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Effects of fasting on disease activity neutrophil function fatty acid composition and leukotriene biosynthesis in patients with rheumatoid arthritis.

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585
EFFECTS OF FASTING ON DISEASE ACTIVITY,
NEUTROPHIL FUNCTION, FATTY ACID
COMPOSITION, AND LEUKOTRIENE BIOSYNTHESIS
IN PATIENTS WITH RHEUMATOID ARTHRITIS
INGIALD HAFSTROM, BO RINGERTZ, HANS GYLLENHAMMAR,
JAN PALMBLAD, and MATS HARMS-RINGDAHL
Fourteen patients with rheumatoid arthritis (RA)
were studied before, during, and after a 1-week total
fast. Disease activity decreased, as did the neutrophil
release of lysozyme induced by the ionophore A23187.
The ability of zymosan-activated RA patient serum to
aggregate control neutrophils was reduced, together
with serum concentrations of C3. The relative contents
of arachidonic acid and eicosapentaenoic acid were
increased in serum, platelets, and neutrophils, whereas
levels of linoleic acid and linolenic acid were unchanged.
Fasting also reduced the release of leukotriene B, from
neutrophils. We thus conclude that a reduced ability to
generate cytotaxins, reduced release of enzyme, and
reduced leukotriene formation from RA neutrophils,
together with an altered fatty acid composition of membrane phospholipids, may be mechanisms for the decrease of inflammatory symptoms that results from
fasting.
From the Rheumatology and Hematology Sections, Department of Medicine 111, Karolinska Institute at Sodersjukhuset,
Stockholm, and the Department of Radiobiology, University of
Stockholm, Stockholm, Sweden.
Supported by grants from the Swedish Medical Research
Council (19X-05991-05A, resp 07A; 19P-7095-01), the Swedish Association Against Rheumatism, King Gustav V’s 80-year Fund, the
P. and A. Hedlunds Fund, the A.-G. and H. Crafoords Fund, and
the Nanna Svartz Fund.
Ingiald Hafstrom, MD: Rheumatology Section, Karolinska
Institute; Bo Ringertz, MD: Rheumatology Section, Karolinska
Institute; Hans Gyllenhammar, MD: Hematology Section, Karolinska Institute; Jan PaImblad, MD: Associate Professor, Hematology Section, Karolinska Ipstitute; Mats Harms-Ringdahl, PhD:
Associate Professor, University of Stockholm.
Address reprint requests to Ingiald Hafstrom, MD, Rheumatology Section, Department of Medicine 111, Sodersjukhuset,
Stockholm 100 64,Sweden.
Submitted for publication May 5 , 1987; accepted in revised
form November 10. 1987.
Arthritis and Rheumatism, Vol. 31, No. 5 (May 1988)
Fasting has been shown to ameliorate clinical
manifestations of rheumatoid arthritis (RA) (1-3), but
the mechanisms by which this occurs are largely
unknown. Suggested explanations for such improvement include reduced food intolerance, diminished
gastrointestinal permeability, and decreased intake of
precursors of the inflammatory mediators, prostaglandins and leukotrienes (4-6).
The rationale for this last hypothesis is based on
findings of increased concentrations of eicosanoids in
synovial fluids from RA patients (7,8), and the knowledge that leukotriene B4 (LTBJ is a potent stimulator
of neutrophil migration (9) and aggregation (10,ll)
and, to a lesser extent, of enzyme release (1 1,12) and
oxidative metabolism (1 1,13), all of which are important cellular responses in the inflammatory process.
Furthermore, it has become evident that changes in
lipid intake alter the phospholipid fatty acid composition of cell membranes and, thereby, the content of
precursor substances for leukotriene and prostaglandin synthesis. For example, a diet of fish oil, which is
rich in eicosapentaenoic acid (EPA), a 20-carbon analog of arachidonic acid (AA), decreases the production
of LTB4by human neutrophils and suppresses neutrophi1 chemotaxis (14). A similar marine diet has been
shown to reduce symptoms in RA patients (15). Likewise, diets deficient in essential fatty acids or diets
enriched with EPA protect (New Zealand black X
New Zealand white)Fi,mice from autoimmune glomerulonephritis (16,17). EPA-enriched diets also reduce
the synthesis of endogenous dienoic prostaglandins
(18). Dietary manipulations of fatty acid intake can
therefore reduce inflammatory reactions, possibly by
way of decreasing the synthesis of proinflammatory
HAFSTROM ET AL
586
substances, such as tetraenoic leukotrienes and dienoic cyclooxygenase metabolites.
Dietary restrictions of protein and calories have
been shown t o have beneficial effects on the expression of murine autoimmune disease (19,20). The mechanism for this protection is largely unknown, but may
be related t o reduced enzymatic conversion of linoleic
acid metabolites (21).
It was thus of interest to determine whether a
total calorie-restriction regimen (fasting) influences the
concentration of phospholipid fatty acids in cell membranes as well as the production of eicosanoids, effects
that may modulate neutrophil functions and, hence,
explain the decreases in inflammatory symptoms in
RA patients during fasting.
PATIENTS AND METHODS
Patients. Fourteen female patients with classic or
definite RA, according to the American Rheumatism Association diagnostic criteria (22), agreed to enter the study.
Their ages ranged from 34 to 65 years (mean 50.7). All
patients had stage I1 or stage 111 disease and class I1 or class
111 functional capacity, according to the criteria described by
Steinbrocker et a1 (23). All patients had clinically active
disease, as defined by the presence of at least 2 of the
following 3 criteria: duration of morning stiffness 260 minutes, tenderness or swelling in at least 6 joints, and Westergren erythrocyte sedimentation rate (ESR) 230 mrdhour,
and their symptoms were not sufficiently controlled with
nonsteroidal antiinflammatory drug (NSAID) treatment.
None of the patients had received gold therapy for the
previous 6 months, nor had they taken any other antirheumatic agents or steroids for the previous 3 months. The
mean duration of disease was 3.5 years (range 0.5-10 years).
None of the patients had gastrointestinal symptoms or symptoms of food intolerance, allergy, or generalized atopy.
Controls. Healthy control subjects of normal weight
were recruited from the hospital staff. None was taking any
medication. Their cells and sera were analyzed together with
samples from the RA patients, as indicated below.
Study design. Fourteen days before entering the
study, the patients stopped their NSAID treatment. During
these initial 2 weeks, they stayed at the hospital during the
day to rest and receive physical therapy in the same manner
as inpatients and, thus, to become acclimated to the hospital
environment. The in-hospital crossover study commenced
thereafter, beginning with 1 week eating a regular diet
(control week) and followed by 1 week (7 days) of fasting, or
vice versa. Of the 14 patients included in the study, 11
started with the control week, and 3 (every fourth patient)
started with the fasting week. During the week of fasting, the
patients drank 3.0-4.5 liters of water each day. All patients
were assessed with clinical and laboratory evaluations on
days 0, 7, and 14 of the in-hospital period. Nine patients
(patients 1-9) were further evaluated for neutrophil function,
and 4 patients (patients 11-14) were evaluated for leuko-
triene release. Sera and platelets or granulocytes from patients 6-13 were analyzed for fatty acid composition.
Measurement of disease activity. RA disease activity
was assessed according to the duration of morning stiffness
(in minutes), the number of tender and swollen joints, using
a modification of the Lansbury articular index (24) (i.e., the
sum of tender and swollen joints, corrected for joint size),
and the ESR.
Laboratory investigations. Blood samples were analyzed for the following values: complete blood count, sodium, potassium, creatinine, alkaline phosphatase, aspartate
aminotransferase, alanine aminotransferase, albumin, orosomucoid, haptoglobin, IgG, IgA, IgM, C3, C4, ESR, total
cholesterol, triglycerides, and apolipoproteins A and B.
Neutrophil function assays. Blood neutrophils were
isolated by Percoll (Pharmacia, Uppsala, Sweden) discontinuous gradient centrifugation (10) and resuspended in Hanks'
balanced salt solution (HBSS) without albumin, unless
stated otherwise. This procedure yielded preparations containing >95% neutrophils.
Assay for release of enzymes. Neutrophils (2 x 106/ml)
were treated with cytochalasin B (5 pg!ml) for 15 minutes
before stimulation with FMLP (1 pill) for 15 minutes or direct
stimulation with A23187 (1 pM;Calbiochem, LaJolla, CA) for
30 minutes. The reaction was stopped rapidly by centrifugation at 4"C, and the supernatant was analyzed for lysozyme
(25) and P-glucuronidase contents (26). The results were
expressed as the net enzyme release (27).
Chemiluminescence analysis. Chemiluminescence, as
augmented by luminol, was assessed with a luminometer, a6
described elsewhere (13). Neutrophils (1.25 x 107/ml) in a
sample containing luminol (final concentration 0.17 mM)
were stimulated with FMLP (0.1 pill), and the chemiluminescence was read continuously for up to I5 minutes.
Analysis of aggregation. Aggregation was assessed in a
platelet aggregometer (Payton, Buffalo, NY), as previously
described (10). Briefly, aggregation of neutrophils, suspended
in HBSS with 0.5% albumin, was induced by the addition of
FMLP (0.1 pM) or zymosan-activated serum (ZAS). ZAS
was obtained by incubating 1.25 mg of zymosan per milliliter
of serum for 30 minutes at 37°C. After centrifugation to
remove zymosan particles, the supernatant was used at a final
concentration of 10% to stimulate the neutrophils (28). The
results of the aggregation were calculated as either the maximal change in light transmission, which for FMLP, is equivalent to the maximal aggregation response, or for ZAS, the
increment in light transmission measured 3 minutes after the
addition of ZAS (29).
LTB, radioimmunoassay. We used the Amersham
LTB, 3H assay reagent system (Amersham, Buckinghamshire, UK). Neutrophils (10 x 106/ml)were stimulated with
A23187 (2 pM) for 5 minutes at 37°C. The reaction was
stopped by rapid centrifugation (12,OOOg for 30 seconds) on
silicone oil to remove neutrophils, and an equal volume of
methanol was added to the supernatant. The samples were
kept at - 70°C until analyzed for LTB, content.
Analysis of fatty acid composition. Neutrophils (10 x
106/ml) were treated with 0.1 mg of EDTA and 0.1 mg of
BHA per milliliter of cell suspension to prevent lipid peroxidation. Platelets were obtained from platelet-rich plasma
layers after initiation of granulocyte purification. Neutro-
587
EFFECTS OF FASTING ON RA
phils, platelets, and serum samples were kept at -70°C until
analyzed.
The method for fatty acid analysis has been described earlier (30). Briefly, total lipids were extracted with
methano1:chloroform 2: 1 (volume/volume). Methanol contained BHT (0.1 mg/ml) to prevent oxidation of unsaturated
fatty acids during the extraction procedure. The lipid extracts were purified by phase partition, and the lipid fraction
was hydrolyzed and esterified with 0.1M sodium methoxide
in methanol. The fatty acid methylesters were further purified on silica gel thin-layer chromatography plates, with
dichloromethane as eluent.
The composition of the fatty acid methylesters was
analyzed by gas-liquid chromatography, with a Varian 3700
gas chromatograph equipped with a 2.2-meter glass column,
2-mm inner diameter, packed with Gp 3% SP-2310/2% SP2300 on chromosorb WAW (Suppelco, Bellefonte, PA) as
stationary phase, and a flame ionization detector. The fatty
acid composition is reported as the molar percentage of
methylesters.
Statistical methods. The statistical significance of differences was evaluated using Student’s t-test for paired data.
morning stiffness
a
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RESULTS
RA disease activity. During fasting, the duration
of morning stiffness, articular index, and ESR decreased in all 14 patients studied (Figure I). In the l l
patients who started with the control regimen, there
was no statistically significant change in these variables
during the control week. However, in the 3 patients
who started with the fasting regimen, there was a
deterioration in the above-mentioned variables after the
patients began the control week of eating a regular diet.
Thus, in these 3 patients, morning stiffness increased
from a mean ( ? SEM) of 30.0 ? 29.9 minutes to 60.0 k
45.0 minutes, the articular index increased from 47.0 2
to21.1 to65.7 ? 31.1, andtheESRincreasedfrom28.3
2 12.9 mmlhour to 43.3 ? 15.9 mmlhour.
The mean level of disease activity did not differ
between the 2 groups of patients (patients 1-9, who
were evaluated for neutrophil function, and patients
10-14, who were evaluated for leukotriene release
and/or lipid composition) before or after fasting.
During the week of fasting, the patients lost a
mean of 4.6 kg (range 2.9-7.4).
Findings of laboratory investigations. During the
fasting week, hemoglobin concentrations increased and
the ESR decreased in all patients; likewise, the concentrations of the acute-phase reactants orosomucoid, haptoglobin, and C3 decreased significantly (Table 1). In
contrast, there were no changes in the serum concentrations of IgG, IgM, IgA, C4, or liver enzymes, and the
results of renal function tests remained the same (data
m
I
120 -
before
fasting
after
fasting
Figure 1. Rheumatoid arthritis disease activity, measured as the
duration of morning stiffness, an articular index of tender or swollen
joints, and the erythrocyte sedimentation rate (ESR), before and
after a week of fasting. The mean f SEM values were, respectively,
103.0 ? 28.5 minutes, 74.0 f 10.7 units, and 34.9 2 7.3 mm/hour
before fasting and 22.9 k 12.8 minutes, 42.3 k 8.8 units, and 21.1 t
4.8 mdhour after fasting.
= P < 0.01;
= P < 0.001.
++
+++
not shown). There were no changes in these variables
during the initial, control week.
Neutrophil function. Neutrophil release of lysozyme, induced by A23 187, decreased during fasting in
all patients tested (patients 1-9), despite an unchanged
total enzyme content (Figure 2). However, no statisTable 1. Selected laboratory findings in 14 patients with rheumatoid arthritis during a week of fasting*
Before fasting
Hemoglobin
ESR
Orosomucoid
Haptoglobin
c3
* Values are the mean
114.1
35
1.40
3.16
0.70
3.1
7
f 0.11
f 0.30
? 0.30
2.3t
5$
1.04
0.10$
1.79 0.17$
0.56 f 0.03$
120.9
21
f
f
____
~
After fasting
~
2
f
2
f
~
SEM. Normal values are hemoglobin
120-160 gditer, Westergren erythrocyte sedimentation rate (ESR)
f
<20 mdhour, orosomucoid 0.40-1.10 gditer, haptoglobin 0.402.90 gditer, and C3 0.55-1.20 gditer.
t P < 0.01 by Student’s t-test for paired data.
$ P < 0.001 by Student’s t-test for paired data.
HAFSTROM ET AL
588
AT
before fasting
75
i#
1
50
Q)
v)
a
Q)
I
Q)
Figure 3. The ability of zymosan-activated rheumatoid arthritis
patient serum zymosan-activated serum to aggregate control neutrophils in a representative patient, before and after a week of
fasting. The mean t SEM values in the 9 patients tested, calculated
as increments in light transmission 3 minutes after the addition of
zymosan-activated serum (A T), were 96.1 t 11.1 before fasting and
75.9 t 7.5 after fasting (P = i 0.01).
L
CI
Q)
25
neutrophil functions or in the aggregating capacity of
zymosan-activated patient serum. However, in 2 patients whose enzymes were analyzed postfasting, the
lysozyme net release induced by A23187 increased
from a mean +- SEM of 47.4 5 2.3% to 58.4 9.4%
of the total content during the control week (prefasting
value 62.2 ? 10.1%).
Results of lipid analysis. In RA patients, the
relative proportions of the individual fatty acids were
similar in serum and platelets, but showed a considerably different pattern in neutrophils. The number of
patients was too small to assess a possible difference in
fatty acid composition between RA patients and normal
subjects.
Fatty acid analysis of serum, platelets, and
neutrophils showed no change in the relative contents
of linoleic acid (18:2w6) during fasting, whereas its
metabolite, di-homo-y-linolenic acid (20:3w6), became
significantly reduced in serum and platelets and was
also reduced in neutrophils (Table 2). In contrast, the
level of arachidonic acid (20:4w6) was significantly
higher in both serum and platelets, with a slight
increase in neutrophils. The concentration of linolenic
acid (18:3w3) was not affected during fasting, whereas
the relative content of its metabolite, eicosapentaenoic
acid (20:5w3), an analog of AA, was increased in
*
before
fasting
after
fasting
Figure 2. Release of lysozyme induced by A23187 treatment of
neutrophils from rheumatoid arthritis patients, before and after a
week of fasting. Results are given individually for the 9 patients tested
and are expressed as the percentage net release. The group mean f
SEM was 50.3 t 5.5% before fasting and 40.0 k 5.5% after fasting (P
< 0.001). Total lysozyme concentrations were, respectively, 4.9 f
1.2 pgl2 x 10' neutrophils and 4.1 ? 0.5 pg/2 x 10' neutrophils.
tically significant change was noted for FMLP-elicited
release of lysozyme or P-glucuronidase. Similarly,
neutrophil chemiluminescence and aggregation induced by FMLP were unaffected (results not shown).
The capacity of RA patient serum to affect
neutrophil function was analyzed as the ability of
zymosan-activated patient serum to aggregate healthy
control neutrophils. This aggregating capacity was
significantly reduced during fasting (Figure 3). During
the initial control week, no change was found in the
EFFECTS OF FASTING ON RA
Table 2.
589
The effects of fasting on the fatty acid composition of serum and platelets or neutrophils from 8 patients with rheumatoid arthritis*
Platelets
Fatty
acid
18:l
18:2w6
18:3w3
20:3w9
20:3w6
20:4w6
20:5w3
22:4w6
Patient serum
Before fasting
After fasting
16.5 ? 3.0
30.0 ? 3.6
0.6 f 0.2
0.1 f 0.1
1.6 f 0.5
5.8 f 1.0
1.2 f 0.2
0.8 2 0.6
16.0 f 2.3
28.4 ? 3.0
1.6 f 1.2
-
0.0 f O.Ot
13.7 f 0.9t
3.2 f 0.8$
0.3 i 0.3
Normal
subjects
14.1 f 0.8
33.6 f 1.3
0.7 f 0.1
Trace
1.1 f 0.1
5.9 f 0.2
1.6 t 0.2
0.4 0.2
*
Neutrophils
Patients
Before fasting
After fasting
14.4 f 1.4
33.3 f 2.9
0.5 f 0.2
13.8 f 1.3
26.5 f 1.2
0.5 & 0.1
Trace
0.6 f 0.2$
13.2 f 0.9t
3.0 ? 0.4$
0.4 f 0.2
-
1.9 f 0.7
7.9 f 0.6
1.7 f 0.2
0.3 t 0.2
Patients
Normal
subjects
36.7
11.8
f
0.2 f 0.1
0.8 f 0.2
11.2 f 1.0
1.8 f 0.5
0.3 f 0.1
0.5
3.5
12.9
0.9
0.6
f 0.2
f 1.8
f 1.1
f 0.4
f 0.3
-
~~
* Values are the mean
After fasting
Before fasting
35.8 f 0.8
14.0 f 1.1
f
-
37.0 ? 4.0
8.9 f 0.7
0.1 f 0.1
1.2 f 0.5
14.9 f 2.7
1.4 ? 1.0
1.8 f 1.6
1.5
0.3
_
_
_
_
_
_
_
~
SEM molar percentage of a number of fatty acid methylesters. Means and SEM for normal subjects represent 8
determinations of platelets and neutrophils from 4 healthy subjects. 18: 1 = oleic acid; 18:2w6 = linoleic acid; 18:3w3 = linolenic acid; 20:3w9
= eicosatneneoic acid; 20:3w6 = di-homo-ylinolenic acid; 20:4w6 = arachidonic acid; 20:5w3 = eicosapentaenoic acid; 22:4w6 =
docosatetraenoic acid.
t P < 0.01 versus prefasting value, by Student’s t-test for paired data.
.t P < 0.05 versus prefasting value, by Student’s t-test for paired data.
2
serum and platelets. Eicosatrienenoic acid (20:3w9), a
metabolite of oleic acid and a marker for essential fatty
acid deficiency, showed no changes during the week of
fasting (Table 2).
None of the levels of these fatty acids changed
during the initial, control week.
Levels of serum triglycerides, total cholesterol,
and apolipoproteinsA and B were within normal limits
in all patients, and did not change during either the
control or the fasting week (results not shown).
Analysis of LTB, release. The effect of fasting on
the release of LTB, from neutrophils stimulated with
A23187 was investigated by 3H-labeled LTB, radioimmunoassay in 4 patients (patients 11-14). The LTB,
release was expressed as the percentage of the release
from simultaneously analyzed neutrophils from a nonfasting healthy control subject (the same control subject’s cells were used for each assessment). The release of LTB, was markedly reduced at the end of the
fasting week (Figure 4); there was also a small decrease in this value during the control week.
The study was designed as an in-hospital crossover study so that the effects of hospitalization could
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DISCUSSION
In this study, we have confirmed that fasting
reduces disease activity in patients with rheumatoid
arthritis. Furthermore, we found that fasting reduced
the ability of serum to generate cytotaxins, reduced
the release of LTB, from neutrophils, and altered the
fatty acid composition of serum, platelet, and neutrophi1 phospholipids, changes that may explain the reduced lysozyme release from neutrophils.
before
fasting
after
fasting
Figure 4. Release of leukotriene B, induced by A23187 treatment of
neutrophils from rheumatoid arthritis patients, before and after a
week of fasting. Results are given individually for the 4 patients
tested and are expressed as the percentage of simultaneously
analyzed control neutrophils. The group mean f SEM values were
100 f 29% before fasting and 55 f 21% after fasting. The group
mean f SEM value before the control week was 135 f 23%.
590
be differentiated from those of fasting. The initial 14
days of hospital visits during the daytime, however,
seemed to be enough to acclimate the patients to the
hospital environment, since we found no changes in
clinical or biochemical evidence of disease activity
during the following in-hospital control week. We
selected patients who had had no experience with
fasting, because such experience could have influenced at least some of the clinical variables (31). Thus,
we took maximal effort to minimize known sources of
errors because fasting cannot be tested blindly.
Disease activity, measured as the duration of
morning stiffness, the number of tender and swollen
joints, and the ESR, decreased in all patients during
fasting, which corresponds to findings in previous reports (1,2); these parameters remained unchanged or
they deteriorated during the control week. No adverse
effects of fasting, except for transient weakness and
lightheadedness, were noted. Thus, fasting is one possible way to induce rapid improvement in RA.
The noted decrease in the levels of acute-phase
reactants (haptoglobin, orosomucoid, and C3) has
been described earlier in RA patients, as well as in
healthy volunteers, during fasting (32,33). The reason
for the decrease in the levels of these substances is not
known, but impaired synthesis and increased catabolism may be contributing factors. Since a reduction in
the levels of acute-phase reactants occurs in healthy
people during fasting, caution must be exercised when
using these values as indicators of inflammatory activity in RA patients during fasting.
During short-term fasting, lipolysis is stimulated, and linoleic acid and other fatty acids are
released from body fat stores (34). The 1-week fasting
period, however, did not result in any change in our
patients’ serum concentrations of triglycerides, cholesterol, or lipoproteins. Fasting did not induce either a
deficiency in essential fatty acid, as confirmed by an
unchanged linoleic acid content, or a rise in the 20:3w9
content (a marker of essential fatty acid deficiency).
The fatty acid composition of serum in RA patients was the same as that in their platelets, as were the
changes in the levels that were induced by fasting. This
finding suggests that there is a rapid exchange of lipids
between serum and platelet membranes. Such findings
have been previously reported in subjects eating a mackerel diet (35). The pattern of changes in fatty acid
composition also included neutrophils, in which the
basal relative fatty acid content before fasting was different compared with that in serum and in platelets.
The finding of a reduced release of LTB, from
HAFSTROM ET AL
neutrophils despite an increased AA content indicates
that fasting may impair a metabolic step of AA conversion. This impairment could be due to a decrease in
metabolic enzymes at the level of phospholipase a n d
or 5-lipoxygenase. Likewise, a postulated impairment
of 5-lipoxygenase can also explain the increase in
EPA, since AA and EPA are metabolized by the same
enzymes (36). In healthy subjects, fasting causes an
increase in the level of AA in plasma (37) as well as a
decrease in prostaglandin formation from AA (38).
These findings are additional evidence for a decreased
metabolism of this fatty acid during fasting.
The decrease in di-homo-y-linolenic acid is
probably due to a decrease in linoleic acid desaturation. It has previously been reported that in rats,
fasting results in a decrease in linoleic acid desaturase
activity (39).
The above-mentioned fasting-induced inhibitions of enzyme activity can result in the reported
changes in fatty acid composition as well as a reduction of leukotriene synthesis. As a comparison, it
should be mentioned that aspirin and indomethacin,
both of which are known to inhibit the conversion of
AA at the cyclooxygenase step, have no effect on the
polyunsaturated fatty acid content of tissue lipids (40).
Fasting also resulted in a reduction in the release
of lysozyme from neutrophils when stimulated with
A23187. However, when a receptor-mediated stimulus
(FMLP) was used to elicit neutrophil lysozyme and
P-glucuronidase release, aggregation, or chemiluminescence, no changes were found. This discrepancy
between non-receptor-mediated and receptor-mediated
functions may be explained by their different potencies
in stimulating leukotriene production. Thus, A23 187
has a strong and rapid ability to generate leukotrienes
(41,42), whereas formylpeptides are weaker stimuli
(4344). As the generation of LTB,, which is supposed
to be part of an intracellular amplification system for
neutrophil function (13), was impaired during fasting,
neutrophil function stimulated by A23187 should be
more sensitive to fasting than receptor-mediated function. This explanation is consistent with the results of a
study on rats with essential fatty acid deficiency, in
which an impairment of 5-lipoxygenase product synthesis was associated with a reduction of neutrophil responsiveness to A23187 and, to a lesser extent, to
formylpeptides, but not to exogenous LTB, (45).
Results of a previous investigation suggest that
changes in circulating immune complexes and other
cytotaxins might be involved in neutrophil responses
during fasting (2). These substances might (in un-
EFFECTS OF FASTING ON RA
treated RA) deactivate surface receptors on circulating
neutrophils and, thus, decrease neutrophil function to
a related cytotaxin. During fasting, the activity of serum
cytotaxins decreased, as indicated here and earlier (2),
by a reduction in aggregating and chemotactic substances that were generated from serum (most probably
related to C5a). Hence, receptor-mediated neutrophil
function remains unchanged during fasting, despite a
reduction in leukotriene synthesis.
We have shown that in RA patients, fasting
reduces levels of cytotaxins in serum and reduces the
release of lysozyme from neutrophils when stimulated
with an ionophore, an effect that could well explain the
decrease in inflammatory symptoms, since the lysosoma1 constituents mediate inflammation and participate in destruction ofjoint tissues. Furthermore, fasting
reduces the release of LTB,, a potent mediator of
inflammation and immunity, that is derived from AA.
The beneficial effect of fasting on RA, however, is
probably not exclusively dependent on these changes.
For example, an altered fatty acid composition of
membrane phospholipids, as shown here, can modulate
membrane fluidity and the activity of many membrane
enzymes and, thus, alter multiple cellular functions
(46,47). It thereby affects other inflammatory events as
well. A modified fast has been shown to improve concanavalin A suppressor cell activity in RA patients (48).
A favored hypothesis for explaining clinical
improvement in RA has been that food deprivation
induces an increase in the levels of cortisol. However,
the excretion of cortisol in urine has been found to be
unaltered during fasting in RA patients (49). An increase in the levels of catecholamines in urine, which
probably does not reflect sympathetic activity, has
been reported and was judged not to be sufficient to
induce biologic effects (50).
Even if fasting is not a feasible approach for
long-term treatment in humans, it is clear that fasting
may serve as a model for studying basal mechanisms
for regulating the inflammatory activity of RA.
ACKNOWLEDGMENTS
We are grateful to Ingegerd Friberg for excellent
technical assistance and to Marja Winberg for preparation of
the manuscript.
REFERENCES
1 . Skoldstam L , Larsson L, Lindstrom F: Effects of fasting
and lactovegetarian diet on rheumatoid arthritis. Scand J
Rheumatol 8:249-255, 1979
2. UdCn A-M, Trang L, Venizeloz N, Palmblad J: Neutro-
591
phi1 function and clinical performance after total fasting in
patients with rheumatoid arthritis. Ann Rheum Dis
42:45-51, 1983
3. Stroud RM: The effect of fasting followed by specific
food challenge on rheumatoid arthritis, Current Topics
in Rheumatology. Edited by BH Kahn, FC Arnett, TM
Zizic, MC Hochberg. Kalamazoo, Upjohn, 1983
4. Panush RS, Stroud RM, Webster EM: Food-induced
(allergic) arthritis: inflammatory arthritis exacerbated by
milk. Arthritis Rheum 29:220-226, 1986
5. Sundqvist T, Lindstrom F, Magnusson KE, Skoldstam L,
Stjernstrom I, Tagesson C: Influence of fasting on intestinal permeability and disease activity in patients with rheumatoid arthritis. Scand J Rheumatol 11:33-38, 1982
6. Darlington LG, Ramsey NW, Mansfield JR: Placebocontrolled, blind study of dietary manipulation therapy
in rheumatoid arthritis. Lancet I:236-238, 1986
7. Klickstein LB, Shapleigh C, Goetzl EJ: Lipoxygenation
of arachidonic acid as a source of polymorphonuclear
leukocyte chemotactic factors in synovial fluid and
tissue in rheumatoid arthritis and spondyloarthritis. J
Clin Invest 66: 1166-1 170, 1980
8. Davidson EM, Rae SA, Smith MJH: Leukotriene B,, a
mediator of inflammation present in synovial fluid in
rheumatoid arthritis. Ann Rheum Dis 42:677-679, 1983
9. Malmsten CL, Palmblad J, Uden A-M, RAdmark 0,
Engstedt L , Samuelsson B: Leukotriene B,: a highly
potent and stereospecific factor stimulating migration of
polymorphonuclear leukocytes. Acta Physiol Scand 110:
449-451, 1980
10. Ringertz B, Palmblad J, RAdmark 0, Malmsten C:
Leukotriene-induced neutrophil aggregation in vitro.
FEBS Lett 147:lSO-182, 1982
1 1 . Serhan CN, Radin A, Smolen JE, Korchak H, Samuelsson B, Weissmann G: Leukotriene B, is a complete
secretagogue in human neutrophils: a kinetic analysis.
Biochem Biophys Res Commun 107:1006-1012, 1982
12. Hafstrom I , Palmblad J, Malmsten CL, R5dmark 0,
Samuelsson B: Leukotriene B,: a stereospecific stimulator for release of lysosomal enzymes from neutrophils.
FEBS Lett 130:146-148, 1981
13. Palmblad J, Gyllenhammar H, Lindgren JA, Malmsten
CL: Effects of leukotrienes and f-met-leu-phe on oxidative metabolism of neutrophils and eosinophils. J Immuno1 132~3041-3045,1984
14. Lee TH, Hoover RL, Williams JD, Sperling RI, Ravalese J 111, Spur BW, Robinson DR, Corey EJ, Lewis
RA, Austen KF: Effect of dietary enrichment with
eicosapentaenoic and docosahexaenoic acids on in vitro
neutrophil and monocyte leukotriene generation and
neutrophil function. N Engl J Med 312:1217-1224, 1985
15. Kremer JM, Bigauoette J, Michalek AV, Timchalk MA,
Lininger L, Rynes RI, Huyck C, Zieminski J, Bartholomew LE: Effects of manipulation of dietary fatty acids
on clinical manifestations of rheumatoid arthritis. Lancet I:184-187, 1985
16. Hurd ER, Johnston JM, Okita JR, MacDonald PC, Ziff
M, Gilliam JN: Prevention of glomerulonephritis and
prolonged survival in New Zealand blackhiew Zealand
white F, hybrid mice fed an essential fatty acid-deficient
diet. J Clin Invest 67:476-485, 1981
592
17. Prickett JD, Robinson DR, Steinberg AD: Effects of
dietary enrichment with eicosapentaenoic acid upon
autoimmune nephritis in female NZB x NZW/F, mice.
Arthritis Rheum 26:133-139, 1983
18. Kelley VE, Ferretti A, Izui S , Strom TB: A fish oil diet
rich in eicosapentaenoic acid reduces cyclooxygenase
metabolites, and suppresses lupus in MRL-lpr mice. J
Immunol 134:1914-1919, 1985
19. Fernandes G,Friend P, Yunis EJ, Good RA: Influence
of dietary restriction on immunologic function and renal
disease in (NZB x NZW)F, mice. Proc Natl Acad Sci
USA 75:1500-1504, 1978
20. Friend PS, Fernandes G,Good RA, Michael AF, Yunis
EJ: Dietary restrictions early and late: effects on the
nephropathy of the NZB x NZW mouse. Lab Invest
38 :629-632, I978
21. Yue TL, Varma DR, Powell WS: Effects of protein
deficiency on the metabolism of arachidonic acid by rat
pleural polymorphonuclear leukocytes. Biochim Biophys
Acta 751:332-339, 1983
22. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
Diagnostic criteria for rheumatoid arthritis. Ann Rheum
Dis 18:49-53, 1959
23. Steinbrocker 0, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659-662,
1949
24. Lansbury J: Report of a three-year study on the systemic and articular indexes in rheumatoid arthritis.
Arthritis Rheum 1505-522, 1958
25. Harrison JF, Barnes AD: The urinary excretion of
lysozyme in dogs. Clin Sci 38533-547, 1970
26. Fishman WH, Kato K, Anstiss CL, Green S: Human
serum p-glucuronidase: its measurement and some of its
properties, Clin Chim Acta 15:435-447, 1967
27. Hafstrom I, UdCn A-M, Palmblad J: Modulation of
neutrophil functions by auranofin. Scand J Rheumatol
12:97-105, 1983
28. Hammersmidt DE, Bowers TK, Lammi-Keefe CJ, Jacob HS, Craddock PR: Granulocyte aggregometry: a
sensitive technique for the detection of C5a and complement activation. Blood 55:898-902, 1980
29. Ringertz €3, Palmblad J, Lindgren JA: Stimulus specific
neutrophil aggregation: evaluation of possible mechanisms for the stimulus-response apparatus. J Lab Clin
Med 106:132-140, 1985
30. Ehrstrom M, Harms-Ringdahl M, Alling C: Osmotic
fragility and fluidity of erythrocyte membranes from rats
raised on the essential fatty acid deficient diet. Biochim
Biophys Acta 644:175-182, 1981
31. Kjellberg J, Levi L, Palmblad J, Paulsson L, Theorell T,
Yensen R: Energy deprivation in man: methodological
problems and possibilities. Acta Med Scand 201 :9-13,
1977
32. Skoldstam L, Jorfelt L, Lindell B, M a e n s s o n J: Specific plasma proteins as indices of inflammation during a
modified fast in patients with rheumatoid arthritis.
Scand J Rheumatol 12:161-165, 1983
33. Palmblad J, Cantell K, Holm G,Norberg R, Strander H,
Sundblad L: Acute energy deprivation in man: effect on
serum immunoglobulins, antibody response, complement factors 3 and 4, acute phase reactants and inter-
HAFSTROM ET AL
feron producing capacity of blood lymphocytes. Clin
Exp Immunol30:50-55, 1977
34. Arner P, Ostman J: Changes in the adrenergic control
and the rate of lipolysis of isolated human adipose tissue
during fasting and after re-feeding. Acta Med Scand
200:273-279, 1976
35. Siess W, Scherer B, Bohlig B, Roth P, Kurzman J,
Weber PC: Platelet-membrane fatty acids, platelet aggregation and thromboxane formation during a mackerel
diet. Lancet I:441-444, 1980
36. Prescott SM: The effect of eicosapentaenoic acid on
leukotriene B production by human neutrophils. J Biol
Chem 259:7615-7621, 1984
37. Imaichi K, Michaels GD, Holton S , Kinsell LW: Plasma
lipid fatty acids during fasting. Am J Clin Nutr 13:226231, 1963
38. Adam 0, Wolfram G,Zollner N: Prostaglandin formation and platelet aggregation during fasting and linoleic
acid intake. Res Exp Med (Berl) 185:169-172, 1985
39. De Gomez Dumm INT, de Alaniz MTJ, Brenner RR:
Effect of diet on linoleic acid desaturation and on some
enzymes of carbohydrate metabolism. J Lipid Res 11:
96-101, 1970
40. Holman RT: Control of polyunsaturated acids in tissue
lipids. J Am Coll Nutr 5:183-211, 1986
41. Samuelsson B: Leukotrienes: mediators of immediate
hypersensitivity reactions and inflammation. Science
220~568-575, 1983
42. Borgeat P, Samuelsson B: Metabolism of arachidonic
acid in polymorphonuclear leukocytes: structural analysis of novel hydroxylated compounds. J Biol Chem
254~7865-7869, 1979
43. Jubiz W, RPdmark 0, Malmsten C, Hansson G,Lindgren JA, Palmblad J, UdCn AM, Samuelsson B: A novel
leukotriene produced by stimulation of leukocytes with
formyl-methionyl-leucyl-phenylalanine.J Biol Chem
257:6106-6110, 1982
44. Ham EA, Soderman DD, Zanetti ME, Dougherty HW,
McCauley E, Kuehl PA: Inhibition by prostaglandins of
leukotriene B, release from activated neutrophils. Proc
Natl Acad Sci USA 80:4349-4353, 1983
45. Gyllenhammar H , Palmblad J , Ringertz B, Hafstrom I,
Borgeat P: Rat neutrophil function, and leukotriene
generation in essential fatty acid deficiency. Lipids (in
press)
46. King ME, Stavens BW, Spector AA: Diet induced
changes in plasma membrane fatty acid composition
affect physical properties detected with spin-label probe.
Biochemistry 16:5280-5285, 1977
47. Hirata F, Axelrod J: Phospholipid methylation and biological signal transmission. Science 209: 1082-1090, 1980
48. Skoldstam L , Lindstrom FD, Lindblom B: Impaired con
A suppressor cell activity in patients with rheumatoid
arthritis shows normalisation during fasting. Scand J
Rheumatol 12:369-373, 1983
49. Trang LE: Biochemical aspects of rheumatoid arthritis
(thesis). Karolinska Institute, Stockholm, 1984
50. Trang LE, Lovgren 0, Roch Nordlund AE, Horn L,
Walaas 0: Cyclic nucleotides and catecholamines in
rheumatoid arthritis. Scand J Rheumatol 12: 171-176,
1983
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acid, patients, fasting, disease, fatty, neutrophils, effect, leukotriene, arthritis, activity, function, composition, rheumatoid, biosynthesis
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