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Thiopronine therapy in rheumatoid arthritis.

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803
LETTERS
Sickle cell anemia, complement, and systemic
lupus erythematosus
To the Editor:
We read with interest the letter of Drs. Karthikeyan, Wallace, and Blum (1) which reported an additional case of the concurrence of systemic lupus erythematosus (SLE)and sickle cell anemia (SCA) in the
same patient. Dr. Karthikeyan et a1 are justified in their
statement that the complement factor B protein concentration in their patient was not significantly reduced,
but we would like to point out that this does not necessarily exclude a reduction in the functional concentration of factor B in serum. We have recently shown (2)
that the factor B concentration measured hemolytically
in a large group of patients with SCA was reduced,
whereas as noted in previous studies (3,4) factor B concentration assayed immunochemically was normal; the
concentration of hemolytically active factor B was
shown to be inversely related to its in vivo fractional
catabolic rate (2). Reduced hemolytic factor B concentration has also been demonstrated in B thalassemia
major (another chronic hemolytic anemia) by means of
a functional assay similar to the one we used (5). It has
also been shown that, unlike the classic pathway of
complement activation, the alternate pathway is functionally aected by small changes in the concentration
of its component and control proteins (6). Activation of
the alternate pathway in vivo would thus be expected to
produce relatively small changes in the concentration of
factor B, which is consumed during the reaction sequence. Thus, in order to exclude an alternate pathway
defect, it seems necessary to screen patients with SCA
with functional alternate pathway assays. In interpreting the results, it should be borne in mind that relatively small changes in factor B concentration may have
functional significance.
Both autologous immune complex nephritis (7)
and poststreptococcal nephritis (8) have been reported
in patients with sickle cell anemia. In the latter study
patients with SCA were noted to be grossly over represented in a hospital population of adult patients with
poststreptococcal nephritis; this suggested that they may
be unduly susceptible to this form of nephritis. The case
reports of the concurrence of SLE and SCA provide an
additional stimulus for a prospective study of the prevaArthritis and Rheumatism, Vol. 22, No.7 (July 1979)
lence of the serologic and clinical features in immune
complex diseases in a large group of patients with sickle
cell anemia; such a study is in progress in our unit.
WENDELL
A. WILSON,MD, MRCP
KARELDE CEULAER,
MD
ANTHONYG. MORGAN,
MD, MRCP
Department of Medicine
University of the West Indies
Kingston 7
Jamaica
REFERENCES
1. Karthikeyan G, Wallace SL, Blum L: SLE and sickle cell
disease. Arthritis Rheum 21:862-863, 1978
2. Wilson WA, Thomas El, Sissons J G P Activation of the
complement system in asymptomatic patients with sickle
cell anemia. Clin Exp Immunol 1979, in press
3. Koethe SM, Casper JT, Rodey GE: Alternative complement pathway activity in sera from patients with sickle
cell disease. Clin Exp Immunol23:56-60,1976
4. Strauss RG, Asbrock T, Foristal J, et a1 Alternate pathway
of complement in sickle cell disease. Pediatr Res 11:285289,1977
5. Auderset MJ, Casali P, Lambert PH: Decreased factor B
activity in B thalassaemia major (abstract). Pathol Biol
25:391, 1977
6. Nydegger UW, Fearon DT, Austen KF: The modulation
of the alternative pathway of complement in C2 deficient
human serum by changes in the concentration of component and control proteins. J Immunol 1201404-1408,
1978
7. Pardo V, Strauss J, Kramer H, Ozawa T, McIntosh RM:
Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. J Med 59:650-659, 1975
8. Nicholson G D Post streptococcal glomerulonephritis in
adult Jamaicans with and without sickle cell anaemia.
West Indian Med J 26:78-84, 1977
Thiopronine therapy in rheumatoid arthritis
To the Editor:
In recent years D-penicillamine proved to be an
effective drug for “specific” therapy of rheumatoid arthritis, although its use is often complicated by untoward reactions (1). Thiopronine (a-mercaptopropio-
LETTERS
Table 1. Results of thiopronine therapy in rheumatoid arthritis
Grip
strength
ESR
mm/hr
Ritchie
index
Lee
index
Steroid
dose
Result
No. of
patients
Before
After
Before
After
Before
After
Before
After
Before
After
Good
Moderate
Null
6
13
3
33
45
23
11
158
32
30
I15
240
128
140
8.5
13.6
14.6
1.5
6.7
14.6
5.0
6.2
5.6
0
4.3
6.3
2.0
5.0
5.0
0
2.3
4.0
141
nylglycine), already utilized as a penicillamine-like
agent in the treatment of cystinuria (2), is reputed to be
devoid of major side effects.
We have initiated a preliminary long-term open
trial with thiopronine in outpatients with active, definite
rheumatoid arthritis (ESR >20 mm/hour, Ritchie’s index >5). Patients admitted to the trial were all on steroidal (6-methyl-prednisolone), as well as nonsteroidal
(indomethacin or diclofenac), antiinflammatory drugs,
but had stopped any other therapy (gold, antimalarials,
immunosuppressors)for at least 6 months. According to
recommended dose regimen for penicillamine (3), we
have initially administered 250 mg/day of thiopronine,
increasing 250 mg/day every 15 days, up to a maximum
daily dose of 1 gm. Patients were examined at least
every 2 months for the following parameters: ESR, grip
strength, Ritchie’s index, Lee’s index, and reduced need
for antiinflammatory agents. Thirty-two patients have
now been on treatment for 4 to 14 months.
A preliminary evaluation of the trial in the patients in which the drug was not discontinued is summarized in Table 1. Six patients obtained good clinical remission and stopped any antiinflammatory agent. In a
further patient with palindromic rheumatism, episodes
of transient monarthritis did not recur. In one of these
patients an initial steroid cataract reversed under
thiopronine treatment; incidentally, thiopronine has
been reported to be effective in inhibiting senile cataract
(4). Thirteen patients obtained an appreciable clinical
remission and reduced the requirement of antiinflammatory agents. Three patients remained unmodified.
Untoward reactions occurred in 13 patients and
in 9 the drug had to be discontinued: 4 patients complained of ageusia, 2 of stomatitis, 2 of skin rash, 1 of
nausea and vomiting; finally 2 had transient proteinuria
and 2 developed a nephrotic syndrome while on treatment. All symptoms reversed after withdrawal of the
drug; in the two with nephrotic syndrome the clinical
picture returned to normal in 2 to 3 weeks after discontinuation of thiopronine and high-dose steroid treat-
ment. The patients with ageusia restarted the treatment
after a transient withdrawal or dose reduction. No one
had hemocytopenia.
On the basis of this very preliminary experience,
thiopronine seems to be of value in the “specific” therapy of rheumatoid arthritis. Recent evidence indicates
that this drug is effective in the pertussis vaccine edema
(5), a promising experimental model for screening of
penicillamine-like agents (6). Surprisingly, incidence of
side effects was more than expected and these were similar to those described with penicillamine. A more extensive assessment of thiopronine seemed therefore justified, and a multicenter long-term controlled trial of
this drug compared with penicillamine is now in progress.
G. PASERO
M. L. ClOMPl
Service of Rheumatology
University of Pisa
Via Roma 2
56100 Pisa, Italy
REFERENCES
I. Jaffe IA: D-penicillamine. Bull Rheum. Dis 28:948-952,
1977
2. King SJ Jr.: Treatment of cystinuria with a-mercaptopropionylglycine: a preliminary report with some notes on
column chromatography of mercaptans. Proc SOCExp Biol
Med 129:927-932, 1968
3. Day AT, Golding JR, Lee PN, Buttenvorth AD: Penicillamine in rheumatoid disease: a long-term study. Br
Med J 1:180-183, 1974
4. Imaizumi K, Atsumi K, Ogawa K: Thiola tablet, a senile
cataract inhibitor. Ophthalmology (Tokyo) 12:468-470,
1970
5 . Arrigoni-Martelli E, Bramm E: Immunopharmacological
investigations on sulfhydryl compounds: comparative
study of D-penicillamine, 5-mercapto-pyridoxine and amercaptopropionylglycine. (Personal communication)
6. Arrigoni-Martelli E, Bramm E, Huskisson EC, Willoughby
DA, Dieppe PA: Pertussis vaccine oedema: an experimental model for the action of penicillamine-like drugs. Agents
Action 6:613-617, 1976
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