Treating acute gouty arthritis with selective COX 2 inhibitors
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7371.980 (Published 02 November 2002) Cite this as: BMJ 2002;325:980
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I AM ASKING IS CHOLCICHINE THERAPY SAFE FOR SOMEONE WHO HAS HAD DOCUMENTED CASE OF IDIOPATHIC THROMBOCYTOPENIA PURPURA, REQUIRING 4 MONTHS OF PREDNISONE THERAPY?
Competing interests:
PURPOSE OF INTEREST IS SAFETY OF CHOLCICHINE THERAPY
Competing interests: No competing interests
Dear Sir,
I have a remarkable patient whose acute gout resolved with celecoxib therapy. More importantly, however, his metastatic malignant melanoma also completely regressed.
In 1995, at age 57, he was found to have a malignant melanoma, stage T4bN1, of the arm. After definitive surgery, he received Cancervax immunotherapy. In June 1998, CT thorax showed multiple pulmonary metastases, Cancervax was discontinued and he received 4 cycles of bio-chemotherapy (Interleukin-2, Interferon alpha 2a, BCNU, cisplatinum, DTIC and tamoxifen) with partial response. By August 1999, pulmonary metastases increased in size and number. In March 2000, the largest lung metastasis measured 2.1 x 3.1 cms. Shortly thereafter, he had an episode of gout and he requested his family doctor to prescribe celecoxib 200 mgs. daily because he had read a report of anti-angiogenic properties of celecoxib in Canada’s National Post newspaper. Follow-up chest X-ray in July 2000 showed regression of lung metastases, which has been sustained with normal chest X-ray through September 2002. He continues to receive celecoxib 200mgs daily.
In primary skin melanoma, COX-2 has been demonstrated by immunohistochemistry in 26 of 28 cases, but was absent in 4 benign nevi (Ref. 1). Constitutive expression of COX-2 mRNA and protein has been reported in five melanoma cell lines (Ref. 1). Previous laboratory studies of COX -2 inhibition in melanoma include observations of a dose and time dependent decrease in invasiveness and collagenase IV production, and reduced lung metastases after intravenous tumor cell injection. Reduced Matrigel invasion of all five malignant melanoma cell lines by 50-68% has been observed after treatment with a specific COX-2 inhibitor (Ref. 1).
Although the non-selective COX-2 inhibitor, indomethacin, has not produced regression in metastatic melanoma (Refs. 2, 3), recent studies of COX-2 anti-sense clones and structurally modified derivatives of celecoxib support the existence of functionally distinct COX-2 inhibitory and pro-apoptotic effects (Ref 4). Hence, celecoxib may be pro-apoptotic by a COX-2 independent mechanism.
While “spontaneous regression” cannot be excluded, the temporal association of celecoxib therapy and its known COX-2 dependent and independent effects, suggest it was causally related to the observed regression of metastatic melanoma.
Sincerely,
K S Wilson.
References
1. Denkert C, Kobel M, Berger S et al. Expression of cyclo-oxygenase 2 in human malignant melanoma. Cancer Res 2001: 61(1), 303-308.
2. Mertens WC and Lohmann RC. Oral indomethacin and ranitidine in advanced melanoma: a phase 2 study. Clin Oncol 1996: 8(2), 112-5.
3. Miller RL, Steis RG, Clark JW, Smith JW, Crum E, McKnight JE, Hawkins MJ, Jones MJ, Longo DL, Urba WJ. Randomized trial of recombinant alpha-2b interferon with or without indomethacin in patients with metastatic malignant melanoma. Cancer Res 1989: 49(7), 1871-6.
4. Song X, Lin H-P, Johnson A J, Tseng P-H, Yang Y T, Kulp S K et al. Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells. J Nat Cancer Inst 2002: 94: 8, 585-591.
Competing interests:
None declared
Editorial note
The patient whose case is described in this response has given his signed informed consent to publication.
Competing interests: No competing interests
I am concerned regarding the recent launch of etoricoxib, a COX2
inhibitor shown to be as effective in the treatment of gout as
indomethacin.
What role does this drug have? Broadly, patients with gout fulfill
one of two stereotypes: men in their 40s with little(if any) comorbidity;
and elderly patients (frequently female) with heart failure, often on
diuretics, and with suspect renal function if not overt renal failure.
The first group are not at high risk of GI toxicity from short
courses of unselective NSAIDs, even potent ones like indomethacin in full
dose. The second group are not candidates for any NSAID, whether COX2
selective or not, as these drugs are just as likely (if not more likely -
but that is another debate) to exacerbate heart and kidney failure.
There are a few young men with gout, without renal disease, who have
GI risk factors and would benefit from a COX2 agent rather than a
conventional NSAID. Unlike patients with other arthritides though, Gout
sufferers usually use NSAIDs only for short periods, so these young men
are few and far between. Elderly ladies with heart failure and renal
problems are, unfortunately, quite common.
I am afraid that the high profile launch of a COX2 agent with a gout
licence will lead to more inappropriate NSAID prescribing in patients with
renal impairment. Oral or intra-articular corticosteroids are a much
better option in this group.
Yours sincerely
Competing interests:
None declared
Competing interests: No competing interests
Re: safety of cholcichine therapy
Colchicine therapy is not recommended for this patient with
idiopathic thrombocytopenic purpura (ITP). In recent years, the use of
colchicine for the treatment and prevention of acute gouty arthritis, has
steadily declined. Drawbacks include slow onset of action, narrow benefit
-to-toxicity ratio with about 80% of patients experiencing nausea,
diarrhea, and/or abdominal pain after oral administration, and reduced
therapeutic efficacy when administered 24hrs or longer after the onset of
acute gouty inflammation. The drug is efficacious in about two-thirds of
patients, and its use is now reserved for those without renal, hepatic or
bone marrow disease, who are intolerant of or hypersensitive to the more
effective and better tolerated nonsteroidal anti-inflammatory drugs
(NSAIDs).
Colchicine is metabolized in the liver and the greater part of the
drug and its metabolites are excreted in the bile. About 20% of the drug
is excreted unchanged in the urine. Following oral administration,
gastrointestinal (GI) symptoms (nausea, vomiting, diarrhea, abdominal
cramps) are the main side-effects. More serious reactions are rare, and
include bone marrow suppression (with leukopenia, thrombocytopenia),
disseminated intravascular coagulation (with severe thrombocytopenia due
to thrombin generation), vomiting, diarrhea, oligouric renal failure,
hepatic necrosis, alopecia, seizures and even death. These mostly occur
following IV administration or as a result of an oral overdose,
particularly in elderly individuals with hepatic or renal impairment.
Thus, in light of its potential toxic effects on platelets, it is prudent
to not administer colchicine to this patient with ITP, presumably to treat
gouty arthritis. Also, given its potential myelotoxicity, colchicine may
intefere with the use of azathioprine, cyclophosphamide or other cytotoxic
drugs that might be required to treat refractory ITP.
Although NSAIDs are considered the drugs of choice in the treatment
of acute gout, given their effects on platelets, these agents are best
avoided in those with ITP. Corticosteroids, intraarticular, oral or
parenteral would,seem to be, therefore, the safest and least hazardous
agents for treating gouty flares in this patient.
Competing interests:
None declared
Competing interests: No competing interests