A brief history of our understanding
of periodic fever syndromes
Author:
Joost P.H. Drenth --- excerpted from
"Hyper-IgD syndrome, a life with fever" (thesis, 1996)
Periodic disease was probably mentioned for the first time in medical literature
in 1806, when Heberden described a clinical entity in which periodic pain
affecting the abdomen and sometimes the chest and extremities predominated.
(1) These patients suffered from "pains which are regularly intermittent,
the fits of which return periodically as those of an ague; such as I have
known in the bowels, stomach, breasts, loins, arms, hips, though it be but
seldom that such parts suffer in days and recur for years at remarkably regular
short intervals. At that time periodic such a manner".
In 1895, Osler described a clinical entity in which periodic pain affecting
the abdomen and sometimes the chest and extremities predominated. (2) A few
years later, Janeway and Mosenthal reported on a case of a 16-year-old Jewish
school girl who suffered from birth onwards from recurrent attacks of periodic
abdominal pain accompanied by fever of short duration. (3) These reports focussed
on the periodic occurrence of symptoms and the term "periodic disease" as
such, was first coined by Reimann in 1948 when he defined it as disorders
featured by regular recurrences of clinical symptoms which last several disease
encompassed a myriad of disorders with recurrent arthralgia, abdominal pain
and skin rashes as the main manifestations. (4) In his view the symptom of
fever within this clinical picture was prominent enough to justify the term
periodic fever.
Soon it became clear that the early cases reported by Osler and Janeway
and Mosenthal constituted a separate syndrome characterised by fever, acute
abdominal, pleuritic and articular pain. (5) It appeared that there was a
frequent familial occurrence and that the disease mainly affected people
from the Mediterranean bassin, hence the name familial Mediterranean fever.
(6) As the number of cases grew its clinical picture became very distinct.
Familial Mediterranean fever (FMF) is
an autosomal recessive disorder occurring mainly in Sephardic Jews, Arabs
and Armenians. Although FMF has a preference for people from Mediterranean
ancestry it does occur in Turks, French, Germans, Swedes, Italians
and Dutch. In a landmark paper from 1967, Sohar and colleagues described the
clinical picture of FMF. (7) The acute febrile attacks, the hallmark of the
disease, are self-limited febrile episodes lasting from 24 to 48 hours and
recurring at irregular intervals, accompanied by peritonitis, pleuritis ands
synovitis. So called erysipelas-like skin lesions are also very typical for
the disease. In early series amyloidosis is mentioned a the second major manifestation
of the disease. Amyloidosis is systemic and of the AA type and leads almost
invariably to nephropathy and death due to renal failure. In 1974 colchicine
was introduced as mainstay in the therapy of FMF. In several double-blind
trials it was shown that colchicine, if dosed adequately, was able to decrease
frequency and severity of attacks in a substantial number of these patients.
(8-10) Subsequently, it was shown that colchicine
was also helpful in preventing and arresting the development of amyloidosis.
(11) Recently, the FMF susceptibility gene
Over time, other separate syndromes typified by periodic fever have been
described. For instance, adult-onset Still's disease,
a variation of Still's disease in children, was for the first time described
in 1971 as a syndrome with high spiking fever, an typical evanescent rash
and arthritis. (13) Familial Hibernian fever
has been noted in a large Irish family presenting as attacks of fever with
localised myalgia and painful erythema. (14) .
has been mapped to the short arm of chromosome 16. (12)
.
Apart from Still's disease other periodic fever syndromes have been recognised
in children such as chronic, infantile, neurological, cutaneous and articular
(CINCA) syndrome (15,16) and a syndrome of periodic
fever, pharyngitis and aphtous stomatitis (FAPA). (17) This list of periodic
fever syndromes is far from exhaustive and all have in common that the diagnosis
still relies upon clinical evaluation.
In 1979, physicians from the University Hospital in Leiden, The Netherlands
were confronted with 3 patients with peculiar attacks of fever, occurring
every 2 to 4 weeks and lasting 3 to 7 days. Two patients were brother and
sister and all patients had a remarkably similar clinical picture. From birth
onwards, the patients were suffering from febrile attacks accompanied by abdominal
pain and diarrhoea, impressive swelling of the cervical lymph nodes, skin
lesions and joint involvement. Laboratory testing revealed an acute phase
reaction with an leucocytosis, neutrophilia and a raised erythrocyte sedimentation
rate. A firm diagnosis could not be made in these patients but recurrent
infections, malignancies, and auto-immune disorders were excluded during
the frequent and prolonged admissions. Although a few Dutch patients with
FMF have been described, the above mentioned clinical picture was completely
dissimilar from FMF. (18) As part of a immunological work-up, 2 patients underwent
a bone marrow biopsy. Fluorescence of bone marrow plasma cells was very similar
in both and showed an abnormally high percentage of delta positive cells.
Subsequent immunoelectrophoresis showed a clear IgD precipitation line.
Further quantification of this IgD revealed very high concentrations of
this protein. The third patient also tested positive for IgD. Within short
period of time 3 other similar patients were found. The clinical picture
of these patients did not fit with any of the previous described syndromes,
especially FMF, and it became clear that this constituted a new syndrome.
In the Lancet of May 1984, Van der Meer et al. presented a series of 6 these
patients as a new syndrome called the hyperimmunoglobulinemia D and periodic
fever syndrome (HIDS). (19) Subsequently, reports
of similar cases came from United Kingdom, France, and later Italy. (20-22)
This firmly established HIDS as a new syndrome. The pathogenesis of this
syndrome, however remained obscure and despite initial enthusiasm for colchicine,
no treatment proved beneficial. Although HIDS can be described as a benign
disease because there are no potentially lethal complications, the disease
has serious personal consequences for patients and their families. If the
disorder remains undiagnosed, these patient suffer from repeated invasive
investigations. The prospect of having a disease which cannot be cured and
will lead to lifelong symptoms is difficult to bear and the recurrent atacks
deeply interferes with the social and economical lifes of patients and families.
In 1992, further research in this syndrome was initiated by the establishment
of the "International Hyper-IgD study group". This study group consists of
physicians treating these patients and goal of this study group is to improve
awareness of, facilitate diagnosis of, and investigate novel therapies for
this syndrome. One of the first tasks was to gather additional patients in
order to describe HIDS more accurately and to delineate it from other periodic
fever syndrome.
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