosteroid-dependent patients need a daily maintenance dose above 10 mg PDN-equivalent for disease control.
High serum IgM levels at presentation predict more severe disease requiring second-line therapy.	Consider introduction of a second-line agent early in disease course in patients with high serum IgM levels.
IFN-alpha is the most effective available second-line option, reducing both abnormal cell counts and the need for corticosteroid treatment. However, treatment often has to be interrupted due to poor tolerance and/or secondary resistance.	Pegylated IFN-alpha is the preferred currently available second-line agent.
Although anti-IL-5 antibodies lower eosinophil counts, clinical responses are disappointing even at high dosing regimens. The only disease manifestation that responded partially in our study was angioedema.	Anti-IL-5 treatment, if initiated, should be given at a high dosing regimen (e.g., 700 mg IV mepolizumab) before concluding it is ineffective.
Disease course
Disease course is extremely heterogeneous.
One third of patients have mild (if any) symptoms that do not warrant maintenance treatment, and that may even regress spontaneously over time.	Avoid (over-)treating patients whose clinical manifestations do not justify maintenance therapy, even if blood eosinophil counts are high. Prefer careful follow-up for occurrence of more serious complications.
One fifth of patients have severe progressive disease manifestations that are largely treatment-refractory.	Novel therapeutic options are desperately needed for this patient subset.
The remaining patients experience variable degrees of disease severity and need prolonged maintenance treatment. They suffer the combined adverse effects of chronic inflammatory disease and of therapeutic agents.	Adapt treatment to achieve the best benefit/risk ratio. Treatment dosing should be tailored to symptom control rather than blood eosinophil count.
Changes in CD3−CD4+ T cell counts over time are generally associated with fluctuations in disease activity.	An increase in CD3−CD4+ T cell counts should prompt investigations for disease progression (including lymphoma), and adaptation of treatment.
Roughly 10% of patients develop T cell lymphoma (estimated on a sample of almost 50 patients when combining this study with the French cohort). No disease features at presentation are predictive of this outcome. Progression of lymphadenopathy led to diagnosis in all 3 patients in our study.	Follow-up should include regular clinical assessment of lymphadenopathy and FDG-PET. ASCT should be considered early to treat T cell lymphoma arising in this setting as conventional chemotherapy is not effective.