Page 859 - Clinical Immunology_ Principles and Practice ( PDFDrive )

830 ParT SIX Systemic Immune Diseases

restricted to myeloid cells has been described recently in two For experienced physicians, it is not difficult to diagnose FMF
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patients with Schnitzler syndrome. Strikingly, these patients in patients who have a medical history compatible with FMF
had the most severe phenotype in this cohort. Somatic mosaicism and who come from an ethnic group with high prevalence of
may be an explanation for the late onset of Schnitzler syndrome, FMF. In countries with a low incidence of FMF, several years of
and low-grade mosaicism may not be picked up by routine gene diagnostic delay are not unusual, as typical attacks remain
sequencing. Other genetic defects have also been described in unrecognized.
very small numbers of patients, but their role in the pathogenesis When FMF is suspected on clinical grounds, treatment with
of Schnitzler syndrome remains unclear. colchicine should be initiated immediately. A positive effect of
Schnitzler syndrome is regarded as a paraneoplastic syn- colchicine is confirmatory for the diagnosis FMF.
drome by some because of its association with Waldenström In populations with a low prevalence of FMF and in atypical
macroglobulinemia. cases, sequencing of the MEFV gene can be helpful in the
diagnostic workup.
LABORATORY TESTS Cryopyrin-Associated Periodic Syndrome

In classic monogenetic autoinflammatory diseases, an explicit CAPS is diagnosed on the basis of typical clinical features,
acute-phase response, with elevated inflammatory markers sometimes supported by a positive family history reflecting
(cross-reactive protein [CRP], erythrocyte sedimentation rate autosomal dominant inheritance. Detection of mutations in the
[ESR], serum amyloid A [SAA]) and leukocytosis, is invariably NLRP3 gene will confirm the diagnosis in most cases, but cases
present during symptomatic periods. In other autoinflammatory with “mutation-negative” CAPS have been described. Some of
diseases, this may be less evident. these patients may have somatic mosaicism. Reaction to treatment
During clinical disease remission, persistent subclinical inflam- is the same for these patients as for patients with proven NLRP3
mation can be found. Cold agglutinins, antinuclear autoantibodies mutation.
(ANAs), or cryoglobulins are usually not present but may be
found in low titers. Proteinuria (over 0.5 g of protein per 24 Tumor Necrosis Factor Receptor–Associated
hours) is highly suggestive for secondary AA amyloidosis. Periodic Syndrome
Elevated serum IgD can be present in MKD. It is discussed A set of clinical criteria for TRAPS has been proposed (Table
in detail in the respective section on the diagnosis of this disease. 60.4) but has not been validated. The cornerstone of the diagnosis
Similarly, the paraproteins encountered in Schnitzler syndrome of TRAPS is detection of mutations in the TNFRSF1A gene.
are discussed in the section on the symptoms of Schnitzler
syndrome. Mevalonate Kinase Deficiency
MKD can be suspected when characteristic clinical findings are
DIAGNOSIS present in combination with persistent elevated serum levels of
IgD >100 international unit per milliliter (IU/mL). Elevation of
Familial Mediterranean Fever serum IgD is not pathognomonic for MKD, as it may also occur
FMF is a clinical diagnosis. A validated set of clinical criteria for in other inflammatory conditions, including FMF and PFAPA.
the diagnosis of FMF has been defined (The Tel Hashomer criteria, Furthermore, in the very young, IgD may be normal, and in
Table 60.3). These criteria have high positive predictive value some of the affected individuals, IgD is never elevated. Elevated
and negative predictive value in populations with high pretest IgD is accompanied by elevated IgA in 80% of patients. The
probability, but their diagnostic accuracy is lower in other serum level of IgD does not correlate with disease severity, and
populations. elevated concentrations are present during asymptomatic periods.
Clinical suspicion of MKD can be confirmed by sequencing
of the MVK gene. During attacks, traces of mevalonic acid may
be found both in urine and serum and can be measured with
special techniques, which are, however, not commonly available.
TABLE 60.3 Tel Hashomer Criteria for the Measurement of mevalonate kinase enzyme activity is usually
Diagnosis of Familial Mediterranean Fever only done in the research setting and requires cell cultures.
Major Criteria (≥1 present)
a
Typical attack with abdominal symptoms
Typical attack with pleural symptoms
a
Typical attack with monoarthritis TABLE 60.4 Diagnostic Criteria for Tumor
a
Typical attack with only fever
a
Incomplete attack with abdominal symptoms Necrosis Factor receptor–associated
b
Periodic Syndrome (TraPS)
Minor Criteria (≥2 present) • Recurrent episodes of inflammatory symptoms spanning a period
Favorable response to colchicine of more than 6 months’ duration. Inflammatory symptoms include
Incomplete attack with monoarthritis fever, abdominal pain, myalgia, rash, conjunctivitis/periorbital
Exertional leg pain edema, chest pain, and arthralgia or monoarticular synovitis
• Episodes lasting ≥5 days
a Typical attacks are defined as at least three attacks with fever >38°C.
b Incomplete attacks are painful and recurrent attacks not meeting the criteria for • Responsiveness to glucocorticosteroids, but not colchicine
typical. • Affected family members (not always present)
The sensitivity and specificity of these criteria for the diagnosis of FMF are >95% and • Any ethnicity may be affected
>97%, respectively.
From: Livneh et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis From: Hull et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging
Rheum 1997;40:1879–85 concepts of an autoinflammatory disorder. Medicine (Baltimore) 2002;81:349–68