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Long-term followup of rheumatoid arthritis patients treated with total lymphoid irradiation.

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Arthritis & Rheumatism
Official Journal of the American Rheumatism Association
LONG-TERM FOLLOWUP O F
RHEUMATOID ARTHRITIS PATIENTS TREATED WITH
TOTAL LYMPHOID IRRADIATION
A. TANAY, E. H. FIELD, R. T. HOPPE, and S . STROBER
Total lymphoid irradiation was administered to
32 patients with intractable rheumatoid arthritis. Twentyfour patients showed at least a 25% improvement in 3 of
4 disease activity parameters, which persisted during
the followup period of up to 48 months. Eight of the 32
patients required adjunctive immunosuppressive drug
therapy to maintain improvement. Four patients died
after total lymphoid irradiation; the causes of death
were acute myocardial infarction (1 patient), pulmonary
embolism (1 patient), and rheumatoid lung disease
complicated by respiratory infection (2 patients). After
therapy, patients exhibited a prolonged reduction in the
number and function of circulating T helper cells.
during a 6-month observation period (7). The frequency and type of complications reported in the 3
uncontrolled studies varied considerably. Brahn et a1
( 5 ) reported a high frequency of staphylococcal septicemia (4 of 12 patients) and xerostomia with tooth
decay (4 of 12 patients); in contrast, Niisslein et a1 (6)
made no mention of the latter complication, but reported a high frequency of amyloidosis ( 2 of 11 patients) and of bacterial infections (2 of 1 1 patients).
The lowest frequency of severe side effects was found
by Field et a1 (3), who reported no staphylococcal
septicemia, xerostomia with tooth decay, or amyloidosis in I I patients.
The present report describes the long-term (up
to 4 years) followup of 32 patients with intractable RA
who were treated with TLI (2,000 rads) at the Stanford
University Medical Center, and who participated in
uncontrolled and controlled studies. The techniques,
efficacy, side effects, and patient characteristics are
compared with those in previously reported studies.
Total lymphoid irradiation (TLI), a radiotherapy procedure that has been used during the past 20
years to treat Hodgkin’s disease, also has been used to
treat intractable rheumatoid arthritis (RA) (1-3). Three
uncontrolled studies of the use of TLI in RA showed
significant improvement in joint disease activity with
followup periods of up to 3 years (2-6). A controlled
study using 2,000 rads versus 200 rads showed that
TLI was effective in reducing joint disease activity
PATIENTS AND METHODS
Patients. Thirty-two patients referred from the
Stanford University Hospital Immunology Clinic or from the
private clinical rheumatology staff affiliated with t h e
Stanford University Medical Center were entered into the
study between May 1979 and April 1984. Patients had no
chronic bacterial infections, vasculitis, history of Felty’s
syndrome, severe anemia (hematocrit <25%), leukopenia
(<4,500 cells/mm3), or t h r o m b o c y t o p e n i a (platelets
< 100,000/mm3) upon entry. The potential risks and benefits
of TLI were explained to the patients and their families, and
signed informed consent was obtained under the guidelines
of the Committee on Medical Human Subjects at the
Stanford University Medical Center.
From the Departments of Medicine and Radiology,
Stanford University School of Medicine, Stanford, California.
Supported by NIH grant AI-11313.
A. Tanay, MD: Postdoctoral Fellow, Division of Immunology, Department of Medicine; E. H. Field, MD: Postdoctoral
Fellow, Division of Immunology, Department of Medicine; R. T.
Hoppe, MD: Associate Professor of Radiology, Division of Radiotherapy, Department of Radiology; S. Strober, MD: Professor of
Medicine, Division of Immunology, Department of Medicine.
Address reprint requests to S . Strober, MD, Department of
Medicine, Division of Immunology, Stanford University Medical
Center, Stanford, CA 94305.
Submitted for publication March 4, 1986; accepted in revised form May 27, 1986.
Arthritis and Rheumatism, Vol. 30, No. 1 (January 1987)
1
TANAY ET AL
2
Table 1. Rheumatoid arthritis patient characteristics before treatment with total lymphoid irradiation*
Parameter
Age
Disease duration (years)
Females/males
Functional class
No. with positive R F
(titer >1:40)
Geometric mean titer in patients with positive
R F (- 10 log,)
No. receiving prednisone at entry
No. previously treated with azathioprine
No. previously treated with
cyclophosphamidet
No. previously treated with chlorambucilt
No. previously treated with methotrexate
* All values are number of patients or mean
47.8 2 3.2
12.1 2 1.3
19/13
2.9 2 0.08
3 1/32
7.5 t 0.31
27/32
14/32
5/32
1/32
4/32
C SEM. RF
rheumatoid factor.
t Duration of therapy 5 6 months (see Patients and Methods).
=
All patients had classic or definite rheumatoid arthritis as judged by American Rheumatism Association criteria
(8), with several joints affected by active synovitis at the
time of entry into the study. In each patient, disease activity
had resulted in loss of function such that normal self-care
and household or professional duties could not be carried
out. All patients were judged to have the capacity for some
return of joint function. Additional characteristics of these
patients are presented in Table 1.
All patients had radiographs of the hands and wrists
obtained within 2-6 months before TLI. One patient had soft
tissue swelling, osteoporosis, and joint space narrowing
without erosions, and the rest of the patients had erosive
joint destruction (at least grade 2, by the grading criteria of
Larsen 191). All patients had been treated previously with
multiple nonsteroidal antiinflammatory drugs (NSAIDs),
gold salts, and D-penicillamine. In each patient, these therapies were considered to have failed because of persistent
disease activity or unacceptable side effects. Twenty-four
patients had previously received at least 1 cytotoxic drug or
antimetabolite (azathioprine, 14 patients; methotrexate, 4
patients; cyclophosphamide, 5 patients; or chlorambucil, 1
patient), without benefit.
Prior to the start of radiotherapy, cytotoxic drugs,
antimetabolites, gold, and D-penicillamine were discontinued for at least 6 weeks. For patients who were receiving
>10 mg of prednisone daily, the dosage was tapered to 510
mg daily on entry into the study. During the treatment period
and for 6 months after radiotherapy, an attempt was made to
maintain the same dosages of NSAIDs and prednisone that
were in use at study entry.
The patients in this long-term followup study were
originally included in 2 previous studies. Eleven patients
were given TLI in an uncontrolled feasibility trial (2), and 21
patients had participated in a randomized, double-blind,
controlled study which compared the efficacy of 2,000-rad
TLI (high-dose group) and 200-rad TLI (low-dose group) (7).
These 21 patients from the double-blind study consisted of
13 patients who were randomly assigned to high-dose TLI
and 8 patients who were randomly assigned to low-dose TLI.
The latter patients had <25% improvement in 3 of 4 joint
disease parameters (to be described later) at the 6-month
point, and were given high-dose TLI shortly thereafter.
Radiotherapy. TLI was administered with a 6-mV
linear accelerator in the Division of Radiation Therapy,
Stanford University Medical Center, by previously described techniques (2,3). Irradiation was first administered
to the “mantle” field, which included the cervical, axillary,
mediastinal, and hilar lymph nodes and the thymus. Then,
without interruption of treatments, irradiation was applied to
lymphoid tissues below the diaphragm, including the
paraaortic, iliac, and inguinal-femoral lymph nodes (“inverted Y” field) and the spleen. In female patients of
childbearing age, the pelvic area was shielded to prevent
damage to the ovaries.
Patients received 200-rad fractions to the “mantle”
field 5 days each week over a period of 2-3 weeks, until a
total dose of 2,000 rads was achieved. Immediately thereafter, 150-rad fractions were administered 4 days each week to
the subdiaphragmatic fields, to achieve a total dose of 2,000
rads over 3 weeks.
Clinical assessment. To establish baseline data, patients were evaluated on 2 occasions before treatment. An
attempt was made to evaluate every patient at least once
every 6 months after TLI. Two physicians and a physical
therapist were involved in obtaining all measurements. On
each occasion, joints were assessed with the use of a
mannequin. Each joint was scored for both tenderness and
swelling, on an arbitrary scale of 0-4 (2,3). Seventy-eight
joints were scored; therefore, the possible total score for all
determinations was 3 12.
Right and left grip strength were measured, and an
overall assessment was made by the examining physician. In
addition, 11 subjective variables were analyzed. Thus, the
following 14 separate components, each scored on an arbitrary scale (W),made up the global composite score (possible total score of 56): 1) duration of morning stiffnessnone = 0, 1-30 minutes = 1, 31-60 minutes = 2, 61-120
minutes =- 3, >121 minutes = 4; 2) further involvement of
joints-no further joints involved = 0, 1 additional joint
involved == 1, 2 4 additional joints involved = 4; 3) development of new nodules-no nodules = 0, 1 nodule = 1, 2 4
nodules = 4; 4) night pain and 5 ) day pain-none = 0, mild
= 1, moderate = 2, severe = 3, the worst possible = 4; 6)
patient’s assessment of general status-very good = 0, good
= 1, fair =- 2, bad = 3, very bad = 4; 7) patient’s assessment
of overall change since last visit-much better = 0, better =
1, same == 2, worse = 3, much worse = 4; 8) bathing, 9)
dressing, 10) eating, and 11) housework-no problem = 0,
mostly possible without help = 1, some difficulty without
help = 2, very difficult without help = 3, impossible without
help = 4; 12) left and 13) right grip strength-2201 mm Hg =
0, 151-200 mm Hg = 1, 101-150 mm Hg = 2,51-100 mm Hg
= 3, 30-50 mm Hg = 4; and 14) physician’s overall impression-very good = 0, good = 1, fair = 2, bad = 3, very bad
= 4. (Change in the duration of morning stiffness is reported
separately in the Results section despite the inclusion of this
measurement in the global composite score, since morning
stiffness has been commonly used by itself as a measure of
disease activity.) It should be noted that some of the
components of the global score, such as night pain and day
pain, may be influenced by factors other than joint disease
activity (i.e., neuromuscular abnormalities).
TLI IN RA
3
STIFFNESS
100
I2
W
5>
-
0 GLOBAL
TENDERNESS
0 SWELLING
80
2
z
60
I-
40
5
20
Q
tu
Q
0
I
1
I
1
I
I
I
[
6
12
18
24
30
36
42
48
MONTHS AFTER T L I
NO. O F PATIENTS
32
32
32
32
STUDIED
MAX No'oF PTS
AVAILABLE
30
20
14
8
11
6
6
31
24
21
18
16
8
8
Figure 1. Changes over time in disease activity, after total
lymphoid irradiation (TLI) in 32 patients. Percent improvement was
calculated by comparing the mean pretreatment values with the
mean values obtained after TLI. The mean post-treatment score for
each 6-month point was obtained by averaging all values obtained
from individual patients during the time interval that began 3 months
before the time point and ended 3 months after the time point (i.e.,
the 6-month time point covers the interval from 3-9 months after
TLI). The mean pretreatment score was obtained at 2 time points for
each patient, within 2 weeks before the start of TLI. Maximum
number of patients available includes all surviving patients who
reached a given time point after TLI. Each point represents the
mean -t SEM percent improvement.
Absolute lymphocyte count. Blood samples were usually obtained at the time of clinical evaluation. The absolute
lymphocyte count was calculated from the total leukocyte
and differential counts.
Mitogen stimulation of peripheral blood mononuclear
cells (PBMC). Peripheral blood mononuclear cells were
separated from fresh defibrinated blood or anticoagulated
white blood cell concentrates on Ficoll-Hypaque gradients
(Ficoll: Sigma, St. Louis, MO; Hypaque: Winthrop Laboratories, New York, NY) as previously described (2). Assays
of the in vitro proliferative response of PBMC after stimulation with phytohemagglutinin were performed as reported
in detail elsewhere (2,3). PBMC (1 x lo5) were stimulated
with mitogen and cultured for 3 or 6 days. Thereafter, 1.0
pCi of 3H-thymidine (6.7 Ci/mmole; New England Nuclear,
Boston, MA) was added to each culture and incubation
was continued for another 18 hours. The cells were harvested, and the incorporation of tritiated thymidine was
measured in a liquid scintillation counter. All tests were
performed in triplicate. Background values were < 1,000
counts per minute.
Mixed leukocyte reaction. A unidirectional mixed
leukocyte reaction (MLR) was carried out with 5 x lo4
responder PBMC and 5 X lo4 irradiated (3,000 rads) stimulator cells, as described previously (2,3). Triplicate cultures
were incubated for 6 days before the addition of 3Hthymidine. Background 3H-thymidine incorporation was
uniformly < 1,000 cpm.
Pokeweed mitogen-stimulated immunoglobulin
synthesis. PBMC (2 X lo5) were stimulated with pokeweed
mitogen (PWM) as reported previously (2,3). On the eighth
day of culture, cells from several wells were pooled, washed
3 times, and assayed for plaque-forming cells. The data are
expressed as number of plaque-forming cells per lo6 cells
placed into culture.
A reverse hemolytic plaque assay was used to detect
cells secreting IgM and IgG (10). Protein A (Pharmacia,
Uppsala, Sweden) was coupled to sheep red blood cells by
the chromic chloride method. Class-specific developing
antisera (rabbit anti-human IgM; Kallestad Laboratories,
Chaska, MN and rabbit anti-human IgG; Dako, Santa
Barbara, CA) were used. Assays were performed in triplicate, and data from each experiment were expressed as
mean ? 1 SEM. Background plaque-forming cells were uniformly < 1OO/per lo6 cells.
Analysis of T lymphocyte subsets with monoclonal
antibodies. Murine monoclonal antibodies to human Leu-2,
Leu-3, and Leu-4 lymphocyte surface antigens were obtained from Becton Dickinson, Mountain View, CA. Previous studies have shown that the Leu-4 antigen identifies all T
cells, the Leu-2 antigen identifies most T suppressor/
cytotoxic cells, and the Leu-3 antigen identifies most T
helperiinducer cells ( I 1,12). The monoclonal antibodies were
used as first-stage reagents for immunofluorescence staining
of PBMC. A fluorescein-conjugated goat anti-mouse IgG
antibody (Tago, Burlingame, CA) was used as the secondstage reagent. Details of analysis of stained cells with the
fluorescence-activated cell sorter (FACS-111) have been described elsewhere (13).
Target lymphoid cells (1 x lo6) were incubated with
saturation levels of first-stage and second-stage reagent.
FACS scatter gates were set to include the small lymphocyte
fraction of PBMC, and the percentage of small lymphocytes
that showed specific staining was determined. Background
staining was obtained by substituting an IgG1 mouse
myeloma protein (MOPC-21; Litton Bionetics, Kensington,
MD) as the first-stage reagent. In general, background staining showed <2% positive cells with the fluorescence intensity thresholds used for analysis.
Followup procedures. After TLI, all 32 patients were
requested to have an evaluation of clinical and laboratory
parameters at least once every 6 months. At each serial time
point, the number of patients who were evaluated declined,
since some patients had not yet reached the given time point.
Four patients died, 1 was lost to followup after leaving the
United States, and some refused to comply with the request
for evaluation at the given time point. The maximum number
of patients available at a given point was taken as the number
of living patients who had reached that interval after TLI.
The 1 patient lost to followup at 6 months was noted as being
not available after that point. Information regarding complications and medications of patients who refused to have an
evaluation was obtained by telephone communication with
either the patients or their local physician(s). In almost all
cases, the reason given for refusal of evaluation at a specific
time point was difficulty in obtaining transportation to the
medical center.
4
TANAY ET AL
RESULTS
other parameters was observed during the 30-48month interval, but too few patients were evaluated
( 5 3 patients) to draw any conclusions.
Changes in joint disease activity of patients who
received adjunctive drugs versus those who did not
receive adjunctive drugs. In all cases, the decision to
administer adjunctive drugs was made by the patient's
private physician, in most cases in concordance with
our clinic. The decision was based on a clear and
sustained trend of increase in the patient's clinical
disease activity. When adjunctive drugs were begun,
the patient began receiving his or her primary care
from the private physician, but continued to be followed up at our clinic for clinical assessment. Six
patients received methotrexate as the first adjunctive
drug, and 1 received methotrexate after a course of
gold compounds. One patient had a combination regimen of cyclophosphamide, azathioprine, and hydroxychloroquine. One of the patients who was taking
methotrexate was switched to D-penicillamine and 1
was switched to azathioprine, due to lack of efficacy of
methotrexate. One patient given adjunctive drugs was
never studied after the drugs were begun; thus, only 7
of 8 patients were studied while receiving adjunctive
drugs (Table 2).
The disease activity of the 8 patients who
received adjunctive drugs was compared with that of
the group who never received these drugs (Figure 3).
The pattern of improvement in the latter group was
similar to that observed for all patients (Figure 1).
However, the former group showed about 30% less
improvement in joint tenderness and swelling scores
during the first 18 months, compared with the nondrug group. In addition, the drug group showed a
decline in improvement in morning stiffness and global
scores in the 6-18-month interval. Up to 30 months,
global scores continued to decline.
Maintenance medications and surgery. Twentyseven of 32 patients were receiving prednisone (mean
6.5 mglday) just before TLI. At the last observation
Changes in joint disease activity after TLI in all
patients. Figure 1 shows the mean changes in clinical
measurements of disease activity noted in the 32
patients. The majority of the patients began to show
clinical improvement after 3 months of therapy. At
about 6 months after TLI, the magnitude of the improvement reached a plateau. At 1 year, 30 of the 32
patients showed a mean (+SEM) improvement of 58 5
8.5% in morning stiffness, 33 t 4.6% in global composite score, 45 + 9.5% in joint tenderness, and 50 5
7.8% in joint swelling. At 24 months after TLI, the
mean improvement was 74 7.9%, 32 t 5.7%, 41 5
17.1%, and 41 t 15.9%, in the 4 parameters, respectively. The 11 patients studied at 3 years maintained
the level of improvement observed earlier. After 3
years, greater fluctuations in the mean scores were
probably due to the small number of patients evaluated
(6). However, even at 48 months, no discernible trend
toward relapse or exacerbation was noted. As seen in
Table 2, 8 patients were given "second-line'' adjunctive drugs at various time points after TLI, due to
worsening joint disease activity.
Changes in joint disease activity in responders
versus nonresponders. In a previous study (7), a responder was arbitrarily defined as a patient who, by 6
months, had at least 25% improvement in 3 of 4
parameters (morning stiffness, joint tenderness, joint
swelling, and global composite score). Figure 2 shows
the joint disease activity changes, as measured by the
4 parameters, in the responder versus the nonresponder groups. These groups initially consisted of 24 and 8
patients, respectively. The mean percent improvement
in the responder group closely followed that of all the
patients (Figure I), but the magnitude was approximately 5-10% higher. The nonresponder group
showed a different pattern. Although there was considerable improvement in morning stiffness during the
6-24-month interval, little or no improvement was
observed in the other parameters. Improvement in the
*
Table 2.
Patient
Type of adjunctive drug and time (months) given after total lymphoid irradiation
Gold
compounds
D-penicillamine
Azathioprine
3748
1
2
3
25-36
3748
4
5
6
7
8
Methotrexate
C yclosphosphamide,
azathioprine, and
hydroxychloroquine
7-12
27-30
25-48
4348
1948
3 1-36
13-18
15-27
5
TLI IN RA
loo[
c
2
5>
60
c
40
g
20
2
0
0
c
80
0
K
n
z
(B)
80
STIFFNESS
GLOBAL
TENDERNESS
SWELLING
5
I-
I
IA
60
n
40
20
W
n
Ih
1;
O!
118
i4
i0
36
3b
418
412
MONTHS AFTER TLI
36
42
48
MONTHS AFTER TLI
NO. OF PATIENTS
STUDIED
24
24
23
16
10
8
9
4
5
8
8
7
4
4
0
2
2
1
MAX N o . o F P T S
24
24
23
17
15
14
11
6
6
8
8
8
7
6
4
5
2
2
AVAILABLE
Figure 2. Changes over time in disease activity, after total lymphoid irradiation (TLI) in 32 patients who, at the 6-month time point after TLI,
were defined as responders (n = 24) (A) or nonresponders (n = 8) (B). At the 12-month, 36-month, and 48-month time points, the number of
responder patients studied who were receiving adjunctive drugs was 1 of 23, 1 of 9, and 3 of 5 , respectively. At the 36-month and 48-month time
points, the number of nonresponder patients studied who were receiving drugs was 1 of 2 and 1 of 1, respectively. At all other time points, none
of the responder or nonresponder patients studied were receiving these drugs. See Figure 1 for explanations.
(A)
0
0
I-
z
F
loor
(B)
STIFFNESS
GLOBAL
TENDERNESS
SWELLING
lOOr
c
80
60
60
40
40
20
20
z
W
u
K
W
n
n
"0
6
24
24
22
14
MAX No'oFPTS
AVAILABLE
24
24
23
17
18
24
-
50
36
42
48
MONTHS AFTER TLI
MONTHS AFTER T L I
NO. OF PATIENTS
STUDIED
12
8
4
3
8
8
8
6
4
2
3
2
3
10
4
4
8
8
8
7
7
7
6
4
4
NO. O F PATIENTS
STUDIED AND
O N DRUGS
0
0
1
0
0
0
2
1
3
FRACTION OF
M A X NO. OF
AVAILABLE PTS
O N DRUGS
0
0
1
0
1
4
4
3
3
8
8
8
7
7
7
6
4
4
14
11
Figure 3. Changes over time in disease activity, after total lymphoid irradiation (TLI) in 24 patients who never received adjunctive drugs after
TLI (A) and in 8 patients who received adjunctive drug therapy at various time points after TLI (B). See Figure 1 for explanations.
TANAY ET AL
point, 23 patients were still taking this drug, at a mean
dosage of 5.7 mg/day. Before TLI, 16 of the patients
were regularly taking aspirin, at a mean dosage of 4.0
gm/day. The mean daily dosage in the same 16 patients
at the last observation point was relatively unchanged
(3.5 gm). Analysis of the mean daily dosage of other
NSAIDs showed minimal changes after TLI.
Eleven patients had a total of 13 reconstructive
hand or foot surgeries performed at various time
points after radiotherapy, ranging from 4 months to 43
months. Two patients had neck surgery (vertebral
body fusion), 2 had total hip replacements, 1 had an
elbow replacement, and 6 patients had 11 total knee
replacements.
Complications. Complications experienced by
the patients are summarized in Table 3. During and
shortly after radiotherapy, all patients had 1 or more of
the following: fatigue, nausea, vomiting, loss of appetite, skin irritation, xerostomia, dysphagia, and transient axillary o r occipital hair loss. These symptoms
were not severe enough to require interruption of
treatment o r work, or to necessitate hospitalization.
All symptoms subsided within 2 months after TLI.
Because of severe neutropenia (<2,000 cells/mm3), 4
patients had their treatment interrupted until the white
blood cell count returned to normal (within a range of
1 4 weeks). Two of the 4 were hospitalized and treated
with antibiotics. In 1 case, a splenectomy was performed, and in the other, a rectal abscess was drained.
One patient developed a transient neutropenia with no
symptoms, 1 month after completion of TLI.
Herpes zoster, localized to a single dermatome,
was found in 6 patients, and in 1 patient, disseminated
zoster was observed. All cases of herpes zoster resolved spontaneously. Transient clinical pericarditis
was observed in 3 patients, and transient pleuritis and
pneumonitis in 1. A bleeding gastric ulcer was found 1
month after TLI in a patient who was receiving
prednisone and NSAIDs. One patient who had documented rheumatoid lung disease prior to TLI had a
pronounced worsening of her respiratory status 3
months after radiation therapy. Eighteen months after
TLI, the patient developed a pulmonary infection and
died. One patient developed severe thrombocytopenia
4 months after TLI; this resolved after intravenous
administration of gamma globulin. During his hospitalization, this patient developed a staphylococcal septicemia, with a normal white blood cell count, due to an
infected indwelling intravenous catheter. This responded favorably to antibiotics.
Four patients died, at 9, 18, 18, and 48 months
after TLI, respectively (Table 3). The first, a 58-year-
Table 3. Morbidity and mortality in 32 rheumatoid arthritis
patients treated with total lymphoid irradiation
Manifestation
Fatigue, nausea, vomiting, loss of appetite,
skin irritation, xerostomia, dysphagia, transient
axillary or occipital hair loss
Leukopenia (<3,000cells/rnrn’)
Thrombocytopenia (<100,000 platelets/mm3)
Severe anemia (hematocrit <25%)
Transient pericarditis
Transient pneumonitis
Bleeding gastric ulcer
Felty’s syndrome
Herpes zoster
Localized
Generalized
Flare of rheumatoid lung disease
Bacterial infections
Pneumonia
Sinusitis
Osteornyelitis
Staphylococcal pericarditis
Xerostomia
Transient
Chronic
Tooth loss, 2 4 teeth
Cutaneous vasculitis
Cardiovascular
Myocardial infarction
Pulmonary embolism
Cerebrovascular accident
Peripheral vascular thrombosis
Hypothyroidism
Malignancy
Persistent thrornbocytopenia
Persistent leukopenia
Enteritis
Deaths
Myocardial infarction
Pulmonary embolism
Respiratory failure complicating
rheumatoid lung disease
No. of patients
32
6
1
0
3
1
1
1
6
1
2
3
1
1
1
6
2
2
1
2
1
I
1
0
0
0
0
0
I
I
2
old woman with a history of arteriosclerotic cardiovascular disease and chronic atrial fibrillation, had an
acute myocardial infarction. The second, a 68-year-old
woman with a history of deep vein thrombophlebitis,
died of a massive pulmonary embolism 14 days after a
total hip replacement. The third patient died of rheumatoid lung disease, as described above. The fourth
patient, a 71-year-old man, had severe obstructive
atherosclerotic peripheral vascular disease, which necessitated amputation of one leg below the knee.
Osteomyelitis developed in the stump. This patient
died of pneumonia and respiratory failure 48 months
after TLI. At autopsy, extensive rheumatoid lung
disease was found.
One patient developed cutaneous vasculitis 24
months after TLI, with ulcerative lesions on the skin
of the lower extremities. One patient had 2 episodes of
TLI IN RA
7nn.
'
o
o
1
0
l 80
F
X
-1
v)
-1
W
0
0
z
E
9
W
2
U
4a
BEFORE
TLI
BEFORE
TLI
MONTHS AFTER TLI
NO. OF PATIENTS
STUDIED
0-12
3o
27
12-24 24-36 36-48
17
BEFORE
TLI
0-12
28
27
12-24 24-36 36-48
18
7
5
0-12 12-24
24
27
16
24-36 36-48
8
5
Figure 4. A, Changes over time in peripheral blood mononuclear cell (PBMC) 'H-thymidine incorporation in the allogeneic mixed leukocyte
reaction, after total lymphoid irradiation (TLI). Each dot represents the mean response of an individual patient against 3 separate allogeneic
stimulators. B, Changes over time in PBMC 'H-thymidine incorporation in response to phytohemagglutinin, after TLI. Each dot represents the
mean of triplicate responses of an individual patient. C,Changes over time in in vitro pokeweed mitogen-stimulated IgG secretion measured
by plaque-forming cells, after TLI. Each dot represents the mean of triplicate values for an individual patient. (Horizontal lines represent the
medians. See Figure 1 for additional explanations.)
sinusitis, which responded to antibiotic therapy and
did not require hospitalization. Two patients each had
2 episodes of infected skin over a protruding first
metatarsal head. Loss of more than 4 teeth was
reported in 2 patients. Both patients complained about
persistent xerostomia, which ensued shortly after TLI.
None of the patients developed enteritis, hypothyroidism, or a malignancy during the followup period.
Complications of blood element depression, infection,
and/or rheumatoid lung disease in this group of patients resulted in hospitalization of a total of 6 patients.
Changes in immunologic parameters after TLI.
Figure 4A shows changes in the in vitro responses of
PBMC to allogeneic lymphocytes (MLR) after TLI.
Prior to TLI, the patients' median MLR response was
33,000 cpm (range 14,000-85,000). In the first year
following TLI, the MLR was reduced to a median of
8,000 cpm and ranged from 3,400-20,000. A substantial decrease in the MLR was observed also in the
second year after radiotherapy (median 12,000 cpm,
range 2,000-33,000). However, in the 7 and 5 patients
studied in the third and the fourth years, respectively,
after TLI, the MLR appeared to be recovering (median
15,000 cpm, range 4,00045,000 and median 21,000
cpm, range 2,600-38,000).
Figure 4B shows changes in the in vitro proliferative response of patients' PBMC after incubation
with phytohemagglutinin (PHA). Before TLI, the patients' median response to PHA was 67,000 cpm
(range 20,000-172,000). This range is similar to that of
healthy controls (7). In the first year following TLI, the
median response to PHA decreased to 15,000 cpm and
ranged from 2,900-81,OOO. This decrease in the responsiveness to PHA continued in the second year
following TLI (median 17,000 cpm, range 5,00089,000). In the 7 patients who were studied in the third
year after TLI, the PHA appeared to be recovering
(median 32,000 cpm, range 4,000-163,000). However,
in the few patients who were studied during the fourth
year after treatment, a continued recovery was not
observed (mean 27,000 cpm, range 9,300-30,000).
Figure 4C shows the ability of PBMC to secrete
IgG in vitro after stimulation with PWM. Before
treatment, PBMC generated a median of 9,000 IgG
plaque-forming cells (PFC) per lo6 plated cells (range
6 3 4 , 0 0 0 ) . During the first year following radiotherapy, the IgG secretion of the PBMC was reduced
profoundly, to a median of 800 PFC (range 37-5,000).
The reduced level of IgG secretion persisted throughout the second and third years after TLI (median 1,600
PFC, range 674,000 and median 1,500 PFC, range
50-5,500, respectively). However, there appeared to
be a partial recovery of the IgG secretion in the 5
patients studied in the fourth year (median 3,000 PFC,
range 110 to 7,000).
Changes in the absolute lymphocyte counts and
T cell subsets in the patients' peripheral blood after
TLI are shown in Figure 5. The mean 2 SEM absolute
lymphocyte count before TLI was 1,287 2 101
cells/mm3, which was within the normal range. The
mean absolute counts of the T helperlinducer (Leu-
8
TANAY ET AL
m
E
0
1200 -
.
2
HELPER/INDUCER T CELLS
E
800 -
J
w
u
NO. OF PTS
Changes in laboratory parameters after TLI.
The patients’ mean erythrocyte sedimentation rate
(Westergren) was essentially unchanged from baseline
at the last observation point after TLI (before TLI,
mean 5 SEM 60.5 ? 4.6 mm/hour, after TLI, 56.4 -+
5.4 mm/hour; P > 0.2, Student’s unpaired t-test).
Little change was found in the hematocrit value (before TLI. 36.9 0.9%, after TLI, 37.5 ? 0.9%; P >
0.2, Student’s unpaired t-test). The serum rheumatoid
factor titer showed a slight rise, but this change was
not significant (-10 log, titer: before TLI, 7.5 2 0.31,
after TLI, 8.1 k 0.25; P > 0.2, Student’s unpaired
t-test). A similar pattern was observed in those patients with positive fluorescent antinuclear antibody
results (--I0 log, titer: before TLI, 2.7 ? 0.2, after
TLI, 3.6 ? 0.3; P > 0.2, Student’s unpaired t-test).
*
322222
STUDIED
32 26
26
20,,17
10, 7
7
5
5
BEFORE
TREATMENT
MONTHS AFTER TLI
0-12
12-24
24-36
36-48
Figure 5. Changes over time in the absolute lymphocyte count, the
absolute number of T suppressodcytotoxic (Leu-2+) cells, and the
absolute number of T helpedinducer (Leu-3+) cells in the peripheral
blood, after total lymphoid irradiation (TLI). Horizontal lines represent the means and SEM. See Figure 1 for additional explanations.
3 t ) cells and T cytotoxic/suppressor (Leu-2+) cells
before treatment were depressed when compared with
normal values (Leu-3+ cells, 563 ? 71 [normal 870 +
591; Leu-2+ cells, 243 5 35 [normal 469 f 591). The
greatest depression in the absolute lymphocyte count
and in the number of Leu-2+ and Leu-3+ cells was
observed during the first month after TLI. By 3
months, the absolute lymphocyte count began to recover, but it still remained at about 35% of the
pretreatment value. By 1 year, this reduction was
about 50% of the pretreatment value, and the I-year
level persisted throughout the followup period of up to
4 years.
Although the numbers of Leu-2+ and Leu-3+
cells decreased during the first year after TLI, the
Leu-2+ cells decreased by only 25%, compared with a
75% reduction in the Leu-3+ population. These
changes persisted for up to 3 years after radiation
therapy. In the fourth year, however, there was a
recovery to the pretreatment level in the number of
Leu-2+ cells, while the level of Leu-3+ cells remained
markedly reduced (50% of the pretreatment level). The
preferential decrease in the Leu-3+ cell counts resulted in a persistent shift in the ratio of Leu-2+:Leu3+ cells. Before TLI, this ratio was 0.43; during the
first, second, third, and fourth years, it was 1.46, 1.04,
0.97, and 0.91, respectively. An attempt to correlate
individual patients’ in vitro functional immunologic
values or absolute lymphocyte and T cell subset
counts to their clinical responses to TLI at various
time points after radiotherapy did not reveal any
significant correlation.
DISCUSSION
We studied the changes in joint disease activity
and immune function in 32 patients who received TLI
(2,000 rads) for rheumatoid arthritis in both uncontrolled and controlled trials (2,3,7). All were considered to have intractable joint disease of long duration
(mean duration at entry 12.1 years). Eight patients
received low-dose TLI (200 rads) at least 6 months
before the full dose (2,000 rads), but they were not
analyzed separately because their changes in immune
function and clinical outcome were similar to those of
the group that received the full dose alone.
At least 25% improvement in 3 of 4 parameters
of joint disease (morning stiffness, joint tenderness,
joint swelling, and global composite score) was observed in 24 patients by 6 months after TLI. These
patients were considered to be responders. Followup
of this group for up to 48 months showed a plateau in
the mean improvement after the 6-month point, without a tendency toward relapse. However, 5 of these
patients had to be given adjunctive immunosuppressive drugs (mainly methotrexate) during the second or
third year after TLI, in order to maintain their improved status. This suggests that, in a subset of
patients, disease activity gradually returns after TLI.
The extent of this trend during the third and fourth
years is difficult to assess because of the limited
number of patients studied (6 at the 4-year time point).
At entry, it was not possible to predict which patients
would eventually make up this subset.
The nonresponder group (8 patients) showed no
tendency to improve with time, except in the 3 patients
who received adjunctive drug therapy. Among all
patients, there was no significant change between the
TLI IN RA
mean entry dosage of steroids and aspirin and the
dosage at the last observation point. Eleven of the
patients had reconstructive surgery during the observation period. This may have contributed to the improvement in the global score in some patients. In
almost all cases, the indications for surgery were
present before TLI, and surgery was scheduled after
reduction in joint disease activity.
All patients had mild constitutional symptoms
during TLI and for about 4-6 weeks after TLI. Six had
a reduction in white blood cell count (to <3,000
cells/mm3), and 1 had a reduction in platelet count (to
< 100,000/mm3). Seven patients developed herpes
zoster; 1 of the cases was generalized. Six patients
developed bacterial infections that required hospitalization or extension of a hospital stay. In the present
study, the incidence of staphylococcal septicemia following TLI for RA appears to be substantially lower
than that reported by Brahn et a1 (5). Those investigators observed 4 of 12 patients with this complication.
The use of a higher total dose of irradiation (3,000
rads) and 3 irradiation fields instead of 2, the longer
duration of irradiation, and the increased age of the
patients may account for the increased risk of infection
in their study. Differences in the extent of radiation of
salivary glands in the 2 studies may also account for
the low incidence of chronic xerostomia and tooth
decay in the present study (2 of 32 patients), and the
high incidence in the latter study.
Four of 32 patients died during the 48-month
observation period. Two of the 4 deaths (1 due to
myocardial infarction and 1 due to pulmonary embolism) appear to be unrelated to the radiotherapy. It is
too early to determine whether TLI improves or
worsens the mortality rate among patients with RA.
Several reports (14-19) have suggested that RA is a
life-shortening disease, and that the most severely
afflicted patients have the highest mortality rates. In
view of the deaths of 2 of our patients with rheumatoid
lung disease that was radiographically apparent before
entry into the study, all subsequent patients with this
extraarticular manifestation were excluded from the
TLI protocol. Thus far, rheumatoid lung disease has
not been observed after TLI in patients with normal
radiographic findings at entry. The risk of neutropenia
and associated infection in the present study appears
higher than that reported for Hodgkin’s disease patients who are treated with TLI (l), and this suggests
the need for greater caution in the use of TLI for RA.
This discrepancy may be due to the presence in RA of
antigranulocyte antibodies, which may reduce granulocyte numbers and function (20). Although TLI may
9
increase the risks of side effects of subsequent immunosuppressive drug therapy, this was not apparent
in the 8 patients who were given adjunctive drugs.
It is of interest that Niisslein et a1 (6) reported
the deaths of 4 of 11 patients with intractable RA, up to
2 years after TLI (2,000 rads). This contrasts with the
4 deaths among 32 patients up to 4 years after TLI in
the present study. It is likely that the difference in the
age of the patients in the 2 studies contributed to the
difference in mortality, since the mean age of patients
in Niisslein’s study was 18 years higher than that in the
present study (66 versus 48 years). In fact, the mortality rates among elderly patients (266 years) were
similar in the 2 studies. Three of the 6 elderly patients
in Niisslein’s study died, and 3 of 7 elderly patients in
our present study died. Only 1 of the 25 non-elderly
patients in the present study died. To determine
whether TLI actually changes the mortality rate favorably or unfavorably in younger or elderly patients with
severe, intractable RA, a matched control population
of similar age, sex, drug history, and severity of
disease would be required for comparison.
Immunologic monitoring of patients showed
that the previously reported reduction in the T
helpedinducer cell subset (Leu-3 + cells) (7) persists
up to 4 years after TLI. Immunoglobulin secretion
after pokeweed mitogen stimulation was the most
severely and persistently reduced response. Despite
the reduction in T helper cell numbers and function,
the serum concentrations of rheumatoid factor and
antinuclear antibodies did not change significantly.
Thus, there was no correlation between improvement
in disease activity and changes in serum autoantibody
levels, but improvement was associated with alterations in T helperhnducer cells. The rate of recovery
of T cell function or numbers did not predict the
course of joint disease activity.
In conclusion, the present study shows that
about 75% of patients given TLI had considerable
improvement in their joint disease, and this persisted
in the majority of patients during the second through
fourth years. In order to determine the role of TLI in
the treatment of intractable rheumatoid arthritis, this
form of radiotherapy must be compared with chemotherapy (i.e., methotrexate, azathioprine, cyclophosphamide) in controlled trials similar to those used to
study the treatment of malignant disease with these
drugs. Comparison of the risks and benefits of the 2
modes of therapy should provide the rationale for
therapeutic choices.
Addenum. Since the preparation of this article, a
second controlled, short-term trial of TLI in RA indicated
10
that 750 rads produced similar efficacy to that of 2,000 rads,
but significantly fewer side effects (21).
1. Kaplan HS: Hodgkin’s Disease. Second edition. Cambridge MA, Harvard University Press, 1980, pp 336441
2. Kotzin BL, Strober S, Engleman EG, Calin A, Hoppe
RT, Kansas GS, Terrell CP, Kaplan HS: Treatment of
intractable rheumatoid arthritis with total lymphoid irradiation. N Engl J Med 305:96%976, 1981
3. Field EH, Strober S, Hoppe RT, Calin A, Engleman
EG, Kotzin BL, Tanay AS, Calin HJ, Terrell CP,
Kaplan HS: Sustained improvement of intractable rheumatoid arthritis after total lymphoid irradiation. Arthritis
Rheum 26:937-946, 1983
4. Trentham DE, Belli JA, Anderson RJ, Buckley JA,
Goetzl EJ, David JR, Austen KF: Clinical and immunologic effects of fractionated total lymphoid irradiation in
refractory rheumatoid arthritis. N Engl J Med 305:
976-982, 1981
5. Brahn E, Helfgott SM, Belli JA, Anderson RJ, Reinherz
EL, Schlossman SF, Austen KF, Trentham DE: Total
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arthritis: fifteen- to forty-month followup. Arthritis
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6. Niisslein HG, Herbst M, Manger BJ, Gramatzki M,
Burmester GR, Fritz H, Sauer R, Kalden JR: Total
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7. Strober S, Tanay A, Field E, Hoppe RT, Calin A,
Engleman EG, Kotzin B, Brown BW, Kaplan HS:
Efficacy of total lymphoid irradiation in intractable rheumatoid arthritis: a double-blind, randomized trial. Ann
Intern Med 102:441-449, 1985
8. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9: 175-176, 1958
9. Larsen A: Radiographic evaluation of rheumatoid arthritis in therapeutic trials, Controversy in Clinical Evaluation of Analgesic, Antinflammatory, and Antirheumatic
Drugs. Edited by HE Paulus, GE Ehrlich, E Linderlaub.
Stuttgart, Schattauer Verlag, 1980, pp 323-329
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TANAY ET AL
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SM, Testa CM, Good RA: Thymus-dependent membrane antigens in man: inhibition of cell-mediated
lympholysis by monoclonal antibodies to the Th2 antigen. Proc Natl Acad Sci USA 78544548, 1981
12. Ledbetter JA, Evans RL, Lipinski M, CunninghamRundles C, Good RA, Herzenberg LA: Evolutionary
conservation of surface molecules that distinguish T
lymphocyte helperlinducer and cytotoxiclsuppressor
subpopulations in mouse and man. J Exp Med 153:
310-323, 1981
13. Herzenberg LA, Herzenberg LA: Analysis and separation using the fluorescence activated cell sorter (FACS),
Handbook of Experimental Immunology. Third edition.
Edited by DM Weir. Oxford, Blackwell, 1978, pp
22.1-22.11
14. Mitchell DM, Spitz PW, Young DY, Bloch DA,
McShane DJ, Fries JF: Survival, prognosis, and causes
of death in rheumatoid arthritis. Arthritis Rheum
29:706-714, 1986
15. Abruzzo JL: Rheumatoid arthritis and mortality. Arthritis Rheum 25:1020-1023, 1982
16. Linos A, Worthington JW, O’Fallon WM, Kurland LT:
The epidemiology of rheumatoid arthritis in Rochester,
Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol 111237-98, 1980
17. Rasker JJ, Cosh JA: Cause and age at death in a
prospective study of 100 patients with rheumatoid arthritis. Ann Rheum Dis 40:115-120, 1981
18. Mutru 0, Laakso M, Isomaki H, Koota K: Ten year
mortality and causes of death in patients with rheumatoid arthritis. Br Med J [Clin Res] 290: 1797-1799, 1985
19. Pincus T, Callahan LF, Sale WG, Brooks AL, Payne
LE, Vaughn WK: Severe functional declines, work
disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 27:864872, 1984
20. Blumfelder TM, Logue GM, Shimm DS: Felty’s syndrome: effects of splenectomy upon granulocyte count
and granulocyte-associated IgG. Ann Intern Med
94:623-628, 1981
21. Hanly JG, Hassan J, Moriarty M, Barry C, Molony J,
Casey E, Whelan A, Feighery C, Bresnihan B: Lymphoid irradiation in intractable rheumatoid arthritis: a
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29: 16-25, 1986
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