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Fatal methotrexate pneumonitis in rheumatoid arthritis.

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To the Editor:
RA, an elegant clinical pharmacologic protocol derived from
the principles of such basic sciences as biochemistry and
physiology. These areas have given us therapeutically rational drugs, e.g., beta blockers, calcium channel blockers,
and angiotensin-converting enzyme inhibitors, to cite but a
few. Rather, our therapeutic advances have been achieved
largely through empiricism and serendipity. Until this
changes in rheumatology, rational methods for choice of
drug will not be forthcoming.
Oral pulse MTX is a highly effective means of
controlling disease activity for a large number of RA patients, with a favorable toxicity profile, which continues to
be favorable for up to 5 years (Kremer JM, Lee JK: A
long-term prospective study of the use of methotrexate in
rheumatoid arthritis: update after a mean of fifty-three
months. Arthritis Rheum 3 1577-584, 1988). Dr. Buhner’s
position that there is “no logical reason” for denying MTX
therapy would be easier to accept were it not for the prompt
and severe flare of the RA, which is a virtual certainty in the
event of drug withdrawal, regardless of the duration of
treatment (Kremer JM, Rynes RI, Bartholomew LE: Severe
flare of rheumatoid arthritis after discontinuation of longterm methotrexate therapy: double-blind study. Am J Med
82:781-786, 1987). This means that when MTX therapy is
initiated in an RA patient, there is a commitment to a
prolonged, uninterrupted, and possibly iddefinite course of
treatment, barring the development of an adverse reaction or
secondary failure.
I believe the requisite safety data in support of this
approach for all RA patients requiring second-line therapy
are not yet available. Until more data are obtained, it would
seem prudent, particularly in younger RA patients, to attempt to control the disease for as long as possible according
to currenfly accepted prescribing practices, before embarking on MTX therapy.
Thank you for the opportunity to respond to Dr.
Buhner’s comments. I am pleased that he is in general
agreement with my position on the use of methotrexate
(MTX) in rheumatoid arthritis (RA); however, there are
some points of apparent misunderstanding that merit clarification. Dr. Buhner objects to such words as “dogmatically
limit,” “arbitrary conditions,” and “mandate” with respect
to the prescribing of certain drugs for RA. These are all his
words, not mine. It was neither the intent nor the content of
my letter to suggest such a rigid approach, and I am sorry
that he misinterpreted my meaning. The treatment of RA is
a most frustrating and humbling experience, which does not
permit an inflexible mind set.
Dr. Buhner believes that MTX is not a cytotoxic drug
as it is used in RA, and he is concerned that cytotoxic drugs
may be assumed to be more “toxic.” I made no such
statements in my letter; indeed, the word cytotoxic does not
even appear. Since he raises the issue, it should be addressed to avoid further confusion. Our classification of
drugs for RA is so imprecise that any reasonable attempt to
bring some sense of order is justified. Cyclophosphamide, an
alkylating agent, azathioprine, an analog inhibitor of purine
biosynthesis, and MTX, a folk acid antagonist, all inhibit
cellular growth and reproduction. Whether they exert this
action on inflammatory cells, immunocompetent cells, or
both is not known in terms of their mode of action in RA, but
they are antiproliferative, the term I used in my letter.
Intramuscular gold and D-penicillamine are “toxic” drugs
with regard to clinically adverse effects, but they are neither
cytotoxic nor antiproliferative. Thus, the apparent mode of
action of these drugs and their “toxic” side effects are two
independent issues, not to be confused.
Dr. Buhner asks how much longer I “propose to
wait” and how I propose to “reduce the uncertainty”
regarding the use of MTX in RA. I think he has missed the
main thrust of my letter. I am a frequent and enthusiastic
prescriber of MTX for certain selected patients with RA.
Indeed, I consider it to be perhaps the most important
antiinflammatory drug for RA since the introduction of
adrenal corticosteroids. The concern I expressed was that I
believe in many instances, MTX is being introduced too
early in the course of treatment of a lifelong illness. Dr.
Buhner finds reassurance in the safety of pulse MTX therapy
in psoriasis; however, a close scrutiny of the prescribing
patterns of most dermatologists reveals differences that may
be significant. They frequently interrupt MTX treatment in
the long-term therapy of psoriasis. These interruptions may
last for many months, and are made either because of clinical
improvement in the skin, which may persist for some time,
or because of an intervention with an alternative modality.
The number of psoriatic patients who are given sustained
MTX for their skin disease over many years is relatively
Dr. Buhner asks for a “rational” method by which
one can choose the most appropriate drug. This must be
considered rhetorical, for if it could be answered within the
framework of our existing knowledge, this dialogue would
not be taking place. We do not have. for the treatment of
Israeli A. Jaffe, MD
Columbia University
College of Physicians and Surgeons
New York. N Y
Fatal methotrexate pneumonitis in rheumatoid
To the Editor:
The widespread use of methotrexate (MTX) to treat
refractory rheumatoid arthritis (RA) has led to increased
awareness of potential toxic effects. Acute pneumonitis,
originally thought to be a complication only of hign-dose
MTX therapy, has been reported in approximately 22 patients with RA who were treated with low-dose weekly oral
therapy (1-6). Three of these patients died. We report
another case of death secondary to MTX pneumonitis in a
patient with RA.
The patient, a 79-year-old woman, had a 17-year
history of seropositive, nodular RA. Her disease course was
remarkable for progressive loss of function, increasing pain,
and persistent synovitis, despite treatment with multiple
nonsteroidal antiinflammatory agents, penicillamine and intramuscular gold, and left total knee replacement. Chest
radiographs taken previously had shown increased interstitial markings; however, she denied having any respiratory
symptoms. In June 1987, MTX was begun at a dosage of 7.5
mdweek, given in 3 divided doses over a 24-hour period.
The initial doses were well tolerated, and over the ensuing
weeks the patient noted decreasing joint swelling and tenderness.
In late July 1987, the patient developed a nonproductive cough, dyspnea, fever, and chills, and on August 2, she
presented to the emergency room. A chest radiograph revealed bilateral lower lobe infiltrates, and she was treated
with erythromycin. Her respiratory symptoms worsened
over the ensuing days, and she was admitted on August 5 to
the rheumatology inpatient service. Medications included
naproxen, hydrochlorothiazide/triamterene, and MTX (total
cumulative dose of MTX was 52.5 mg). She was afebrile and
in moderate respiratory distress. Pulmonary examination
revealed bilateral rales posteriorly. The remainder of the
physical examination was noncontributory. Laboratory tests
showed a white blood cell count of 13,600/mm3 (88% neutrophils and 1% bands). The hemoglobin value was 13 gm/dl;
blood gas values while breathing room air were pH 7.49,
Pco, 24 mm Hg, PO, 51 mm Hg. Chest radiographs showed
diffuse interstitial infiltrates. She was given methylprednisolone, 100 mg every 8 hours, and the MTX was withheld.
Bronchoscopy with lavage and brushing and biopsy were
performed and showed no evidence of Legionella, Pneumocystis, or Mycobacterium tuberculosis. Pathologic examination of the transbronchial biopsy specimen revealed interstitial pneumonitis and alveolitis compatible with MTX
pulmonary toxicity. Her pulmonary status worsened, and
she was placed on a regimen of erythromycin and gentamicin. Despite intensive respiratory support and broadening of
her antibiotic regimen with amphotericin and trimethoprim/
sulfamethoxazole, her condition continued to deteriorate,
and she died 19 days after admission. Postmortem examination of the lungs failed to disclose any infectious etiology.
Methotrexate pneumonitis is believed to be a hypersensitivity pneumonitis and has been reported with total
cumulative doses as low as 15 mg ( 5 ) . Corticosteroids,
cessation of MTX, and supportive care are the recommended mainstays of therapy once the diagnosis is established (i.e., an infectious etiology has been excluded) (1).
Risk factors for the development of MTX pneumonitis in RA
patients are unknown. Underlying rheumatoid lung disease
and drug interactions have been suggested, but reports have
been conflicting (4).
Previous studies suggest that 3-5% of all patients
with RA who are treated with MTX will develop pneumonitis (1,3,4,6). We have seen 1 other case in a population of
approximately 100 patients with RA who took this drug.
Although some patients recover after the withdrawal of
MTX alone, corticosteroid therapy has been advocated as
the treatment of choice (4). This case illustrates that despite
treatment with corticosteroids and intensive respiratory support, MTX pneumonitis can be fatal. Since MTX is being
used with greater frequency in the treatment of RA, we
believe the following points need to be emphasized: (a)
Acute pulmonary toxicity secondary to MTX therapy in RA
is unpredictable. (b) Early symptoms of cough, dyspnea, and
fever are often missed by physicians and patients. (c) Pneu-
monitis may be a fatal complication of MTX treatment,
despite corticosteroid therapy.
Given this information, we suggest cautious, informed use of MTX to ameliorate the symptoms of RA, and
we believe that a cooperative study to further investigate
risk factors involving acute pulmonary toxicity is warranted.
Eric D. Newman, MD
Thomas M. Harrington, MD, FACP
Geisinger Medical Center
Danville, PA
1. Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg DO:
Pulmonary disease during the treatment of rheumatoid arthritis
with low-dose pulse methotrexate. Semin Arthritis Rheum 16:
186-195, 1987
2. Engelbrecht JA, Calhoon SL, Scherrer JJ: Methotrexate pneumonitis after low-dose therapy for rheumatoid arthritis. Arthritis
Rheum 26:1275-1278, 1983
3. St Clair EW, Rice JR, Snyderman R: Pneumonitis complicating
low-dose methotrexate therapy in rheumatoid arthritis. Arch
Intern Med 145:2035-2038, 1985
4. Searles G, McKendry RJ: Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors: four case reports and a
review of the literature. J Rheumatol 14:116&1171, 1987
5 . Bell MJ, Geddie WR, Gordon DA, Reynolds WJ: Pre-existing
lung disease in patients with rheumatoid arthritis may predispose
to methotrexate lung (abstract). Arthritis Rheum 29 (suppl 4):
S75. 1986
6. Gispen JG, Alarcon GS, Johnson JJ, Acton RT, Barger BO,
Koopman WJ: Toxicity to methotrexate in rheumatoid arthritis.
J Rheumatol 14:74-79, 1987
Methotrexate-associated bone marrow suppression
following surgery
To the Editor:
I report herein the case of a patient who, during the
course of methotrexate (MTX) treatment for rheumatoid
arthritis (RA), developed bone marrow suppression after
surgery. The patient, a 73-year-old man who had unrelenting
rheumatoid arthritis in spite of trials of gold and penicillamine, began treatment with oral MTX in September 1986,
and was much improved while on a regimen of 10 mg, 1 day/
week. On October 20, 1987, he fell while ascending stairs
(before beginning MTX treatment, he had been unable to
climb stairs). His left hip was fractured, and he underwent
surgery (Austin Moore procedure) on October 22. On that
date, he was given his usual dose of MTX. On October 20,
his white blood cell (WBC) count had been 5,400/p11,with a
hemoglobin level of 12.5 gm/dl and a platelet count of
178,000/mm3. On October 25, these values were 6,900/p.1,
10.3 gm/dl, and 187,000/mm3, respectively. These were in
keeping with his complete blood count findings over the
preceding 12 years of gold, penicillamine, and MTX therapy,
except that his hemoglobin level was slightly decreased (this
was thought to be associated with his surgery).
On October 29, prior to transfer to an extended care
facility, his WBC count was 500/p1(30% segmented neutrophils, 54% lymphocytes, 6% monocytes, 6% eosinophils,
and 4% basophils), with a hemoglobin level of 9.5 gm/dl and
a platelet count of 107,000/mm3.Prior to this blood count, on
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pneumonitis, fatal, arthritis, methotrexate, rheumatoid
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