Duell PB, Chesnut CH. (1991). Exacerbation of
rheumatoid arthritis by sodium fluoride treatment of osteoporosis.
Archives of Internal Medicine 151:783-4.
"Recent studies have suggested that sodium
fluoride therapy may be an effective treatment for vertebral
osteoporosis. Unfortunately, the high frequency of side effects
may limit the use of this treatment modality. This
report documents the repeated exacerbation of rheumatoid arthritis
on three occasions after the initiation of sodium fluoride therapy.
This apparent complication of sodium fluoride treatment may be
mediated by stimulation of leukocyte production of reactive oxygen
species and other mediators of the acute inflammatory response.
We suggest that sodium fluoride should be used cautiously in patients
with rheumatoid arthritis.
Several days after starting sodium fluoride therapy (22 mg F/day),
she developed rapidly increasing upper- and lower- extremity joint
inflammation with moderate to marked redness, swelling, synovial
thickening, and increased warmth and pain in several areas previously
affected by rheumatoid arthritis (shoulders, elbows, wrists, hands,
ankles, and feet). Her wrists, hands, ankles, and feet were most
severely affected. The arthritic flare was accompanied by an increase
in morning stiffness lasting from 1 to 4 hours, increased fatigability,
and a subjective decrease in grip strength. The joint inflammation,
morning stiffness, fatigability, and reduced grip strength improved
significantly after the sodium fluoride therapy was discontinued
for 1 week, but worsened again several days after a brief rechallenge
with sodium fluoride. Both flares of arthritis resolved 5 to 8
days after sodium fluoride therapy was discontinued, without the
need for other changes in the patient's medication regimen. After
10 weeks of stable rheumatoid arthritis, a third and final trial
of sodium fluoride was initiated, again resulting in an acute
exacerbation of joint inflammation and pain, increasing morning
stiffness, increased fatigability, and reduced grip strength.
This case documents the repeated aggravation of rheumatoid arthritis
following sodium fluoride treatment. Although these data do not
conclusively prove that sodium fluoride caused the worsening of
our patient's rheumatoid arthritis, the
reproducibility of this effect on three occasions suggests that
there is a high probability that sodium fluoride has a causative
role in this previously unreported complication.
Moreover, there are experimental data that suggest
that one might expect sodium fluoride to increase the activity
of rheumatoid arthritis.
Activation of T lymphocytes and polymorponuclear leukocytes in
the synovial fluid is believed to play an important role in the
etiology of joint inflammation and destruction associated with
rheumatoid arthritis. In particular, the production of reactive
oxygen species and other inflammatory mediators by polymorphonuclear
leukocytes is thought to help mediate acute inflammatory processes
in the synovial fluid. (7)
Recent studies in a cell-free system have indicated that fluoride
ion stimulates the activity of neutrophil-derived reduced nicotinamide-adenine
dinucleotide phosphate (NADPH)-dependent superoxide-generating
oxidase and increases the production of superoxide. (8) Other
investigators have shown that superoxide production by blood monocytes
is stimulated ex vivo by fluoride ion. (9) Preliminary results
(unpublished) in our laboratory have demonstrated dose-dependent
stimulation of superoxide production by 10- to 100- umol/L fluoride
ion in cultured human monocyte-derived macrophages, as measured
per the method of Heinecke et al. (10) The therapeutic plasma
concentration of fluoride is believed to be approximately 10 to
20 umol/L, although the associated concentration in synovial fluid
is unknown. Hence, it is conceivable that fluoride ion may stimulate
superoxide production in vivo in patients receiving sodium fluoride
therapy, thereby increasing the activity of rheumatoid arthritis.
Fluoride ion may also contribute to leukocyte activation and
inflammation via an unrelated mechanism. Mo1 is a plasma membrane
glycoprotein found on human myeloid cells that functions as an
adhesion-promoting molecule and as the C3bi receptor. Factors
that increase expression of Mo1 would be expected to enhance cell
activation and the attendant inflammatory responses. Stimulation
of human neutrophils with fluoride ion ex vivo has been shown
to increase expression of Mo1. (11) Thus, fluorie
ion might stimulate the inflammatory response in vivo and cause
worsening of rheumatoid arthritis by two or more potential mechanisms."
References
(7) Lipsky PE. Rheumatoid arthritis. In: Braunwald E, Isselbacher
KJ, Petersdorf RG, Wilson JD, Martin JB, Franci AS, eds. Harrison's
Principles of Internal Medicine 11th ed. New York, NY: McGraw-Hill
International Book Co; 1987:1423-1428.
(8) Gabig TG, English D, Akard LP, Schell MJ. Regulation of neutrophil
NADPH oxidase activation in a cell-free system by guanine nucleotides
and fluoride. Evidence for participation of a pertussis and cholera
toxin-insensitive G protein. J Biol Chem. 1987;262:1685-90.
(9) Bell AL, Hurst NP, Nuki G. Effect of corticosteroid therapy
on blood monocyte superoxide generation in rheumatoid arthritis:
studies in vitro and ex vivo. Br J Rheumatol. 1986;25:366-71.
(10) Heinecke JW, Baker L, Rosen H, Chait A. Superoxide-mediated
modification of low density lipoprotein by arterial smooth muscle
cells. J Clin Invest. 1986;77:757-61.
(11) Petrequin PR, Todd RF 3rd, Devall LJ, Boxer LA, Curnutte
JT III. Association between gelatinase release and increased plasma
membrane expression of the Mo1 glycoprotein. Blood. 1987;69:605-10.
