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`353 Kozarek, Patterson,
`Remission in Patients with Refractory Inflammatory
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`(cid:9)
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`1 March 1989 • Annals of Internal Medicine • Volume 110 0 Number 5 (cid:9)
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Methotrexate Induces Clinical and Histologic Remission in
`Patients with Refractory Inflammatory Bowel Disease
`Richard A. Kozarek, MD; David J. Patterson, MD; Martin D. Gelfand, MD;
`V. Alin Botoman, MD; Terrence J. Ball, MD; and Kenneth R. Wilske, MD
`
`Study Objective: To determine whether methotrexate has
`anti-inflammatory activity in refractory inflammatory bowel
`disease.
`Design: Nonrandomized, open-label, preliminary trial of
`methotrexate along with standard medications for 12 weeks.
`Setting: Referral-based gastroenterology practice.
`Patients: Twenty-one patients with refractory inflammato-
`ry bowel disease (14, Crohn disease; 7, chronic ulcerative
`colitis); 17 taking variable doses of corticosteroids and 14 on
`sulfasalazine or metronidazole. Of the 21 patients, 10 had
`previously failed azathioprine or 6-mercaptopurine trials.
`Interventions: Sulfasalazine and metronidazole were con-
`tinued and prednisone dose was tapered according to clinical
`response. Methotrexate was given as a 25-mg intramuscular
`injection weekly for 12 weeks, then switched to a tapering
`oral dose if a clinical and objective improvement was noted.
`Measurements and Main Results: Sixteen of twenty-one
`patients (11 of 14 patients with Crohn disease, 5 of 7 pa-
`tients with chronic ulcerative colitis) had an objecti;/e re-
`sponse as measured by disease activity indices (modified
`Crohn's Disease Activity Index, 13.3 to 5,4 [P = 0,0001],
`Ulcerative Colitis Activity Index, 13,3 to 6.3 [P = 0.007] ).
`Prednisone dosage decreased from 21.4 mg ± 5.6 (SEM) to
`5,5 mg ± 2.0; P = 0.006 and 38.6 mg ± 6.35 to
`12.9mg ± 3.4; P = 0,01, respectively. Five patients with
`Crohn colitis had colonoscopic healing and 4 had normal
`histology at 12 weeks. In contrast, none of the 7 patients
`with ulcerative colitis had normal flexible sigmoidoscopies,
`despite histologic improvement in 5. Side effects included
`mild rises in transaminase levels in 2 patients, transient leu-
`kopenia in 1, self-limited diarrhea and nausea in 2 patients,
`and 1 case each of brittle nails and atypical pneumonitis.
`Conclusions: Although this pilot study is encouraging,
`further work is needed before methotrexate can be recom-
`mended for inflammatory bowel disease,
`
`Annals of Internal Medicine, 1989;110;353-356.
`
`From the Virginia Mason Clinic, Seattle, Washington. For
`current author addresses, see end of text.
`
`The immunosuppressive agents azathioprine and 6-
`mercaptopurine have been used to treat refractory in-
`flammatory bowel disease, but side effects and delayed
`induction of remission have limited their acceptance
`and application (1, 2). Methotrexate, a folic acid an-
`tagonist, is an antimetabolite and anti-inflammatory
`agent (3). Because of its anti-inflammatory capabili-
`ties, it is widely used in psoriasis (4) and various
`forms of arthritis (5-8) and is currently being investi-
`gated in asthma (9, 10), sclerosing cholangitis (11),
`and primary biliary cirrhosis (12). For similar rea-
`sons, methotrexate may be useful in inflammatory
`bowel disease, We used this drug in an open-label
`study in chronic ulcerative colitis and for patients with
`Crohn disease who had failed all trials with conven-
`tional medication.
`
`Materials and Methods
`
`Twenty-one patients (Crohn disease, 14; chronic ulcerative
`colitis, 7) with refractory inflammatory bowel disease were
`treated with methotrexate. After the investigational nature
`of the treatment and potential side effect liability were ex-
`plained, informed consent was obtained. The mean disease
`duration was 12 years and only 1 patient with ulcerative
`colitis had been diagnosed within the previous 3 years. Sev-
`enteen of the twenty-one patients were dependent on ster-
`oids, 3 requiring home intravenous hyperalimentation. The
`range of chronic steroid use varied between 2 months and 23
`years, with all but 1 of the patients having been chronically
`treated for at least the previous 6 months, Ten patients had
`failed previous therapy with azathioprine, and 5 patients
`with Crohn disease had previous small-bowel or colon. resec-
`tions. Fourteen patients were also taking either sulfasalazine
`or metronidazole. Four patients with Crohn disease had
`chronic rectal fistulas, and all patients with Crohn disease
`had intractable pain, diarrhea, low-grade bleeding, or a com-
`bination of these symptoms. A single patient with Crohn
`disease with four previous small-bowel resections had chron-
`ic obstruction with proximal small-bowel dilation as her pre-
`senting complaint. The patients with chronic ulcerative
`colitis, in turn, had refractory diarrhea, gross bleeding, or
`both. All patients were being considered for segmental
`small-bowel or colon resection or for total colectomy.
`Baseline evaluation included laboratory studies (complete
`blood count, erythrocyte sedimentation rate, chemistry pro-
`file, and urinalysis) and either colonoscopy (all patients
`with Crohn disease) or flexible sigmoidoscopy (patients
`with chronic ulcerative colitis) and biopsy. All patients with
`chronic ulcerative colitis had pancolonoscopic examinations
`including serial biopsies within 1 year of methotrexate'treat-
`ment. These biopsies showed moderate to severe histologic
`colitis, and no dysplasia was noted. A previously published
`modification of the Crohn's Disease Activity Index (13),
`ranging from 0 (no clinical disease) to 15 (severe disease),
`was recorded for patients with Crohn disease at baseline and
`weekly thereafter, For patients with chronic ulcerative coli-
`tis, a clinical activity index ranging between 0 and 15 was
`defined and consisted of the sum of the following; number of
`
`©1989 American College of Physicians (cid:9)
`
`353
`
`Ex. 1082 - Page 3
`
`

`

`Table 1. Clinical Response and Corticosteroid Dosing with Methotrexate Administration in Seven Patients with Refractory
`Chronic Ulcerative Colitis
`
`Patient
`
`Disease
`Site
`
`Follow-up
`in
`Weeks
`
`Response
`
`Prednisone Dose
`at
`at
`12 Weeks
`Onset
`
`Activity Index
`at
`at
`12 Weeks
`Onset
`
`Ongoing
`Methotrexate
`Therapy
`
`Pancolitis
`Pancolitis
`Left colon
`Pancolitis
`Pancolitis
`Left colon
`Left colon
`
`2
`3
`4
`5
`6
`7
`
`Meant
`
`12
`34
`12
`20
`20
`20
`24
`20.3
`
`* Patient relapsed off parenteral methotrexate,
`t Mean is ± SE where applicable.
`P - -- 0.01 determined by paired t-test,
`§ P = 0,007 determined by paired t-test,
`
`No
`Yes
`No
`Yes
`Yes
`Yes*
`Yes*
`
`30
`60
`30
`15
`60
`35
`40
`38.6 ± 6,35
`
`13
`30
`15
`10
`11
`10
`15
`0
`15
`10
`15
`15
`9
`15
`12,9 ± 3,44 1.3,3 .± 0.9
`
`12
`7
`10
`2
`4
`7
`2
`6.3 ± 1.5§
`
`No
`Yes
`Yes
`Yes
`Yes
`No
`No
`
`liquid stools daily, degree of bleeding (0 = none, 1 = mild,
`2 = moderate, 3 = severe), number of extracolonic symp-
`toms (aphthoid ulcers, erythema nodosum, peripheral ar-
`thritis, acute iritis), abdominal pain (0 = none, 1 = mild,
`2 = moderate), and feeling of health (0 = well, 1 = fair,
`2 = poor, 3 = terrible), This activity index was defined at
`baseline and weekly thereafter,
`Treatment consisted of 25 mg of methotrexate adminis-
`tered intramuscularly each week for 12 weeks followed by a
`tapering oral dose down to a minimum of 7,5 mg per week if
`improvement was evident by week 12. In addition to the
`activity index as previously defined, repeat lab studies were
`obtained weekly for the first 3 months and thereafter every 6
`to 8 weeks if medication was continued. Twenty-four hour
`methotrexate levels were obtained at week 8, and all patients
`had repeat endoscopic and histologic studies at week 12.
`Patients who had no sustained improvement by week 12
`were withdrawn from the drug and treated conventionally.
`
`Results
`
`Sixteen of the twenty-one patients had significant clini-
`cal improvement initially as evidenced by the modified
`Crohn's Disease Activity Index, which fell from a
`
`mean of 13,3 to 5.4 (P = 0.0001), and the chronic
`ulcerative colitis activity index, which decreased from
`13.3 to 6.3 (P = 0.007) (Tables 1 and 2). Because of
`previous right colon resection or terminal ileal diseh3e,
`all patients with Crohn disease were evaluable colono-
`scopically. Five of fourteen patients with Crohn dis-
`ease, all with colon disease alone, went into endoscop-
`ic, and 4 of 14, into histologic remission. Whereas 5 of
`7 patients with ulcerative colitis improved clinically,
`no patient had either complete histologic or endo-
`scopic remission. The histologic findings of 3 of these
`7 improved from severe to mild inflammatory changes,
`2 to moderate inflammatory changes, and 2 were un-
`changed. Steroid therapy was tapered in 14 of 17 pa-
`tients and withdrawn in 5. The mean dose of predni-
`sone at 12 weeks fell from 27 mg to 8.5 mg (Tables 1
`and 2). Hyperalimentation was discontinued in 2 of 3
`patients, including 1 of 2 patients with Crohn disease
`who had intractable diarrhea and abdominal pain and
`a single patient with chronic ulcerative colitis being
`considered for colectomy.
`
`Table 2, Clinical Response and Corticosteroid Dosing with Methotrexate Administration in 14 Patients with Refractory
`Crohn Disease
`
`Patient
`
`Disease
`Site
`
`Response
`
`Follow-up
`in
`Weeks
`
`Prednisone Dose
`at
`at
`Onset
`12 Weeks
`
`Modified Crohn's
`Activity Index
`at
`at
`Onset
`12 Weeks
`
`Ongoing
`Methotrexate
`Therapy
`
`Colon
`Colon
`Small bowel
`Colon
`Colon
`Colon
`Small bowel
`Small bowel
`Small bowel, colon
`Small bowel
`Small bowel
`Colon
`Small bowel, colon
`Small bowel, colon
`
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`Meant
`
`40
`30
`36
`22
`22
`12
`12
`9
`18
`12
`20
`32
`12
`26
`22.5
`
`* Patient relapsed off parenteral methotrexate,
`t Mean is ± SE where applicable.
`P = 0,0006 determined by paired t-test.
`§ P = 0,0001 determined by paired t-test.
`
`Yes
`Yes
`Yes
`Yes
`Yes
`No
`No
`Yes
`Yes*
`Yes
`Yes
`Yes
`No
`Yes
`
`15
`20
`5
`0
`10
`0
`0
`2
`6
`15
`0
`20
`2
`15
`10
`15
`10
`2
`7
`2.5
`14
`15
`40
`9
`0
`15
`15
`0
`15
`0
`7
`60
`7
`15
`0
`0
`15
`13
`15
`6
`60
`15
`20
`3
`1
`20
`11
`0
`10
`12
`40
`15
`0
`4
`0
`0
`21.4 ± 5.6 5.5 ± 2.01: 13.3 ± 0.9 5.4 ± 1,5*
`
`Yes
`Yes
`Yes
`No
`Yes
`No
`No
`Yes
`Yes
`Yes
`Yes
`Yes
`No
`Yes
`
`354 (cid:9)
`
`1 March 1989 • Annals of Internal Medicine • Volume 110 • Number 5
`
`Ex. 1082 - Page 4
`
`

`

`Seven patients were ultimately withdrawn from
`therapy because of lack of sustained improve-
`ment (chronic ulcerative colitis, three; Crohn disease,
`four), five at the 12-week study termination period, and
`two later. Of the five patients withdrawn at week 12,
`two had transient improvement beginning at week 4
`of methotrexate therapy that lasted approximately
`1 month. In addition to the flve patients mentioned above,
`two patients with ulcerative colitis relapsed on oral
`therapy and were withdrawn from therapy at 20 and 24
`weeks, respectively. An additional patient with Crohn
`disease also relapsed on oral therapy at week 14 but went
`into a second remission with reinstitution of parenteral
`methotrexate.
`Four patients have later had surgery. The ileum of
`one patient with four previous small-bowel resections
`for Crohn disease healed by cicatrization and required
`a fifth resection after 24 weeks of therapy. Residual
`Crohn disease was present. A second patient with pan-
`colitis and ileitis developed stenosis of her right colon.
`Healing of her left colon was noted colonoscopically.
`Residual disease was noted in both the endoscopic
`biopsy sample and the resected specimen. A nonre-
`sponding patient with Crohn disease had a diverting
`ileostomy for severe perianal disease. Finally, a non-
`responder with chronic ulcerative colitis required total
`colectomy for intractable symptoms.
`Side effects included a patient who developed tran-
`sient leukopenia (leukocyte count, 3.5 X 109/L) brit-
`tle nails, and mild increase in AST level, another with
`a transient AST level increase, two who experienced
`nausea and diarrhea for 24 hours after injections, and
`a fifth who developed atypical pneumonia (Table 3).
`The latter patient was subsequently found to have an
`obstructing endobronchial neoplasm. No other com-
`plications were noted.
`The 24-hour methotrexate levels ranged from 0.010
`to 0,027. Neither improvement nor side effects corre-
`lated with 24-hour blood levels.
`
`Discussion
`
`Methotrexate is an antimetabolite which, as a folic
`acid inhibitor, was originally used in the treatment of
`childhood leukemias (1-3). More recently, its anti-in-
`flammatory properties have led to its application in a
`heterogeneous group of illnesses, including psoriasis,
`rheumatoid arthritis, polymyositis, and the Reiter syn-
`drome (4-8). Still more recently the drug has been
`shown to be effective in refractory asthma (9, 10) and
`has been reported anecdotally to have resulted in the
`improvement of liver function tests in one patient with
`sclerosing cholangitis (11) and two patients with pri-
`mary biliary cirrhosis (12).
`The efficacy of the drug in this disparate group of
`illnesses in which local inflammation plays a promi-
`nent role prompted us to evaluate its effect in a group
`of patients with refractory inflammatory bowel dis-
`ease. Although there is a precedent in treating refrac-
`tory chronic ulcerative colitis or Crohn disease with
`immunosuppressive agents such as 6-mercaptopurine
`or azathioprine (1, 2), methotrexate therapy differs in
`
`Table 3. Side Effects of Methotrexate in 21 Patients with
`Refractory Inflammatory Bowel Disease
`
`Side Effect
`Transient nausea, diarrhea (cid:9)
`AST increase*
`Leukopenia
`Brittle nails
`Atypical pneumonitist
`
`Number of Patients
`
`2
`2
`
`* AST (aspartate aminotransferase) level increased to less than 1.5
`greater than the normal range.
`f Endobronchial neoplasm was subsequently diagnosed.
`
`several ways. In the dosage used, immunosuppression
`does not appear to occur (14). In addition, whereas
`azathioprine and 6-mercaptopurine often require be-
`tween 3 and 6 months to induce remission, methotrex-
`ate may work more quickly (15). Thus, several pa-
`tients with inflammatory bowel disease improved dra-
`matically in as little as 2 weeks, and most patients who
`responded improved markedly after 8 to 10 weeks. Be-
`cause of the investigational nature of this treatment,
`we elected to discontinue methotrexate therapy if
`there was no significant clinical improvement after 12
`weeks. It is possible, however, that a longer treatment
`course may have been beneficial in the nonresponding
`patients similar to the course sometimes required for
`response to 6-mercaptopurine or azathioprine.
`Our data show that a subset of chronically ill pa-
`tients with Crohn disease improve clinically and in a
`statistically significant fashion despite previous treat-
`ment failure vAth conventional medications. More-
`over, 5 of 13 patients with Crohn colitis had no endo-
`scopic evidence of residual mucosal disease, often
`healing deep longitudinal ulcerations and cobbleston-
`ing into an area of atrophy and mild stenosis. Four of
`these five patients had no evidence of residual Crohn
`disease on mucosal biopsy. These latter data remain
`tentative, however, and may represent sampling error
`and lack of transmural tissue for analysis.
`In contrast to Crohn colitis, in which symptomatic
`and endoscopic healing was often dramatic, patients
`with chronic ulcerative colitis maintained low-grade
`disease activity as manifested by continued minor
`bleeding or diarrhea. Moreover, endoscopic evidence
`of mild colitis persisted, and no patient was felt to
`have completely normal histologic findings on repeat
`biopsies. This tendency of incomplete remission in
`chronic ulcerative colitis has also been noted when
`azathioprine and 6-mercaptopurine have been used
`(16). Patients with chronic ulcerative colitis who re-
`sponded, however, were able to significantly decrease
`or discontinue their corticosteroid therapy (mean
`prednisone dose, 39 to 13 mg; P = 0.01).
`The side effects of methotrexate deserve special
`mention. Although limited in our patient population
`to two instances of nausea and diarrhea as well as
`minor liver function test elevations and leukopenia,
`long-term administration of methotrexate may be as-
`sociated with additional toxicities. Thus, although not
`carcinogenic, the drug is teratogenic and must be used
`in conjunction with birth control in young patients of
`either sex (5). A second concern with long-term ad-
`
`1 March 1989 • Annals of Internal Medicine • Volume 110 • Number 5 (cid:9)
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`355
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`Ex. 1082 - Page 5
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`ministration is development of hepatotoxicity with fi-
`brosis and cirrhosis (17-24). This side effect has not
`occurred in patients with arthritis who have been
`treated for several years with a weekly regimen of
`methotrexate (4). Rather it appears to be daily metho-
`trexate dosing that' causes prolonged high blood levels
`and subsequent liver changes. A cumulative dose of
`methotrexate in excess of 3 g total may also be toxic.
`Accordingly, patients having long-term methotrexate
`treatment should have follow-up liver function tests
`and possibly serial liver biopsies to assure that hepato-
`toxicity does not develop (25).
`The dosage regimen used for our patients was an
`arbitrary one based on clinical experience in our insti-
`tution in inducing remission in patients with rheuma-
`toid arthritis. Parenteral dosing was chosen initially
`for two reasons: It assured patient compliance; and
`oral dosing is associated with variable absorption, a
`fact felt to have particular import in patients with in-
`flamed or previously resected small bowel. Important
`and currently unanswered questions remain: Was a
`12-week trial long enough in the nonresponders?
`Would remission have been induced as well orally?
`What is the minimum dose of drug required to main-
`tain remission?
`Despite methotrexate's acceptable short-term toxici-
`ty and its efficacy in a subset of patients with refracto-
`ry inflammatory bowel disease, further work is
`obviously needed to define the ideal patient and appro-
`priate acute and chronic dosage regimens. Random-
`ized, placebo-controlled studies are needed before
`methotrexate can be advocated with certainty for ul-
`cerative colitis or Crohn disease.
`Acknowledgments: The authors thank Gloria Bailey, PhD, for statistical
`analysis.
`
`Requests for Reprints: Richard A. Kozarek, MD, Section of Therapeutic
`Endoscopy, Virginia Mason Clinic, P.O. Box 900, Seattle, WA 98111,
`
`Current Author Addresses: Drs. Kozarek, Patterson, Gelfand, Botoman,
`Ball, and Wilske: Virginia Mason Clinic, P,O. Box 900, Seattle, WA
`98111.
`
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`1 March 1989 • Annals of Internal Medicine • Volume 110 • Number 5
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`Ex. 1082 - Page 6
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