Page 1050 - Williams Hematology ( PDFDrive )

1024 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1025

349
pain and fever. Subsequently additional cases were identified, but it without abdominal symptoms. Recurrent pericarditis is rare. The
348
took nearly a half century to establish this disorder as familial Mediter- course of peritonitis in FMF is similar to attacks at other serosal sites;
ranean fever. 350 however, it tends to appear at a late stage of the disease. Mild arthralgia
Epidemiology More than 10,000 patients worldwide are affected is a common feature of febrile attacks, and monoarticular or oligoartic-
with FMF. It occurs predominantly in Sephardic Jews, Arabs, Turks, ular arthritis may occur. Arthritis usually affects large joints, the knees
Italians, and Armenians. The disorder can occur in other populations, in particular, and effusions are common. As many as one-third of the
348
but it is unusual. The frequency of the susceptibility gene varies widely; patients experience transient erysipelas-like skin lesions that appear
it is very high among Armenians (ratio of persons with the gene to those typically on the lower leg, ankle, or dorsum of the foot. These lesions
without it is 1:7) and Sephardic Jews (1:5 to 1:16), but is lower in Ash- are circumscribed, painful, erythematous areas of swelling, which usu-
kenazi Jews (1:135). ally subsides within 24 to 48 hours.
Etiology and Pathogenesis The pathologic findings in FMF are In approximately 25 percent of affected patients, a form of renal
those of nonspecific acute inflammation affecting serosal tissues such amyloidosis develops in which the amyloid derives from a normal
as the pleura, peritoneum, and synovium. Neutrophilic infiltration pre- serum protein called serum amyloid A (amyloidosis of the AA type;
dominates in the affected tissues. Physical and emotional stress, men- Chap. 108). The amyloidosis progresses over a period of years to
struation, and a high-fat diet may trigger the attacks. 351 renal failure in almost all cases, and the cause of death in patients
The gene responsible for FMF has been identified to be located on with FMF is usually attributed to this complication. It appears that
chromosome 16. It encodes for a 781-amino-acid protein called pyrin polymorphisms in the gene for serum amyloid A increase the sus-
or marenostrin. The gene (MEFV) is predominantly expressed in ceptibility to renal amyloidosis and that polymorphisms in a gene
352
neutrophils, eosinophils, monocytes, dendritic cells, and synovial and for the major histocompatibility complex class 1 α-chain influence
peritoneal fibroblasts, and its expression is upregulated by IFN-γ and the severity of the disease. 350
TNF, and by the process of myeloid differentiation itself. Nearly all the Laboratory Features Laboratory findings in FMF are nonspecific.
353
50 mutations in the MEFV gene are missense changes, most of which Nonspecific findings include increases in inflammatory mediators such
354
350
are clustered in on exon 2 and 10. Founder effects in FMF have been as amyloid A, fibrinogen, and C-reactive protein during febrile attacks.
established, and the two most common mutations, V726A and M694V, Proteinuria greater than 0.5 g of protein per 24 hours in patients with
originated in common ancestors who lived about 2500 years ago in the FMF may suggest amyloidosis.
Middle East. 352 The cloning of the FMF gene now allows a reliable diagnostic
Pyrin plays a role in controlling the activity of inflammasomes (see test. Five founder mutations account for 74 percent of FMF carrier
“Neutrophil Surface Receptors”). PYRIN, one of the four domains of chromosomes from typical populations known to harbor the dis-
357
pyrin, bears homology to a number of proteins involved in apoptosis ease. Carrier rates for FMF mutations may be as high as 1:3 in
and in inflammation, and is similar to a member of the six-helix-bundle some populations, suggesting that the disease is often underdiag-
death-domain superfamily that includes death domains and death effec- nosed. Some amino acids that cause human disease are often present
355
tor domains known as CARDs. The PYD appears to allow for the inter- in wild-type in primates. 358
action of macromolecular complexes by PYRIN–PYRIN interactions. Differential Diagnosis The TNF receptor–associated periodic
This interaction has led to the identification of pyrin’s ability to interact syndrome (TRAPS) was first described in 1982 in a large Irish family.
359
specifically with another PYRIN-domain protein termed apoptosis-asso- The affected family members had recurrent fever with localized myalgia
356
ciated speck-like protein with a CARD (ASC). Besides the aminotermi- and painful erythema. Differentiating this disorder from FMF was its
nal PYD, ASC has a C-terminal CARD domain that allows binding to response to corticosteroids and the autosomal dominant inheritance of
the CARD of procaspase-1 (IL-1β–converting enzyme), which results in the disorder. Affected patients can have attacks that last for at least 1
355
procaspase-1 autoactivation. Activated caspase-1 then converts proin- or 2 days, but prolonged attacks lasting longer than a week are com-
terleukin-1β to IL-1β, which is, in turn, secreted and interacts with the mon. Localized pain and tightness in one muscle group and a migratory
IL-1 receptor to mediate inflammation. It has been suggested that pyrin pattern of the symptoms are prominent features. The disorder may be
may act as an antiinflammatory molecule by inhibiting ASC-induced associated with colicky abdominal pain, diarrhea or constipation, nau-
IL-1 processing, which, in turn, could be defective in FMF. This hypoth- sea, and or vomiting. Painful conjunctivitis, periorbital edema, or both
esis is supported by observing increased IL-1 processing and heightened are common as well as chest pain secondary to sterile pleuritis. Dur-
350
sensitivity to LPS and impaired apoptosis in peritoneal macrophages ing febrile attacks, painless skin lesions may develop on the trunk or
from pyrin knockout mice. The puzzle, however, remains as to why sero- extremities and may migrate distally. Missense mutations in the gene
sal tissues are the main targets of inflammation in FMF. for the type-1 TNF 55-kDa cell membrane receptor, which is required
Clinical Features Febrile episodes in FMF may begin in infancy, for diagnosis, have been identified. Patients with TRAPS respond dra-
but by age 20 years, 90 percent of patients have had their first attack. matically to high doses of oral prednisone (>20 mg). In time, however,
The duration and frequency of attacks may vary considerably, even in the responses wane, requiring higher doses of corticosteroids. Standard
351
the same patient. Acute attacks frequently last 24 to 48 hours and doses of a p75:Fc fusion protein, etanercept, administrated subcutane-
recur once or twice a month. In some patients, attacks may recur as ously twice weekly decreases the frequency, duration, and severity of
frequently as several times a week, or as infrequently as once a year, attacks; thus, etanercept may provide a safer, more effective alternative
and symptoms may persist as long as a week during individual epi- then corticosteroids in controlling the disease.
sodes. Some patients experience spontaneous remission that per- Therapy Colchicine treatment is effective in FMF and may pre-
351
sists for years, followed by recurrence of frequent attacks. Peritonitis vent the development of amyloidosis. Prophylactic colchicine, 0.6
caused by FMF may resemble an acute abdomen, thereby leading to mg orally, two to three times a day, prevents or substantially reduces
potential uncertainties about the clinical management of the acute the acute attacks of FMF in most patients. Some patients can abort
abdominal episode. Attacks of pleuritic pain occur in approximately attack with intermittent doses of colchicine beginning at the onset of
25 to 80 percent of patients. Symptoms of pleuritis may sometimes pre- attacks (0.6 mg orally every hour for 4 hours, then every 2 hours for
cede abdominal pain, and some patients experience pleuritic attacks four doses, and then every 12 hours for 2 days). In general, patients who

Kaushansky_chapter 66_p1005-1042.indd 1025 9/21/15 10:48 AM