Page 861 - Clinical Immunology_ Principles and Practice ( PDFDrive )

832 ParT SIX Systemic Immune Diseases

first injection. This vivid response to treatment is so characteristic
that IL-1 inhibition can serve as a diagnostic tool in the diagnosis Simvastatin
of these autoinflammatory disorders. Anakinra and canakinumab The finding of dysregulation of the mevalonate kinase pathway,
have both been approved for the treatment of CAPS by the US with cholesterol as its major end product, has led to the hypothesis
American Food and Drug Association (FDA) and the European that blockage of this pathway by HMG-CoA reductase inhibitors
Medical Association (EMA). These agents were given “orphan” (statins) would possible be beneficial in patients with MKD.
status for the treatment of TRAPS by the EMA. In 2016, the Small trials and case reports showed a statistically significant,
FDA and EMA approved the use of canakinumab in patients but clinically negligible, effect in some patients. Statins have,
with HIDS, TRAPS and colchicine-resistant FMF. Rilonacept is therefore, been abandoned as treatment for MKD in clinical
approved for the treatment of CAPS by the FDA but is not practice.
commonly used in Europe. 24
In patients with mild MKD and periodic symptoms with Other Immunosuppressive Drugs
long symptom-free intervals, anakinra can be used on demand. In the past, numerous immunosuppressive drugs were tried in
In these cases it can be started at the first signs of an attack and a trial-and-error approach to find an effective treatment for the
only be continued for a few days. 25 disabling symptoms of autoinflammation. The results have been
Side effects of IL-1 inhibition include painful injection-site mostly disappointing, and there is no strong evidence to support
reactions, which are most commonly seen with anakinra, and the use of other immunosuppressants in autoinflammation. When
increased frequency of infections, mostly mild upper respiratory other treatments are ineffective, some patients may, however,
tract infections. More severe infections are rarely seen. benefit from immunosuppressive drugs.
Inhibition of Interleukin-6 Other Treatments
Tocilizumab, a monoclonal antibody (mAb) against the IL-6 It remains a matter of debate whether adenotonsillectomy
receptor, has been registered for the treatment of rheumatoid effectively resolves symptoms in PFAPA. Few meta-analyses have
arthritis and systemic-onset juvenile idiopathic arthritis (SoJIA) focused on this subject; one of them found two small randomized
27
and is used with increasing frequency in autoinflammatory controlled trials of unclear risk–benefit ratio. A case cohort
diseases. It is available as an intravenous infusion or subcutaneous study on the use of the histamine type 2 receptor antagonist
injection. The most common dose is 8 mg/kg in children and cimetidine (150 mg twice daily) in PFAPA showed that this drug
6
adults, or 10 to 12 mg/kg in children with body weight under is able to resolve fever episodes in 25% of patients. There are
30 kg, with an interval of 2–4 weeks. Side effects of tocilizumab no clinical trials supporting this observation.
are increased susceptibility to infections, most commonly upper Several case reports on the positive effects of hematopoietic
respiratory tract infections, elevated liver enzymes, and hema- stem cell transplantation (HSCT) in patients with severe MKD
tological abnormalities. Bowel perforations have been reported. have been published. 28-30 Because of the severe side effects, HSCT
As IL-6 induces the production of CRP in the liver, anti–IL-6 should be considered the last resort.
therapy always normalizes CRP, making it impossible to use it
as a marker for disease activity. Tocilizumab has been shown to AMYLOIDOSIS
be effective in patients with anakinra-resistant Schnitzler syn-
drome, MKD, and TRAPS. Secondary or type AA amyloidosis is a serious complication of
all autoinflammatory syndromes. It is caused by tissue deposition
Inhibition of Tumor Necrosis Factor of insoluble degradation products of the inflammatory protein
Three widely used inhibitors of TNF are the mAbs infliximab SAA. Kidneys are most commonly affected. Since SAA is an
and adalimumab and the recombinant soluble TNF receptor acute-phase reactant, there is a close relationship between the
etanercept. The most common side effect of TNF inhibition is duration and level of inflammation and the development of
increased risk of serious infections. amyloidosis. The incidence of AA amyloidosis varies among
Originally, TNF inhibition was regarded the treatment of first autoinflammatory diseases. Patients with FMF are at highest
choice in patients with TRAPS unresponsive to nonsteroidal risk, with an incidence of up to 75% before the introduction of
antiinflammatory drugs (NSAIDs). However, TNF inhibition colchicine treatment for this disease. There is a strong correlation
induces complete response only in a minority of patients with between ethnicity and risk of amyloidosis in FMF, with increased
TRAPS and is therefore far less effective than anti–IL-1 treatment. 26 risk among Sephardi Jews.
Anti-TNF treatment may also be effective in MKD, but Up to 25% of patients with TRAPS will develop amyloidosis
responses are mostly partial. It may be tried in patients who if left untreated. There seems to be a strong familial predilection.
show unsatisfactory response to anti–IL-1 treatment. 24,26 In CAPS, approximately one-third of patients develop amyloidosis
in the absence of treatment. Patients with MKD and Schnitzler
Corticosteroids syndrome have a relatively small risk of amyloidosis, with only
Corticosteroids are very effective in PFAPA. Prednisone 1 mg/ a few patients with these diseases and amyloidosis known
19
kg is most commonly used during attacks, although lower doses worldwide. It is unclear why some patients with the same level
may also be effective. Use of corticosteroids may increase attack of inflammation may develop or never develop amyloidosis. This
26
frequency in PFAPA. Mild TRAPS can be treated with a short may be related to single nucleotide polymorphisms (SNPs) in
course of steroids (30 mg daily for 7 days), and patients experienc- the SAA gene or certain genotypes.
ing more severe attacks may respond to higher doses. The As proteinuria is often the first sign of AA amyloidosis, patients
beneficial effect of corticosteroids may decrease over time, with autoinflammation should be screened for it with regular
necessitating dose escalation. 24,26 Short-term corticosteroids may urine sampling. Amyloidosis can be confirmed by Congo red
also be effective in patients with mild MKD. 24,26 staining of the biopsy specimen of affected tissue. This will show