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Radiographic healing with sustained clinical remission in a patient with rheumatoid arthritis receiving methotrexate monotherapy.

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Vol. 46, No. 10, October 2002, pp 2804–2807
DOI 10.1002/art.10568
© 2002, American College of Rheumatology
Radiographic Healing With Sustained Clinical Remission in a Patient With
Rheumatoid Arthritis Receiving Methotrexate Monotherapy
Siegfried Wassenberg and Rolf Rau
The most important goal in the treatment of
rheumatoid arthritis (RA) is to slow or even stop joint
destruction. Investigators have often questioned
whether radiographic improvement of joint damage
actually occurs, but such improvement can provide direct evidence that the destructive process has been
reversed. The recognition of reparative changes may
become even more important with the availability and
further development of more potent and faster-acting
antirheumatic drugs. To date, reparative changes have
been observed only with long-term monitoring of patients and when radiographs are obtained after profound
clinical improvement or remission has been achieved.
There may be a time lag of 6–12 months between the
time clinical improvement has been achieved and the
time improvement is evident radiographically. As a rule,
patients have to be followed up for several years before
radiographic repair can be recognized indisputably.
The present case report with radiologic images
demonstrates that remission and impressive repair of
severely damaged joints may occur with conventional
disease-modifying antirheumatic drug (DMARD)
monotherapy (in this case, methotrexate [MTX]) as
early as within 1 year of treatment initiation and that
improvement may continue over several years.
sulfasalazine was replaced by parenteral gold in April
1995. In August 1995, azathioprine (100 mg daily) was
added to the gold salt regimen.
At the time of first admission to the hospital in
February 1997, the patient had persistent swelling of
multiple joints of the hands, wrists, and forefeet. She
reported early morning stiffness of ⬎30 minutes. The
erythrocyte sedimentation rate (ESR) was elevated 39
mm/hour, and the C-reactive protein (CRP) level was
4.09 mg/dl. Rheumatoid factor had become weakly
positive (28 IU/liter). Radiographs of the hands, wrists,
and forefeet demonstrated severe destructive changes at
both wrists and the second metacarpophalangeal (MCP)
joints of both hands, and erosive changes at the left third
proximal interphalangeal (PIP) joint and the third distal
interphalangeal (DIP) joints on both sides; there were
also large erosions at the first, third, and fifth metatarsophalangeal (MTP) joints of the left foot and the first,
third, fourth, and fifth MTP joints of the right foot.
The combined treatment with parenteral gold
and azathioprine was switched to 15 mg MTX administered intramuscularly once a week without folic acid
supplementation. In addition, the patient underwent
inpatient treatment with rest, physiotherapy, occupational therapy, etc. During her hospital stay, the prednisolone dosage was reduced to 3 mg daily.
Four months later, in July 1997, the daily prednisolone dosage was tapered to 1.5 mg. The number of
swollen joints and intensity of the swelling had decreased significantly. The patient reported having no
early morning stiffness. The ESR was 25 mm/hour, and
the CRP level was 2.4 mg/dl. The MTX dosage and route
of administration were changed to 20 mg orally/week.
At followup in March 1998, 1 year after her first
admission, the patient noted no problems with her
joints. Prednisolone treatment had been stopped in
September 1997. There was only minimal soft tissue
swelling around the left third PIP joint. There was no
joint tenderness. The mobility of all joints was completely normal. The patient was very active, performing
Clinical course
The patient developed typical symptoms of RA
early in 1994, when she was 56 years old. The diagnosis
of seronegative RA was confirmed in September, and
treatment with sulfasalazine and prednisolone (10 mg
daily) was started. Because of incomplete response,
Siegfried Wassenberg, MD, Rolf Rau, MD, PhD: Evangelisches Fachkrankenhaus, Ratingen, Germany.
Address correspondence and reprint requests to Siegfried
Wassenberg, MD, Department of Rheumatology, Evangelisches Fachkrankenhaus, Rosenstrasse 2, D-40882 Ratingen, Germany. E-mail:
[email protected]
Submitted for publication March 25, 2002; accepted in revised
form July 10, 2002.
Radiographic changes
Left hand and wrist. In 1997 there was soft tissue
swelling at the ulnar and radial aspects of the left wrist,
the second MCP joint, and the second and third PIP
joints. Erosions were present at the ulnar styloid process
and the distal radius; the navicular bone was almost
Figure 1. Second metacarpophalangeal joint of the left hand. 1997,
The distal portion of the metacarpal head, representing ⬃70% of the
head, has nearly completely disappeared, with almost no bone structure left; the cortical plate is mostly destroyed. Bone resorption and
cortex destruction are also present at the base of the proximal phalanx.
1998, New bone fills the previous “osteolysis”; the margin of this new
bone is sclerosed and the cortical plate is rebuilt. The joint surface is
still somewhat irregular. The bone at the base of the phalanx is also
sclerosed. 1999/2000, The tendency toward rebuilding a normal shape
of the joint continues.
gymnastics, swimming, bicycling, working in the garden,
and managing her household. The ESR was 19 mm/
hour, the CRP level was normal (0.5 mg/dl), and rheumatoid factor was again negative. The patient was then
followed up in the outpatient clinic every 6 months, and
her RA remained in remission (last visit November
2001). Her functional capacity remained completely
normal. She continued to bicycle, jog, work in the
garden, and run her household without any limitations.
Her hemoglobin level had increased from 11.3 gm/dl in
1997 to 13.8 gm/dl in 2001. The ESR at the last visit was
14 mm/hour.
Figure 2. Fifth metatarsophalangeal joint of the left foot. 1997, The
metatarsal head appears to be severely destroyed by a long erosion at
the fibular aspect; the margin of this erosion is fuzzy and indistinct.
The cortical plate is resorbed. Within the subchondral bone there are
additional erosions shown en face, appearing as cysts. There is a large
radiolucent area (“cyst”) near the tibial aspect of the bone. Subchondral osteoporosis is evident at the base of the proximal phalanx. 1998,
The bone structure appears to be more dense and somewhat sclerosed,
the “cysts” have been filled in, the edge of the fibular erosion has
become less irregular, and there is again an impression of a cortical
plate. The erosion has flattened compared with 1997. 1999, The bone
sclerosis has further increased. The shape of the erosion, previously
concave, has become convex, partly due to new bone formation. 2000,
There is a tendency toward rebuilding of the original metatarsal head
cysts and erosions were present at the ulnar styloid, the
distal radius, and the navicular, multangular, and capitate bones. Erosions could also be seen at all metacarpal
bases, the second MCP joint, and the third DIP joint,
with smaller erosions also at the second and fourth DIP
joints. With time, filling in of these erosions and development of bony sclerosis could be observed. Soft tissue
swelling disappeared.
Both forefeet. In 1997 radiographs demonstrated
splay feet, with subluxation of the MTP joints and hallux
valgus. There were extensive erosions at the first, third,
and fifth MTP joints of the left foot, and erosions were
also present, though less extensive, at all MTP joints of
the right foot. During followup, impressive reparative
changes with remodeling became obvious.
Sequential radiographs obtained between 1997
and 2000 are shown in Figures 1–3.
Figure 3. Third metatarsophalangeal joint of the left foot. 1997,
There are several large and deep erosions with indistinct margins on
both sides of the metatarsal head and at the base of the proximal
phalanx. At these sites, the bone is almost completely resorbed. The
cortical plate has disappeared, and nearly no articulating joint surface
is preserved. 1998, At the sites of previous “osteolysis” at the metatarsal head, bone structure has reappeared. New bone fills in the
previous defects. The bone is sclerosed. The erosion at the base of the
proximal phalanx has also been filled in. 1999/2000, New bone
formation has continued, and the cortical plate appears normal again.
There is a tendency toward formation of a normal metatarsal head and
a normal base of the phalanx, including restoration of joint space. In
2001 (not shown), the tendency toward normalization continued.
completely destroyed. There were also erosions at the
multangular and capitate bones and the second MCP,
third PIP, and third DIP joints. During followup, soft
tissue swelling disappeared, and the erosions were filled
in by newly formed bone; the subchondral bone showed
signs of sclerosis.
Right hand and wrist. Radiographs obtained in
1997 revealed soft tissue swelling at the right wrist, the
second MCP joint, and the third DIP joint. Subchondral
The present case demonstrates that clinical remission could be achieved within 1 year of monotherapy
with MTX in a patient with active and severely erosive
RA and that after 1 year, clear reparative changes with
filling in of erosions and bone sclerosis could be observed radiographically. Clinical remission has been
sustained for 4 years, with complete restoration of
functional capacity and further stabilization of the previously severely destroyed joints. Several forms of repair
were observed: 1) recortication, 2) partial or complete
filling in of erosions, and 3) remodeling with a tendency
to regain shape for normal function. In some cases,
secondary “osteoarthritis” may develop in other joints,
characterized by joint space narrowing, subchondral
sclerosis, and osteophyte formation. Previous reports
have also described healing of eroded joints in RA
With conventional DMARDs (sometimes called
“slow-acting” drugs), it takes time to achieve clinical
remission, and the process of bone repair does not start
until after clinical remission has occurred. There is a gap
of 6–12 months between the time clinical improvement
occurs and the time signs of repair can be recognized on
plain radiographs (12). Complete clinical remissions are
rarely seen during clinical trials and followup is usually
too short to detect radiographic repair; therefore, investigators have not deemed it necessary to consider radiographic healing in the context of assessing improvement
in clinical trials. With the availability of more rapidly
acting and more effective drugs (i.e., tumor necrosis
factor inhibitors), the need to describe repair, even
within the relatively short period of clinical trials, may
become crucial. Healing phenomena (or repair) can
serve as direct evidence of arrested destruction in an
individual joint.
The scientific community should try to agree on
whether and how healing phenomena can be integrated
into existing scoring methods, for example, by reducing
the radiographic score in the case of recortication and/or
filling in. Alternatively, joints with different radiographic
indicators of repair, for example recortication, filling in,
“secondary” osteoarthritis, or a combination of these,
could be considered in addition to conventional scoring.
Moreover, the number of joints with remodeling, having
regained apparently normal shape for regular function,
could be noted. A standard method to quantify healing
or repair of joint destruction would certainly be of
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receiving, patients, clinical, radiographic, arthritis, sustained, methotrexate, healing, monotherapy, rheumatoid, remission
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