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Treatment with anti-cd4 monoclonal antibody and acute interstitial nephritis.

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CONCISE COMMUNICATIONS
and diarrhea in another 2 for 2-3 weeks. No other side
effects occurred, and all patients completed the trial.
Clinical parameters of disease activity (purpura, arthralgias, asthenia) significantly improved in 6 patients;
cutaneous ulcers did not resolve. Cryoglobulins (measured
by cryocrit) were reduced to 550% of initial values in 6 of
the 8 patients. Rheumatoid factor activity (by the standard
latex methods) decreased in 7 patients. Hematuria resolved
in 5 of 6 patients with this feature. C4 levels improved in 2 of
the 8 patients. Liver enzyme values returned to normal in 3
of the 8 patients, all of whom had EMC (Table 1).
In conclusion, the clinical features of purpura and
arthralgias improved with improvement in the leukocytoclastic vasculitis in most of the patients. Liver enzyme
values returned to normal in those with EMC. A similar
effect has been demonstrated in primary biliary , alcoholic,
and postnecrotic cirrhosis (6). Cryoglobulins decreased in
association with a decrease in rheumatoid factor levels,
features relatable to the inhibition of the secretory process of
immunoglobulins by plasma cells (3). The lack of improvement in cutaneous ulcers is not an unexpected finding;
equivocal responses to dextran, heparin, and penicillamine
have been reported (7), and only the combination of steroids
plus a cytotoxic agent may be effective.
The open study and small sample size of this trial
undoubtedly affect the value of our findings. Nevertheless,
the results are s a c i e n t l y encouraging to warrant further
controlled studies of a larger group of patients. Colchicine’s
effects on both the humoral and cellular aspects of immune
response underscore its potential benefit in other immunologic diseases.
Fulvio Invernizzi, MD
University of Milan
Milan, Italy
Giuseppe Monti, MD
Saronno Hospital
Saronno, Italy
1. Callen JP: Oral colchicine therapy is effective for chronic cuta-
2.
3.
4.
5.
6.
7.
neous leukocytoclastic vasculitis (abstract). Arthritis Rheum 30
(suppl4):S106, 1987
Plotnick S, Huppert AS, Kantor G: Colchicine and leukocytoclastic vasculitis (letter). Arthritis Rheum 32: 148%1490, 1989
Antoine JC, Maurice M, Feldrnann G, Avrameas S: In vitro and
in vivo effects of colchicine and vinblastine on the secretory
process of antibody-producing cells. J Immunol 125:1939-1949,
1980
Mekory YA, Chowers Y, Drucker I, Klajman A: Inhibition of
delayed hypersensitivity reaction by colchicine: colchicine inhibits interferon-gamma induced expression of HLA-DR on gut
epithelial cell line. Clin Exp Irnmunol 78:230-232, 1989
Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA,
Peper M: Colchicine myopathy and neuropathy. N Engl J Med
316~1562-1568, 1987
Kershenobich D, Vargas F, Garcia-Tsao G, Tamayo RP, Gent
M, Roykind M: Colchicine in the treatment of cirrhosis of the
liver. N Engl J Med 318:170%1713, 1988
Gorevich PD, Kassab HJ, Lev0 Y, Kohn R, Meltzer M, Prose P,
Franklin EC: Mixed cryoglobulinemia: clinical aspects and longterm follow-up of 40 patients. Am J Med 69:287-308, 1980
723
Treatment with anti-CD4 monoclonal antibody and
acute interstitial nephritis
In recent open studies using murine anti-CD4 monoclonal antibody (MAb) as a treatment for rheumatoid arthritis (RA), reported adverse reactions have included fever,
chills, and rigor, which usually occurred during antibody
infusion (1,2). No persistent side effects have been reported.
We have treated a patient with RA using M-T151, the murine
antLCD4 MAb used in the open study by Reiter et a1 (2)
(kindly provided by Professor G. Riethmiiller, Munich,
Germany). Acute interstitial nephritis developed in the patient 4 weeks after treatment. Although a direct causal
relationship cannot be established, the temporal relationship
suggested a possible link between the murine antLCD4 MAb
treatment and the development of interstitial nephritis in this
patient.
The patient, a 69-year-old man, had seropositive,
erosive RA of 37 years duration. In 1990, 36 years after the
onset of RA, he reported having dry eyes and mouth, and
Schirmer’s test confirmed decreased tear production (left
eye 0 mm, right eye 2 mm, after 5 minutes). Rheumatoid
factor (RF) was positive at a titer of 15,120, but antinuclear,
anti-SS-AIRo, and anti-SS-B/La antibodies were negative.
Labial biopsy was not performed. Renal function was normal. On the basis of these results, a provisional diagnosis of
secondary Sjogren’s syndrome (SS) was made and he was
treated with hypromellose eyedrops. He continued to have
aggressive RA, which did not respond to conventional
disease-modifying drugs including gold, D-penicillamine,
sulfasalazine, phenytoin, azathioprine, and methotrexate.
He also had severe erosive esophagitis and gastritis, which
precluded treatment with nonsteroidal antiinflammatory
drugs (NSAIDs).
All second-line drugs were stopped 6 months before
the patient was admitted to the hospital for MAb treatment.
Treatment at the time of admission consisted of coproxamol
(paracetamol and dextropropoxyphene hydrochloride), isosorbide mononitrate, and diltiazem, which he took for pain
and ischemic heart disease. He was not taking diuretics. At
the time of initiation of treatment with M-T151, he had
synovitis of the hands, wrists, feet, and knees, with bilateral
knee effusions, early morning stiffness of 60 minutes, joint
pain scored at 6.7 cm on a 0-10-cm visual analog scale
(VAS), and a Ritchie Articular Index (RAI) score (3) of 11
(possible range 0-63). Results of laboratory investigations
were as follows: hemoglobin 9.0 gm/dl, platelet count 689 x
109/liter, erythrocyte sedimentation rate (ESR) 82 mmhour,
urea 4 mmolesfliter, creatinine 98 pmoleslliter, random
blood sugar 6.4 mmoleslliter, RF titer 1:5,120 (RoseWaaler), IgG 16.8 gmhiter (normal 7.2-19), IgA 5.8 gmfliter
(normal 0.&5.0), IgM 1.8 gmfliter (normal 0.5-2). No paraprotein band was detected, and results of urinalysis and
urine microscopy were normal. Analysis of peripheral blood
lymphocyte subsets revealed the following: CD4 1.1 x
10’Aiter (normal 0.35-2.2) and CD8 0.46 x 109/liter (normal
0.2-1.44).
He received M-T151 intravenously at 10 mg/day for 7
consecutive days. Chills and slight shaking were experienced during the infusion, which lasted for 30 minutes, but
CONCISE COMMUNICATIONS
724
no other reaction was observed. Two weeks posttreatment
there was no significant clinical improvement. He had early
morning stiffness lasting 120 minutes, an RAI score of 8, and
a VAS pain score of 5.5 cm.
Four weeks after M-T151 treatment he was admitted
to the hospital on an emergency basis because of acute renal
failure. On admission, he was dehydrated and oliguric.
There was no clinical evidence of vasculitis. The hemoglobin
level was 8.1 gdliter, platelet count was 708 X 109/liter, and
ESR was 18 mm/hour. Urine microscopy showed 88 white
cells/mm3 with granular casts; no eosinophils were seen, and
culture was sterile. Serum creatinine was 552 pmoles/liter,
urea 21.7 mmoles/liter, and potassium 6.5 mmoleshter.
Results of liver function tests were normal. Electrocardiogram showed a small P-wave and tenting of the T-wave,
consistent with hyperkalemia. Findings on ultrasound of the
kidneys were normal. Autoantibodies, including anti-DNA,
were again negative. Serum complement levels were normal.
Creatinine clearance was 6 d m i n u t e , and the 24-hour
urinary protein estimation was 0.8 g d i t e r . Peripheral blood
lymphocyte subset analysis showed the following: CD4 1 x
109/liter and CD8 0.34 x 10’Aiter. DTPA (diethylene triamine penta-acetic acid) scan showed perfused, functioning
kidneys of equal size, but selective accumulation of tracer
with increased parenchymal transit time. Renal biopsy
showed interstitial nephritis with pronounced plasma cell
infiltrate.
His condition improved with intravenous fluid and
furosemide. Over the next few days, urine output improved
and his serum creatinine level continued to decrease. Three
months later, the serum creatinine level had returned to 112
pmoledliter.
There are many causes of acquired interstitial nephritis. Among the most common is drug-induced disease,
caused especially by NSAIDs. However, our patient was not
receiving such treatment, and there was no other obvious
cause. Interstitial nephritis can occur in primary SS (4), but
renal manifestations are uncommon in secondary SS. In a
review by Tu et a1 (9,patients with interstitial nephritis had
primary SS with only minor arthritis. Interstitial nephritis is
a histologic diagnosis and, because renal biopsy is not
performed routinely in patients with RA and secondary SS
who have normal renal function, it is possible that mild
subclinical interstitial nephritis may occur in secondary SS.
Our patient experienced chills and rigor during treatment,
which has been attributed to cytokine release by the antiCD4 MAb (6). The latter may have led to an exacerbation of
preexisting subclinical interstitial nephritis related to secondary SS. Other possible pathogenic mechanisms by which
anti-CD4 MAb could induce interstitial nephritis include
formation of immune complexes (7).
Although it is impossible to know the exact role of
anti-CD4 monoclonal antibodies in this patient’s acute renal
failure, the possibility of a link, either causal or by exacerbation of a preexisting subclinical condition, cannot be
excluded. When anti-CD4 MAb is used as an experimental
treatment, investigators should be vigilant in monitoring
possible side effects.
E. H. S. Choy, MB, BCh, MRCP
G. H. Kingsley, BSc (Hons), MB, MRCP
G. S. Panayi, ScD, MD, FRCP
United Medical and Dental Schools
Guy’s Hospital
London, UK
1. Horneff G, Bunnester GR, Emmrich F, Kalden JR: Treatment of
2.
3.
4.
5.
6.
7
rheumatoid arthritis with an anti-CD4 monoclonal antibody.
Arthritis Rheum 34: 129-140, 1991
Reiter C, Kakavand B, Rieber EP, Schattenkirchner M, Riethmiiller G, Kruger K: Treatment of rheumatoid arthritis with
monoclonal CD4 antibody M-T151: clinical results. and immunopharmacologic effects in an open study including repeated administration. Arthritis Rheum 34525-536, 1991
Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG,
Grieveson P, Buchanan WW: Clinical studies with an articular
index for the assessment of joint tenderness in patients with
rheumatoid arthritis. Q J Med 37:393-406, 1968
Tala1 N, Zisman E, Schur PH: Renal tubular acidosis, glomerulonephritis and immunologic factors in Sjogren’s syndrome.
Arthritis Rheum 11:774-786, 1968
Tu WH, Shearn MA, Lee JC, Hopper J Jr: Interstitial nephritis in
Sjogren’s syndrome. Ann Intern Med 69: 1163-1170, 1968
Horneff G, Krause A, Emmrich F, Kalden JR, Burmester GR:
Elevated levels of circulating tumor necrosis factor-alpha, interferon-gamma and interleukin-2 in systemic reaction induced by
anti-CM therapy in patients with rheumatoid arthritis. Cytokine
3:266-267, 1991
Williams RC Jr: Immune Complexes in Clinical and Experimental Medicine. Cambridge, Harvard University Press, 1980
The watermelon stomach in scleroderma
Gastric antral vascular ectasia, or “watermelon
stomach,” is a rare cause of chronic gastrointestinal bleeding, with characteristic endoscopic and histologic features.
This unusual disorder has rarely been reported in association
with scleroderma.
The patient described here is a 46-year-old woman
with a 4-year history of scleroderma. In April 1992, she was
evaluated by her primary care physician and was found to be
anemic (hemoglobin value 7.0 gm/dl). Esophagogastroduodenoscopy (EGD) (performed elsewhere) showed gastric
ulceration, with no evidence of active bleeding. Treatment
was initiated with omeprazole (Prilosec; Merck, West Point,
PA), 20 mg/day, and hemotransfusion. During the subsequent 4 months, she continued to require 2 units of blood
every 3 weeks. Further investigations, including colonoscopy, radiographic barium study of the upper gastrointestinal tract with small bowel follow-through, radionuclide scan
for sites of bleeding, and mesenteric angiography, revealed
no active gastrointestinal bleeding. At that time, she was
referred to us for further evaluation.
The patient was a nonsmoker, did not drink alcohol,
and did not take nonsteroidal antiinflammatory drugs. Pertinent review of systems revealed only occasional melena and
infrequent blood-tinged stools over the preceding 4 months.
She was taking omeprazole, 20 mglday, and fluoxetine
(Prozac; Dista, Indianapolis, IN), 20 mglday ,for depression.
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treatment, cd4, interstitial, monoclonal, nephritis, anti, antibody, acute
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