PE
`
`CASE REPORTS
`
`
`
`Treatment of Therapy-Resistant
`Perineal Metastatic Crohn's Disease
`After Proctectomy Using Anti-Tumor
`Necrosis Factor Chimeric Monoclonal
`Antibody, cA2
`Report of Two Cases
`Hendrik M. van Dullemen, Ph.D.,* Ella de Jong, M.D.,t Frederik Slors, Ph.a.f
`Guido N. J. Tytgat, Ph.D.,* Sander J. H. van Deventer, Ph.D.*
`From the Departments of *Gastroenterology and Hepatology and I-Surgery, Academic Medical Center.
`Amsterdam, The Netherlands
`
`PURPOSE: Two young females with well-documented
`Crohn's disease and nonhealing perineal wounds following
`proctectomy compatible with "metastatic Crohn's disease"
`are described. We hypothesized that metastatic Crohn's
`disease would be a tumor necrosis factor-dependent inflam-
`matory reaction and have treated these two patients with
`the anti-tumor necrosis factor chimeric monoclonal anti-
`body, cA2. MAIN FINDINGS: Administration of cA2 was
`followed by a rapid reduction of subjective and objective
`parameters of inflammation and caused a substantial reduc-
`tion of the wound size. CONCLUSION: These preliminary
`data are consistent with a tumor necrosis factor-dependent
`inflammatory cause of Crohn's disease and its extraintesti-
`nal manifestations and provide support for targeting tumor
`necrosis factor in this condition. (Key words: Crohn's dis-
`ease, metastatic; Anti-tumor necrosis factor chimeric mono-
`clonal antibody; Proctectomy; Perinea! wound; Tumor ne-
`crosis factor]
`van Dullemen HM, de Jong E, Slors F, Tytgat GNJ, van
`Deventer SJH. Treatment of therapy-resistant perinea! met-
`astatic Crohn's disease after proctectomy using anti-tumor
`necrosis factor chimeric monoclonal antibody, cA2: report
`of two cases. Dis Colon Rectum 1998;41:98-102.
`
`herapy-resistant Crohn's disease of the distal
`large bowel may necessitate proctocolectomy. A
`major complication of this procedure is delayed per-
`Meal wound-healing, which is a particularly notorious
`event after proctectomy in patients with pre-existent
`
`Address reprint requests to Dr. van Dullemen: Department of Gas-
`troenterology and Hepatology, Academic Hospital Groningen, P.O.
`Box 30.001, 9700 RB Groningen, The Netherlands.
`
`perianal Crohn's disease and a major cause of dixi
`ity in these patients. t 2 Keighley and Allan' repo.
`70 percent of 27 proctectomies in patients
`Crohn's disease had persistent sinuses. Scammellk
`Keighley'' report on 112 proctectomies for *-
`with Crohn's disease, of which 21 patients had:
`layed healing that was observed beyond nneyla
`10 patients whose perineal wounds never healed
`notorious cause of delayed healing is "melt
`Crohn's disease," which is thought to be rebind
`remaining foci of granulomatous inflamrnatimit
`agement of patients with metastatic Crohn's dig
`following proctocolectomy is usually difficult- Stm
`cal treatment is associated with a high recurrences
`and no satisfactory medical treatment is know -
`ing of severe perineal and cutaneous Crohn'sthse'
`
`with hyperbaric oxygen has been described.!'
`patient with perineal Crohn's disease that Novo-
`sponsive to surgical and medical therapy for
`years was reported to have a dramatic response
`hyperbaric oxygen therapy.s A group of six Pane'
`with perinea! and perivaginal fistulas, desPiteaPP,
`priate antibiotics and surgery, received hYllefb
`oxygen treatment twice per day, six days Per aT
`for four weeks. All six improved during a folio
`\I'
`period of 18 months, but the fistulas did pot In
`completely.'
`(cid:9) may be useful in the ire'
`
`98
`
`Ex. 1022 - Page 1
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`

`

`Vol. 41, No. 1
`
`ANTI-TNF FOR METASTATIC CROHN'S DISEASE (cid:9)
`
`99
`
`ment of fistulous Crohn's disease, but its therapeutic
`efficacy in metastatic Crohn's disease is unknown.
`Tumor necrosis factor (TNF) is a proinflammatory
`cvtokine that is necessary for formation of granulo-
`mas, in part through induction of monocyte chemoat-
`tractant protein-1.7-10 We hypothesized that meta-
`static Crohn's disease would be a TNF-dependent
`inflammatory reaction and have treated two patients
`who developed granulomatous inflammation and
`nonhealing perineal wounds following proctectomy
`using a chimeric anti-TNF monoclonal antibody. We,
`here, report the clinical responses of these patients
`following this treatment.
`
`REPORT OF CASES
`Case 1
`A 25-year-old female had well-documented Crohn's
`disease since 1988. In 1989, she underwent a subtotal
`colectomy and ileostomy because of severe colonic
`inflammation and perianal fistulas that were refractory
`to treatment. Initially, the symptoms improved and
`the perianal lesions healed. In 1991, continuity of the
`
`bowel was restored. Unfortunately, the severe ped-
`anal fistulas recurred, for which an ileostomy was
`performed in 1992. Despite this treatment, the peri-
`anal fistulas persisted, and eventually an intersphinc-
`teric proctectomy was performed. Following this pro-
`cedure, a progressive perineal defect developed,
`originating from the vicinity of the incision, compli-
`cated by discharge of pus and intractable pain. In-
`spection under general anesthesia revealed no signs
`of persistent fistulas or abscesses (Fig. 1). Biopsies
`taken from the base of the defect showed inflamma-
`tion and noncaseating granulomas (Fig. 2). The clin-
`ical course and histology was considered to be com-
`patible with extraintestinal Crohn's or "metastatic
`Crohn's" disease. Treatment with hyperbaric oxygen
`failed. Because of the unresponsive disabling disease,
`the possibility of anti-TNF treatment was discussed
`with the patient. After informed consent was ob-
`tained, a single intravenous infusion of the anti-TNF
`chimeric monoclonal antibody (cA2, Centocor Inc.,
`Malvem, PA) at a dose of 10 mg/kg was administered
`as a two-hour infusion. A second dose of cA2 (20
`mg/kg) was infused four months later. The appropri-
`
`Figure 1. Inspection of the perineal wound of patient 1 under general anesthesia before the first infusion with cA2. Note
`the large defect with swollen edges. A small satellite lesion is seen.
`
`Ex. 1022 - Page 2
`
`

`

`Ills Colon Rectum,JanuarylyrA
`
`4
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`VAN DULLEMEN ET AL
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`Figure 2. Biopsy taken from the base of the wound of patient 1 before the first cA2 infusion.
`granulomas (arrow) are seen. (Flematoxylin and eosin; x180.)
`
`Severe inflammation and
`
`CRP mg/t
`70
`
`60
`
`50
`
`20
`
`10
`
`pre (cid:9)
`wk 1
`o (cid:9)
`Figure 3. C-reactive protein (CRP)
`
`wk 2 (cid:9)
`
`wk 3 (cid:9)
`wk 4
`following cA2 infusions of patient 1.
`
`ate amount of cA2 was withdrawn through a 0.2-mM
`low-protein binding sterile filter, diluted with 0.9 M
`saline to a total volume of 300 ml. The concomitant
`medication consisted of diclofenac, morfinhydrochlo-
`ride, and amitriptyline, but no immunosuppressive
`drugs were used.
`
`No adverse events were observed following the
`
`first and second infusions. The perineal pain rapidly
`decreased within days following the infusion, and the
`opiates could be rapidly discontinued. The amount of
`discharge decreased substantially, and one week f°1-
`lowing the infusion, the C-reactive protein completely
`normalized (Fig. 3). Follow-up inspections of the
`wound showed remarkable healing, and the patient
`
`Ex. 1022 - Page 3
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Vol. 41, No. 1
`
`ANTI-TNF FOR METASTATIC CROHN'S DISEASE
`
`101
`
`was able to resume daily work. After four months,
`there was only a small defect left (Fig. 4).
`
`Case 2
`
`A 26-year-old female was initially diagnosed as hav-
`ing ulcerative colitis in 1990. In that year, she under-
`went a subtotal colectomy with an ileorectal anasto-
`mosis. However, she developed a rectovaginal fistula
`and an anal ulcer. Biopsies from this ulcer revealed
`noncaseating granulomas, and the diagnosis was
`changed to Crohn's disease. A rectum amputation and
`an ileostomy was performed in 1994, because of the
`persistent nature of the ulcer and the intractable per-
`Meal pain. The postoperative course was complicated
`by a persistent perinea! defect with small satellite
`lesions with a maximum diameter of 1 cm. The patient
`was not treated with any immunosuppressive medi-
`cation. After informed consent, a single infusion of
`cA2 of 20 mg per body weight was given intrave-
`nously. No side effects during and following infusion
`were encountered. A few days after infusion, there
`was a marked subjective improvement, especially im-
`provement of the pain. Inspection of the perineal
`wound was performed under general anesthesia be-
`
`fore the second infusion. The defect was smaller, with
`disappearance of the small skin lesions. The second
`and third infusions of 10 mg per body weight were
`administered at 2.5 and 6 months, respectively, in an
`attempt to completely close the defect. No side effects
`were seen, and both infusions were followed by
`rapid, subjective improvement. Inspection showed
`improvement, but no disappearance of the defect. In
`conclusion, clinical improvement, but not complete
`healing of the wound, was seen after the cA2 infu-
`sions. No side effects were observed.
`
`DISCUSSION
`Both patients had an extraintestinal complication of
`the Crohn's disease with a persistent wound after
`proctectomy, compatible with "metastatic Crohn's dis-
`ease." This complication is characterized by granulo-
`matous inflammation, which is not contiguous with
`the bowel or enterocutaneous fistulous tracts." The
`characteristic early lesions consist of small erythema-
`tous papules that may enlarge, ulcerate, and ulti-
`mately, drain pus. These lesions may occur in the
`vulva, on the face, on extremities, and the abdominal
`wall but seem to preferentially involve intertriginous
`
`Figure 4. Perinea! wound after two infusions of cA2.
`
`Ex. 1022 - Page 4
`
`(cid:9)
`(cid:9)
`

`

`102
`
`VAN DULLEMEN ET AL
`
`Dis Colon Rectum, Januaiym
`
`areas. Delayed healing of the surgical wound after
`proctectomy in patients with severe anorectal inflam-
`mation is not uncommon and is often therapy-resis-
`tant. It has been hypothesized that "metastatic"
`Crohn's disease results as a consequence of ischemia,
`and treatment with hyperbaric oxygen resulted in
`symptomatic improvement in a few patients. We rea-
`soned that metastatic Crohn's disease is an inflamma-
`tory process that, in view of its granulomatous nature,
`would be dependent on the presence of tumor ne-
`crosis factor.9' 12.13 Indeed, our observations in two
`patients with metastatic Crohn's disease seem to be
`congruent with this notion. Administration of cA2 was
`followed by a rapid reduction of subjective (pain,
`well-being) and objective (discharge, C-reactive pro-
`tein) parameters of inflammation and caused a sub-
`stantial reduction of the wound size, albeit not com-
`plete healing. Repeat cA2 treatment in these patients
`could possibly result in complete wound-healing.
`These results should be interpreted with caution and
`need further confirmation in controlled, clinical stud-
`ies. Nonetheless, our data suggest that anti-TNF treat-
`ment in patients with metastatic Crohn's disease may
`cause rapid improvement, and anti-TNF treatment is
`not associated with a high incidence of side ef-
`fects.10, 14-16
`
`CONCLUSION
`These preliminary data are consistent with a TNF-
`dependent inflammatory origin of metastatic Crohn's
`disease and provide support for targeting TNF in this
`condition.
`
`REFERENCES
`1. Marks CG, Ritchie JK, Todd IP, Wadsworth J. Primary
`suture of the perineal wound following rectal excision
`for inflammatory bowel disease. Br J Surg 1978;65:
`560-4.
`2. Williams N, Scott NA, Watson JS, Irving MH. Surgical
`management of perineal and metastatic cutaneous
`Crohn's disease. Br J Surg 1993;80:1596-8.
`3. Keighley MR, Allan RN. Current status and influence of
`operation on perianal Crohn's disease. Int J Colorectal
`Dis 1986;1:104-7.
`4. Scammell B, Keighley MR. Delayed perineal wound
`
`healing after proctocolectomy for Crohn's disease. Brj
`Surg 1986;73:150-2.
`5. Brady CE, Cooley 13j, Davis JC. Healing of severe pe,
`neal and cutaneous Crohn's disease with hypertk
`oxygen. Gastroenterology 1989;97:756-60.
`6. Potter WA, Bicks RO. The effects of hyperbaric oxir
`therapy on the perineal/perivaginal fistulas of Cr*,
`disease with hyperbaric oxygen labstractl. Gastment
`ology 1991;100:A241.
`7. Kinder V, Sappino AP, Grau G, Piguet PF, VassalliP
`The inducing role of tumor necrosis factor in the dert
`opment of bacterial granulomas during BCG infeaix
`Cell 1989;56:731--40.
`8. Lukacs NW, Chensue SW, Strieter RM, Warmingtont
`Kunkel SL. Inflammatory granuloma formation is mei
`ated by TNF-a-inducible intercellular adhesion mole.
`cule-1. J Immunol 1994;152:5883-9.
`9. Flory CM, Jones ML, Miller BF, Warren JS. Regulator
`roles of tumor necrosis factor-alpha and interleukin-I
`beta in monocyte chemoattractant protein-l-meditec
`pulmonary granulomaforrnation in the rat. Am J Patted
`1995;146:450-62.
`10. van Dullemen HM, Deventer SJ, Hommes DW,
`Tytgat GN, Woody J. Treatment of severe Crohn's dis-
`ease with an anti-tumor necrosis factor chimeric mono-
`clonal antibody. Gastroenterology 1995;109:129-35.
`11. Kafity AA, Pelligrini AE, Fromkes D. Metastatic Crohn's
`disease: a rare cutaneous manifestation. J Clin Gast*
`enterol 1993;17:300-3.
`12. Flynn JL, Goldstein MM, Chan J, el at Tumor necrosis
`factor-alpha is required in the protective immune re
`sponse against Mycobacterium tuberculosis in mice
`Immunity 1995;2:561-72.
`13. Chensue SW, Warmington KS, Ruth JH, Lincoln P.
`Kunkel SL. Cytokine function during mycobacterial and
`schistosomal antigen-induced pulmo-nary granuloma
`formation: local and regional participation of IR:-
`gamma, IL-10, and TNF. J Immunol 1995;54:5969-~6.
`14. Elliot MJ, Maini RN, Feldman M, et al. Randomised
`double-blind comparison of chimeric monoclonal aft-
`body to tumour necrosis factor 181 (cA2) versus
`cebo in rheumatoid arthritis. Lancet 1994;344:1105-10.
`15. Elliott MJ, Maini RN, Feldman M, et al. Repeated ther1l
`with monoclonal antibody to tumour necrosis facmr
`181 (cA2) in patients with rheumatoid arthritis- uncet
`1994;344:1125-7.
`16. Elliott MJ, Maini RN, Feldman M, et al. Treatment of
`rheumatoid arthritis with chimeric monoclonal allub°6
`ies to tumor necrosis factor 181. Arthritis Rheum 1993;
`36:1681-90.
`
`Ex. 1022 - Page 5
`
`(cid:9)
`(cid:9)
`

`

`Anal Duct/Gland Cyst
`Report of a Case and Review of the Literature
`Mahmoud N. Kulaylat, M.B., B.Ch.,* Ralph J. Doerr, M.D.,*
`Mike Neuwirth, M.D.,* Sateesh K. Satchidanand, M.D.t
`
`From the State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Departments
`of *Surgery and (Pathology, Buffalo General Hospital, Buffalo, New York
`
`PURPOSE: The purpose of this communication is to report
`a case of anal duct/gland cyst and review cases of perianal
`and presacrococcygeal mucus-secreting cysts reported in
`the literature with emphasis on their histopathologic fea-
`tures. METHOD: Our patient presented with coccydynia.
`An extraluminal retrorectal tumor was felt on rectal exam-
`ination. A computerized tomographic scan demonstrated a
`presacrococcygeal mass closely related to the anorectal
`junction. The tumor and the coccyx were excised using a
`posterior approach. Cases of perianal and presacrococcy-
`geal mucus-secreting cysts reported in the literature were
`reviewed. RESULTS: In our case, the tumor proved to be an
`anal duct/gland cyst. Some of the reported cases of presa-
`crococcygeal glandular cysts had histopathologic features
`suggestive of anal duct/gland origin. CONCLUSION: Diag-
`nosis of anal duct/gland cyst is based on routine histologic
`features, histochemical characteristics of mucus, and/or the
`presence of a communication with an anal duct or crypt.
`Based on these criteria, some of the reported cases of
`mucus-secreting cysts occurring around the anorectum may
`prove to be anal duct/gland in origin. [Key words: Anal
`duct/gland; Mucus-secreting cyst; Presacrococcygeal cyst;
`Developmental cyst]
`Kulaylat MN, Doerr RJ, Neuwirth M, Satchidanand SK. Anal
`duct/gland cyst: report of a case and review of the litera-
`ture. Dis Colon Rectum 1998;41:103-110.
`
`A (though infection is the most common disease
`A process that occurs around the anorectum, tu-
`mors and cysts are occasionally encountered. t-12
`These tumors and cysts commonly occur in the pre-
`sacrococcygeal space and are classified according to
`their origin and histopathology into congenital, neu-
`rogenic, osseus, and miscellaneous.13 There is con-
`troversy as to classification of the congenital lesions
`and their organ of origin. This is because of the
`complex embryologic changes that occur in the sa-
`crococcygeal area and the varied and often complex
`histopathology of these lesions. Benign developmen-
`tal cysts comprise the great majority of congenital
`]esions.9-11 The nomenclature of such cysts is diverse,
`often descriptive, and their histopathologic features
`overlap. This is particularly true for mucus-secreting
`cysts, Of interest, anal duct/gland cyst, an infre-
`quently reported lesion, is not included in any classi-
`
`Address reprint requests to Dr. Kulaylat: Buffalo General Hospital,
`100 High Street, Buffalo, New York 14203.
`
`fication concerning presacrococcygeal cysts, and the
`anal ducts/glands are not considered as a possible
`source of some of the cysts occurring in that area. This
`is because of the obscure embryologic origin of anal
`ducts/glands and controversy surrounding the exact
`nature and anatomic extent of these structures. We
`report a case of anal duct/gland cyst and review the
`literature for similar lesions and for other mucus-
`secreting cysts occurring in the presacrococcygeal
`area. We further review the anatomy, pathology, and
`histochemistry of the anal glands and the embryologic
`developments that occur in the caudal area of the
`body. Support is given that some of the reported
`mucus-secreting cysts arose from the anal ducts/
`glands.
`
`REPORT OF A CASE
`
`A 71-year-old white male presented to our clinic
`with coccydynia. He gave a history of trauma to the
`coccyx in the past. On examination, no findings were
`noted in the sacrococcygeal or perianal area. Digital
`rectal examination revealed a posterior extraluminal
`mass. A computerized tomographic scan demon-
`strated a mass in the retrorectal space involving the
`coccyx, with an inflammatory reaction surrounding
`the tumor and extending to the right ischioanal space
`(Fig. 1). The tumor mass, coccyx, and portion of the
`gluteus maximus muscle were excised through a dor-
`sal sacrococcygeal incision. The postoperative course
`was complicated by a wound infection. The wound
`was opened and a diverting colostomy was fashioned
`for control of wound sepsis. A communication be-
`tween the abscess cavity and the anal canal was found
`at the level of the dentate line, posteriorly. The patient
`was discharged home on the 30th postoperative day.
`The fistula was closed five months later with an en-
`doanal rectal advancement flap. At this time, the pa-
`tient is awaiting takedown colostomy pending com-
`plete healing of the presacral wound by secondary
`intention.
`The surgical specimen measured 11.5 X 7.8 x 5.8
`
`103
`
`Ex. 1022 - Page 6
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`

`

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`Ex. 1022 - Page 7
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`

`

`Diseases of the
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`ANNUAL MEETING OF THE AMERICAN SOCIETY
`OF COLON AND RECTAL SURGEONS
`
`San Antonio Convention Center, San Antonio, Texas, May 3-8. 1998
`
`OFFICIAL JOURNAL OF
`THE AMERICAN SOCIETY OF
`COLON AND RECTAL SURGEONS
`
`Williams & Wilkins
`
`Ex. 1022 - Page 8
`
`