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Background
Patients with rare, severe, therapy-refractory immune-mediated inflammatory diseases (IMIDs), are particularly difficult to treat, since treatment protocols are mostly lacking and randomised controlled trials are often impossible to conduct. Therefore, these patients are increasingly treated off-label with targeted therapies after failing on standard therapies. Off-label prescription may give early access to new valuable treatments for patients and teach us more about the pathophysiology of the disease. Consequently, off-label treatment adds to the innovation of clinical practice.
Our manuscript highlights the difficulty of finding the optimal treatment for patients with rare, severe IMIDs who are refractory to 'standard' therapies. We illustrate this using a case of a young woman with hyper-IgD syndrome (HIDS), a rare, hereditary autoinflammatory disease. After failing on several treatment strategies, rational anti-interleukin 6 receptor therapy was initiated off-label, based on pathophysiological indications that this cytokine may play an important role in the disease. This resulted in remarkable clinical improvement with a substantial reduction in the number of hospital admissions per year. Besides this discovery of a potential valuable therapy for patients with HIDS, this case and the 'reverse immunology' approach may also teach us more about the pathophysiology of this disease.
Case presentation
A 36-year-old woman was diagnosed with HIDS in 2002, when she was 23 years of age. The diagnosis was based on episodic fever since childhood accompanied by abdominal pain, lymphadenopathy and hepatosplenomegaly. In addition, she had many recurring otorhinolaryngeal infections, for which she was treated with tympanostomy tubes and adenotomy. At the time of diagnosis, her serum IgD level was 750 kU/L (upper limit 120 kU/L). This was accompanied by a relatively low mevalonate excretion in urine (urine mevalonic acid/creatinine ratio of 3.0 mmol/moL) creatinine. Mevalonate excretion in urine is usually slightly elevated during a HIDS attack, but this sample was not taken during an attack. Nevertheless, the mevalonate kinase (MK) activity was 0 pmol/min/mg. Therefore these results were interpreted as consistent with MK deficiency. DNA analysis revealed heterozygosity for 417insC and the frequently found a v3771 mutation. These combined features led to the final diagnosis of HIDS and periodic fever syndrome.
In the first years after diagnosis, due to a poor social network, almost every attack this patient experienced resulted in hospital admission (on average 11 times...