Familial Mediterranean fever responds well to infliximab: Single case experience

Abstract

The most common arthritic involvement in familial Mediterranean fever (FMF) is acute recurrent monoarthritis; however, sometimes spondyloarthropathy-like findings or typical ankylosing spondylitis may also ensue. Reported here is our favorable experience with infliximab in an FMF patient who had been resistant to colchicine and disease-modifying antirheumatic drugs (sulfasalazine and methotrexate) treatments. A 72-week follow-up of the patient yielded complete remission of the febrile abdominal episodes, and spondylitis responded well. The patient's bilateral aseptic necrosis of the femoral head deteriorated and caused hip pain, discomfort, and disability. Overall, we believe that tumor necrosis factor (TNF) alpha has an important role in the disease pathogenesis and also that anti-TNF may represent a promising robust treatment alternative in FMF.

Full text

CASE REPORT
Salih Ozgocmen ÆLevent O
¨zc¸ akar ÆOzge Ardicoglu
Ercan Kocakoc ÆArzu Kaya ÆAdem Kiris
Familial Mediterranean fever responds well to infliximab:
single case experience
Received: 16 September 2004 / Revised: 6 January 2005 / Accepted: 6 January 2005 / Published online: 20 September 2005
ÓClinical Rheumatology 2005
Abstract The most common arthritic involvement in
familial Mediterranean fever (FMF) is acute recurrent
monoarthritis; however, sometimes spondyloarthropa-
thy-like findings or typical ankylosing spondylitis may
also ensue. Reported here is our favorable experience
with infliximab in an FMF patient who had been resis-
tant to colchicine and disease-modifying antirheumatic
drugs (sulfasalazine and methotrexate) treatments. A
72-week follow-up of the patient yielded complete
remission of the febrile abdominal episodes, and spon-
dylitis responded well. The patient’s bilateral aseptic
necrosis of the femoral head deteriorated and caused hip
pain, discomfort, and disability. Overall, we believe that
tumor necrosis factor (TNF) alpha has an important
role in the disease pathogenesis and also that anti-TNF
may represent a promising robust treatment alternative
in FMF.
Keywords Aseptic necrosis ÆFamilial Mediterranean
fever ÆInfliximab ÆSpondylitis
Introduction
Familial Mediterranean fever (FMF) is a genetic disease
with autosomal recessive inheritance, affecting people of
Mediterranean origin, particularly, non-Askhenazi Jews,
Armenians, Turks, and Arabs [1,2]. The disease is
characterized by recurrent, self-limiting painful febrile
episodes of peritonitis, pleuritis, and synovitis. The
arthritis of FMF consists of acute attacks of mono-
oligoarthritis predominantly involving the large joints of
the lower extremities [1–5]. Permanent joint disease can
occur, especially at the hips. It can be related to either
FMF or to a coexisting chronic inflammatory dis-
ease—frequently a spondyloarthropathy (SpA) includ-
ing ankylosing spondylitis (AS) [1,4,6–8]. SpA is one of
the well-known musculoskeletal manifestations of FMF
and usually requires a specific treatment other than
merely colchicine [1,4,6,8]. Tumor necrosis factor-a
(TNF-a) blockade has recently been demonstrated to be
effective in patients with AS and in other forms of SpA
[9–12]. Herein, we report our experience with infliximab
treatment in a case of FMF with spondylitis, sacroiliitis,
and bilateral osteonecrosis of the hip joints.
Case report
Our patient, a 35-year-old woman, had been followed
for FMF since 1992 and she had been diagnosed to have
spondylitis and bilateral protracted arthritis in her hip
joints since 2001. Her sister is also an FMF patient
under colchicine treatment. In 2001, when she was first
referred to our clinic, she was suffering from febrile
abdominal attacks and she also complained of inflam-
matory pain in her lower back and ankle joints. She was
using colchicine 1.5 mg daily. The medical history was
unremarkable for psoriasis, inflammatory bowel disease
(IBD), or eye involvement. The family history was
negative for SpA. The physical examination was, then,
consistent with bilateral painful and limited hip motions
and pain and swelling in her ankles. The small joints of
the hands and feet, knee, elbow and wrist joints were
free of any arthritis. Lumbar motions were limited, and
spinous processes of lumbar vertebrae were tender to
palpation. Straight leg raising and femoral stretching
S. Ozgocmen (&)ÆO. Ardicoglu ÆA. Kaya
Division of Rheumatology, Department of Physical Medicine
and Rehabilitation, Faculty of Medicine, Firat University,
Elazig, Turkey
E-mail: sozgocmen@hotmail.com
Tel.: +90-424-2333555
Fax: +90-424-2480509
L. O
¨zc¸ akar
Department of Physical Medicine and Rehabilitation,
Hacettepe University Medical School, Ankara, Turkey
E. Kocakoc ÆA. Kiris
Department of Radiology, Faculty of Medicine,
Firat University, Elazig, Turkey
Clin Rheumatol (2005) 25: 83–87
DOI 10.1007/s10067-005-1122-9

tests were bilaterally negative. Neurological examination
was normal. The sacroiliac (SI) joints were painful
during palpation; Gaenslen and Mennel tests were
bilaterally positive. Lumbar Schober was 3.1 cm and
chest expansion at the fourth intercostal space was 4 cm.
Radiological examinations disclosed bilateral sacroiliitis
and destructive hip joint lesions. Pelvic magnetic reso-
nance imaging (MRI) demonstrated bilateral arthritic
involvement in the hip joints and destruction of the
femoral head and irregular SI joints with hypointense
T1-weighted and T2-weighted signal changes consistent
with sclerosis (Fig. 1a). Lumbar MRI demonstrated low
signal intensity in L1-2, L2-3, and L3-4 discs in T2-
weighted images, decreased disc spaces and post-con-
trast focal enhancement at L2-3 and L3-4 levels (disci-
tis), and Schmorl nodules at L2, L3, and L4 vertebrae
superior end plates. There were also hyperintense
changes at L2, L3, and L4 vertebra corpus end plates in
T1-weighted and T2-weighted images (Fig. 2a). Com-
puted tomography of the SI joints was relevant with
bilateral grade 3 sacroiliitis. Laboratory evaluations
were as follows: erythrocyte sedimentation rate (ESR)
76 mm/h, C-reactive protein (CRP) 33.2 mg/l, rheuma-
toid factor (RF) 59 U/ml, hemoglobin (Hb) 10 g/dl,
platelets (Plt) 443,000/ml, and white blood cells 8500/ml.
Antinuclear antibodies (ANA) and HLA-B27 were
negative. She was maintained on 1.5 mg/day colchicine
and sulfasalazine was commenced; her previously star-
ted prednisolone was gradually decreased.
On follow-up, she was observed to experience FMF
attacks every 2–3 months despite colchicine and the
arthritic findings could not be controlled sufficiently.
Thereafter, methotrexate (15 mg/week) was added to
her treatment regimen. Simultaneously performed
rectosigmoidoscopy and rectal biopsy were noncon-
tributory for either IBD or amyloidosis, nor did she
have any proteinuria in several controls. In June 2002,
she had morning stiffness for 2 h and the laboratory
evaluations yielded ESR 82 mm/h, CRP 32 mg/l, Hb
9.4 g/dl, Plt 463,000/ml, and RF 56.7 U/ml. She was
then on started treatment with 3 mg/kg infliximab at
weeks 0, 2, and 6 and repeat infusions every 6 weeks.
The combination of colchicine 1.5 mg/day, sulfasal-
azine 2 g/day, and methotrexate 15 mg/week was also
maintained.
After the 14th week of treatment, she started to feel
tremendously better. At the 26th week, laboratory
parameters were as follows: ESR 32 mm/h, CRP nega-
tive (<6 mg/l), Plt 340,000/ml, and Hb 10.8 g/dl. The
patient’s laboratory results and overall pain measured
using a visual analog scale (VAS) at different time points
during the treatment are shown in Table 1). Although
the hip pain was found to be persisting, her low back
pain and morning stiffness improved significantly.
During the infusions, she suffered from genitourinary
infections twice and she responded well to treatment
with appropriate antibiotics according to the culture
results. At week 72 (13th dose), she experienced a
recurrence—with increased hip pain and CRP levels in-
creased to 16 mg/l, ESR 75 mm/h, Hb 10.4 g/dl, Plt
385,000/ml, and RF 100 U/ml. She complained of
morning stiffness and low back pain lasting more than
2 h. The limitations of her hip joint motions had in-
creased and the chest expansion was 3 cm. The SI joint
maneuvers were negative; however, there was tenderness
on palpation of the lumbar spinous processes. On the
other hand, since the onset of infliximab therapy, her
previously persistent febrile abdominal FMF attacks
had never occurred and had completely vanished. The
control hip joint MRI unmasked an overt worsening of
the osteonecrosis and the hip destruction and uncovered
a regression in the aforementioned SI joint findings
(Fig. 1b). The involvement of the lumbar vertebrae was
still present on lumbar MRI (Fig. 2b).
Fig. 1 a Coronal T1-weighted MR image shows bilateral decreased
hip joint space and irregular femoral heads with heterogeneous
signal intensity (May 2001). bCoronal T1-weighted MR image
shows bilateral decreased height in the femoral heads and
hypointense T1-weighted signal changes with aseptic necrosis. In
comparison with the previous MRI there was significant worsening
(March 2004).
84

Discussion
Familial Mediterranean fever is the most prevalent
periodic fever syndrome and also known as recurrent
polyserositis or periodic fever. Articular involvement
ensues in approximately 70–75% of the patients and in
one-third of those even can be the presenting manifes-
tation [13]. Though these arthritis attacks generally
subside in 2–3 days and do not leave any sequelae [3,
13], a protracted course—mainly affecting the hip and
knee joints—can be seen in 5% of the cases [3,5,13]. A
less likely involvement can be in the form of HLA-B27-
negative SpA. These patients usually have unilateral or
bilateral sacroiliitis, recurrent enthesitis, and inflamma-
tory neck/low back pain with minimal radiological
spinal involvement [1,6]. Some of them can also display
an AS-like clinical course whereby chest expansion and
lumbar motions are found to be restricted and typical
radiological findings exist [1,7,14]. Either seronegative
SpA or FMF patients normally have negative RF. In
our case, we always detected low-titer IgM-RF positiv-
ity. Rheumatoid factor can rarely be positive in FMF
patients [15,16] and likewise in AS [17]. In this regard,
our seropositive FMF patient—also consistent with AS
criteria—presents an interesting clinical scenario.
Hip involvement has been reported previously in
FMF [4,8] and it is known that protracted attacks cause
Fig. 2 a T1-weighted sagittal MR image shows decreased disc spaces and end plate irregularities (discitis) at L2-3 and L3-4 levels (June
2001). bT1-weighted sagittal control MR showing the same findings with similar severity (March 2004).
85

cartilage destruction and, in some cases, aseptic necrosis
[4,8,18]. Sneh et al. [19] have mentioned that the poor
prognosis during hip involvement may be due not only
to the underlying metabolic aberration of the disease but
also to the impairment of the femoral head blood supply
secondary to the recurrent synovial exudation. Thus,
they have suggested early aspiration in preventing
aseptic necrosis. We must note in addition that our pa-
tient also had an important risk factor—steroid use—for
aseptic necrosis of the femoral head. Although our
patient’s spondylitic findings responded well to inflix-
imab treatment, a more satisfactory result might have
been overshadowed by unrelenting hip pain and dis-
ability, which could be attributed to osteonecrosis and
hip destruction.
The role of TNF-ain FMF has not yet been clarified.
The pertinent reports mention decreased/slightly in-
creased TNF-alevels during acute attacks or normal/
increased levels between the attacks [20–23]. Gang et al.
[24] have found increased levels of soluble TNF receptor
fusion protein p55 (sTNFr p55) and p75 (sTNFr p75)
during attacks. Besides, it is also known that the MEFV
gene is upregulated by TNF-a[25]. These data present
an insight towards a better understanding of the possible
benefit of anti-TNF treatment in FMF.
In closing, we overcame the FMF attacks of our
patient with infliximab, a murine-human chimeric
monoclonal antibody. Although the clinical findings of
our patient pertaining to spondylitis improved, we could
not achieve a significant change in the persistent hip pain
which was thought to occur due to osteonecrotic
destruction. In any case, a favorable effect of infliximab
on the structural destruction of the vertebral end plates
and the hip—which had been detected in the beginning
and had also persisted in the control MRIs—was not
expected. It is suggested that contrast enhance-
ment—which has a better capability for evaluating the
disease activity—and short sinversion recovery (STIR)
sequences could be used for better delineation of the
disease activity.
Overall, we believe that our results further highlight
the important role TNF-aplays in the pathogenesis of
FMF and that therapies targeting TNF-ahave the po-
tential to be a cornerstone in the treatment of FMF.
Take Home Message
The arthritis in FMF may sometimes resist colchicine
and DMARD treatments. The clinical scenario may
comprise spondylitic involvement and also seropositiv-
ity. Our case may shed light on the possible role of TNF-
ain the disease pathogenesis. This way, we believe that
anti-TNF therapy may reasonably be a future target in
FMF treatment.
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