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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/193—Colony stimulating factors [CSF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Crohn's disease persists as an enigma: without a deciphered etiology and without adequate therapy.
• Prevailing explanations of the pathogenesis of Crohn's disease (Crohn's Disease) hold that the characteristic chronic intestinal inflammation results from an aberrant, activated immune response generated against ubiquitous bacteria or bacterial products that gain access to the lamina intestinal, perhaps through a more permeable intestinal barrier.
• the abnormal reaction has been suggested to be mediated principally by T-cells enhanced by an intrinsic imbalance in pro-inflammatory and contra-inflammatory mediators.
• most therapy aims to counteract that inflammatory state with increasingly potent and sophisticated immune suppressants.
• a method is provided of treating Crohn's Disease in which an immune stimulatory amount of an agonist of CD 114 (Granulocyte Colony Stimulating Factor Receptor (G-CSFR)) is administered to a patient with Crohn's Disease not associated with Glycogen Storage Disease lb.
• G-CSFR Granulocyte Colony Stimulating Factor Receptor
• Another method of treating Crohn's Disease is provided.
• An immune stimulatory amount of an agonist of CD 116 (Granulocyte-Macrophage Colony Stimulating Factor Receptor) is administered to a patient with Crohn's Disease not associated with Glycogen Storage Disease lb.
• another method is provided of treating Crohn's Disease.
• An immune stimulatory amount of an agonist of CD114 (Granulocyte Colony Stimulating Factor Receptor (G-CSFR)) is administered to a patient with Crohn's Disease not associated with Chronic Granulomatous Disease.
• Granulocyte-Macrophage Colony Stimulating Factor Receptor is administered to a patient with Crohn's Disease not associated with Chronic Granulomatous Disease.
• Another method is provided of treating Crohn's Disease.
• An immune stimulatory amount of an agonist of CD114 (Granulocyte Colony Stimulating Factor Receptor (G-CSFR)) is administered to a patient with Crohn's Disease not associated with a presently characterized and identifiable specific neutrophil disorder caused by a genetic disease.
• G-CSFR Granulocyte Colony Stimulating Factor Receptor
• Another method is provided of treating Crohn's Disease.
• An immune stimulatory amount of an agonist of CD116 (Granulocyte-Macrophage Colony Stimulating Factor Receptor) is administered to a patient with Crohn's Disease not associated with a presently characterized and identifiable specific neutrophil disorder caused by a genetic disease.
• a method is provided of treating Ulcerative Colitis.
• An immune stimulatory amount of an agonist of CD114 (Granulocyte Colony Stimulating Factor Receptor (G-CSFR)) is administered to a patient with Ulcerative Colitis.
• G-CSFR Granulocyte Colony Stimulating Factor Receptor
• a method is provided of treating Ulcerative Colitis.
• An immune stimulatory amount of an agonist of CD116 (Granulocyte-Macrophage Colony Stimulating Factor Receptor) is administered to a patient with Ulcerative Colitis.
• Another aspect of the invention is a method of treating extraintestinal manifestations of Ulcerative Colitis.
• An immune stimulatory amount of an agonist of CD 114 (Granulocyte Colony Stimulating Factor Receptor (G-CSFR)) is administered to a patient with extraintestinal manifestations of Ulcerative Colitis.
• G-CSFR Granulocyte Colony Stimulating Factor Receptor
• Another aspect of the invention is a method of treating extraintestinal manifestations of Ulcerative Colitis.
• CD116 (Granulocyte-Macrophage Colony Stimulating Factor Receptor) is administered to a patient with extraintestinal manifestations of Ulcerative Colitis.
• a method is provided of treating pouchitis.
• An immune stimulatory amount of an agonist of CD114 (Granulocyte Colony Stimulating Factor Receptor (G-CSFR)) is administered to a patient with pouchitis.
• G-CSFR Granulocyte Colony Stimulating Factor Receptor
• a method is provided of treating pouchitis.
• An immune stimulatory amount of an agonist of CD116 (Granulocyte-Macrophage Colony Stimulating Factor Receptor) is administered to a patient with pouchitis.
• CD116 Gramulocyte-Macrophage Colony Stimulating Factor Receptor
• a method is provided of preventing or reducing the risk of fistula recurrence.
• An immune stimulatory amount of an agonist of CD114 (Granulocyte Colony Stimulating Factor Receptor (G- CSFR)) is administered to a patient with Crohn's disease who has previously had a fistula, whereby the risk of recurrence of a fistula is reduced.
• G- CSFR Gramulocyte Colony Stimulating Factor Receptor
• An immune stimulatory amount of an agonist of CD116 is administered to a patient with Crohn's disease who has previously had a fistula, whereby the risk of recurrence of a fistula is reduced.
• CD116 Gramulocyte-Macrophage Colony Stimulating Factor Receptor
• the present invention thus opens a new realm of treatment modalities for inflammatory bowel diseases which have proven refractory to discovery of safe and effective ministrations. Contrary to the prior paradigm in the art of treating inflammatory bowel diseases with immunosuppressive agents, the present invention uses agents known to be immunostimulatory to treat, prevent, and maintain remission of such diseases.
• Figure 1 shows the response of 17 patients to a 12-week regimen of therapy with G-CSF.
• FIG. 2 shows the response of patient D during treatment and retreatment.
• immune modulatory factors which act at CD114 and CD116 can be successfully used to treat various forms of inflammatory bowel disease. These include but are not limited to Crohn's Disease, with or without a presently characterized and identifiable specific neutrophil disorder (such as Glycogen Storage Disease lb or Chronic Granulomatous Diseases) pouchitis, fistulas, extraintestinal manifestations of Crohn's Disease, and Ulcerative Colitis.
• the Ulcerative Colitis can be of any extent, including proctitis, proctosigmoiditis, left-sided colitis, or pan-colitis.
• the immune modulatory factor can be any which binds to CD114 or CD116, including G-CSF, GM-CSF, and peptidomimetics or non-peptidomimetics of these factors which induce tyrosine phosphorylation of multiple signaling proteins, which stimulate primary bone marrow cells to form granulocytic colonies in vitro, and/or which elevate peripheral blood neutrophil counts.
• Nartograstim, myelopoietins, circularly permuted G-CSF sequences, SB247464 are among the known mimetics of G-CSF. See, McWherter et al, Biochemistry 14:4564-11, 1999; Feng et al, Biochemistry 14:4553-63, 1999; Tian et al, Science 281:251-59, 1998; and
• M-CSF may also be used in accordance with the present invention.
• the agonist may be administered as is known in the art. Typically this will be by subcutaneous injection or intravenous infusion, however other methods such as oral, intraperitoneal, subdermal, and intramuscular administrations can be used. Doses which are delivered may be the same as those which are delivered to stimulate an immune response in humans for other disease purposes. Typically doses of the factors will be between about 0.1 and 100 ⁇ g/kg of body weight per day. More preferably this will be between about 1.0 and 10 ⁇ g/kg of body weight per day.
• the dose will be between about 2 and 8 ⁇ g/kg of body weight per day.
• Corresponding amounts of peptidomimetics and non- peptidomimetics to achieve the same activity can be used.
• White blood cell counts can be monitored to maintain a value in the range of 10 and 60.
• the immune modulatory factors are typically growth factors or colony stimulating factors which affect the growth of hematopoietic cells, particularly myeloid cells, including polymorphonuclear leukocytes, monocytes, and macrophages.
• myeloid cells including polymorphonuclear leukocytes, monocytes, and macrophages.
• myeloid cell stimulatory factors include but are not limited to myeloid cell stimulatory factors, polymorphonuclear leukocyte stimulatory factors, and granulocytic cell stimulatory factors.
• Particularly useful factors are GCSF, GMCSF, and MCSF. Any form of such factors known in the art can be used. The form may be an isoform or a differently post-translationally modified form of the factor.
• the factor may be one which is isolated from humans or other primates or mammals.
• the factor may be one which is made in a recombinant organism, from bacteria to yeast to sheep.
• Chronic Granulomatous Disease Glycogen storage disease lb
• leukocyte adhesion deficiency a chronic Granulomatous disease
• Turner's syndrome a chronic Granulomatous disease
• Chediak-Higashi myeloproliferative disease
• neutropenias of various causes a myelodysplastic disease.
• Ulcerative colitis can be manifested as proctosigmoiditis, left-sided colitis, or pan-colitis. All of these are included in the term "Ulcerative colitis”.
• Pouchitis is an inflammation of an surgically created pouch in the gastrointestinal tract.
• One goal of treatment is the amelioration, either partial or complete, either temporary or permanent, of patient symptoms, including inflammation of the mucosa, extraintestinal manifestations of the disease, or epithelial damage. Any amelioration is considered successful treatment. This is especially true as amelioration of some magnitude may allow reduction of other medical or surgical treatment which may be more toxic or invasive to the patient.
• Extraintestinal disease manifestations include those of the liver, bile duct, eyes, and skin.
• Another goal of the treatment is to maintain a lack of excess intestinal inflammation in persons who have already achieved remission.
• the present invention is based on the theory that the fundamental immune dysregulation of Crohn's Disease results not from an excessive immune response but from a primary immune deficiency.
• This deficiency likely results from genetic variations in neutrophil and/or macrophage phenotypes interacting with a discrete set of bacteria which suppress neutrophil macrophage function. In turn, this deficiency provokes a broader compensatory response, amplifying inflammation, activating lymphocytes, culminating in Crohn's Disease.
• Crohn's Disease may be extraintestinal, perhaps partly an intrinsic marrow defect, and that Crohn's Disease is not an inherent intestinal abnormality. Consequently, Crohn's Disease ought to be considered not as a disease of primary intestinal dysfunction but the result of an interaction between marrow constituents and the intestinal environment.
• Crohn's Disease Several genetic syndromes with which Crohn's Disease has been associated provide insight into the possible marrow defects of Crohn's Disease.
• five genetic diseases can present with a clinical/histopathological process indistinguishable from Crohn's Disease: chronic granulomatous disease, glycogen storage disease lb, Leukocyte Adhesion Deficiency, Chediak-Higashi syndrome and Turner's syndrome. A distinct deficiency in neutrophil function has been described in each of these syndromes.
• Crohn's Disease has been described in association with congenital, autoimmune, and cyclic neutropenias, familial Mediterranean fever, myelodysplastic, and myeloproliferative diseases.
• These syndromes provide evidence that a variety of functional neutrophil deficiencies can result in a pathophysiology indistinguishable from Crohn's Disease.
• Disorders of neutrophil/macrophage function represent a potential starting point for understanding Crohn's Disease.
• Bacteroides species have been shown to impair phagocytosis as well as the microbicidal activity of neutrophils for aerobic bacteria.
• a discrete subset of the intestinal flora may be responsible for influencing neutrophil/macrophage function in Crohn's Disease.
• Recent work with animal models of IBD also support a protective role for Lactobacillus and Bifidobacteria which may act to counter effects of other bacteria and stimulate immune function.
• the ratio between these different classes of bacteria may be the critical factor in maintaining intestinal health in a susceptible subgroup. Consequently, as suggested by periodontitis, it is unlikely that a single bacteria would be demonstrated as the sole causative agent in Crohn's Disease; instead, these data highlight the complexity of bacterial-immune interactions.
• the localized nature of the interaction between specific bacteria and leukocytes would account for the specific intestinal manifestations, rather than more systemic findings.
• This example demonstrates the treatment of 17 Crohn's disease patients with G-CSF.
• Subjects were enrolled with active disease (CDAI > 200) or with active fistulous disease. Patients were not included if other immunosuppressants had been used for standard periods of time (4 weeks for steroids, azathioprine/6-MP; 3 months for infliximab) and were allowed to be on 5-AS A products (if on for at least 8 weeks and same dose for at least 4 weeks). Subjects had a complete blood count (CBC) test weekly and were examined at least every other week for Crohn's Disease activity index (CDAI) determination and/or evaluation of fistulae. Figure 2 shows the Crohn's Disease Activity Index (CDAI) at the onset (week 0) and followed over a 12-week course of treatment.
• CDAI Crohn's Disease Activity Index
• Clinical "response” in Crohn's disease protocols is typically defined as a decrease in CDAI greater than 70.
• Ten of the 17 patients were responders, with a mean decrease in disease activity of 140 points. Seven of the ten achieved remission. Seven non-responders, including patient M who was withdrawn early from the study for concurrent illness, had a mean increase in CDAI of 41 points.
• Spontaneous closure of perianal fistulas is very rare.
• This example shows the protocol for a further study of the method of the present invention using G-CSF
• An open-labeled trial of G-CSF for 12 weeks for patients with active CD and/or active fistulae secondary to Crohn's disease is initiated.
• the trial involves two separate, interrelated protocols.
• functional neutrophil studies are performed.
• Treatment of active mucosal inflammation in Crohn's disease is the primary focus of Part A.
• Disease activity is defined by a standard Crohn's disease activity index. Patients are enrolled if they have moderate to severe disease activity using entry criteria outlined below. The study is an open-labeled study of fifteen patients with a dose titration protocol designed to provide neutrophil functional stimulation and achieve a moderate leukocytosis. Each subject is studied for twelve weeks of every day subcutaneous administration of G-CSF. Disease activity is followed by standard CDAI, and the quality of life (IBDQ) scale. We are treating new patients (those not included in our initial study) and offer retreatment to any of the previously treated mucosa patients meeting inclusion criteria.
• IBDQ quality of life
• the primary focus of Part B is to determine the efficacy of G-CSF in patients with perianal and rectovaginal fistula associated with Crohn's disease.
• Perianal fistulae are common lesions in Crohn's disease and pose a serious threat to the integrity of the normal rectal sphincter. Current therapy for these lesions are suboptimal.
• This study is designed as an open-labeled study of fifteen patients with a dose titration protocol designed to stimulate neutrophil function and associated leukocytosis. Fistulae are assessed by photography, standard examination scoring criteria, as well as a patient subjective assessment of pain, drainage, and overall well-being. Each subject is studied for twelve weeks on daily subcutaneous G-CSF.
• ANC response-based dosing of G-CSF Treatment continues for 12 weeks.
• CDAI is calculated at enrollment, at the start of therapy, and every other week.
• the Inflammatory Bowel Disease Quality of Life Survey is completed initially and at weeks four, eight, twelve, and sixteen.
• follow-up is performed at week 16 with telephone follow-up monthly out to six months from the date of enrollment or up to relapse.
• Part B Treatment of perianal and rectovaginal fistula in Crohn's disease. Patients are assigned to receive a starting dose of 3.5 micrograms/kilogram/day of
• G-CSF as a subcutaneous bolus injection. Dosages are adjusted as outlined below - "ANC response-based dosing of G-CSF.” Patients who have closed all fistulae before week 8, have G-CSF therapy discontinued at 8 weeks. Patients who have had partial or no response are treated for a full twelve weeks. Fistulae are assessed at weeks 0, 1, 2, 4, 6, 8 and 12 by physical examination scoring criteria, photography, and a subjective patient survey. CDAI is calculated at enrollment, at the start of therapy, and every other week. The Inflammatory Bowel Disease Quality of Life Survey is completed initially and at weeks four, eight, twelve, and sixteen. Follow-up is performed at week 16 with telephone follow-up monthly out to six months from the date of enrollment or up to relapse.
• Part A Crohn's Disease Activity Index (CDAI) > 200 and ⁇ 450.
• Part B At least 1 draining perianal and/or rectovaginal fistula, refractory to general medical management. Previously treated patients who have had a previous response or remission are eligible for retreatment if they have evidence of increased disease activity manifest by reopening of previously closed fistulas (Part B) or who have a CDAI of >220 and have an absolute increase of more than 70 from the treatment nadir (Part A).
• aminosalicylate medication (Sulfasalazine, Pentasa, Asacol, Dipentum, Rowasa enemas), must be on for eight weeks and a stable dose for four weeks. If recently discontinued, must be off for at least two weeks prior to study enrollment.
• a patient with any of the following medical conditions Liver disease with a prothrombin time > 2 second prolongation, portal hypertension, severe hypertension (systolic blood pressure >200 mmHg or a diastolic blood pressure >105 mmHg), renal failure requiring dialysis or a creatinine >2.5, presence of a transplanted organ. 6) Patients with a known, clinically significant, small intestine or colonic stenosis or stricture.
• lymphadenopathy A history of leukemia or lymphoma, or other lymphoproliferative disease, or signs and symptoms of lymphoproliferative disease such as abnormal cells on CBC, or suggestive physical exam findings of lymphadenopathy of unusual size or location.
• New patients are screened within 14 days of initiating the medication with a history, physical and recall estimation of a Crohn's disease activity index (CDAI). If the estimated CDAI is > 200 and ⁇ 450, subjects have a CBC drawn, beta-HCG (if female and premenopausal) and complete a diary for 1 consecutive week within the next 14 days. The subject will return for initiation at day 0. If subject meets entry/exclusion criteria, blood is drawn for CBC, electrolytes, BUN, creatinine, liver enzymes (AST, ALT, alkaline phosphatase, bilirubin), albumin, ESR, and CRP. Instruction is provided for self-administration of the medication (subcutaneous injection). Subjects are titrated to a stable WBC response .
• CDAI Crohn's disease activity index
• CBC are performed at screening, at the times indicated by the flow sheet during treatment, and at the scheduled visit 4 weeks after completion of therapy.
• a panel of serum chemistry studies (electrolytes, BUN, creatinine, liver enzymes (AST, ALT, alkaline phosphatase, bilirubin) is measured at screening, and at weeks 4, 8, 12, and 16.
• C-Reactive Protein (CRP) and erythrocyte sedimentation rate (ESR) are measured at week 0, 2, 4, 8, 12, and 16. Laboratory results that deviate significantly from baseline (except the WBC and alkaline phosphatase) are repeated by obtaining new samples.
• CRP C-Reactive Protein
• ESR erythrocyte sedimentation rate
• the next scheduled dose is lowered by 0.5 mcg/kg/day.
• the ANC is rechecked in 1 week.
• the next scheduled dose is kept the same.
• the ANC is rechecked in 1 week.
• the next ANC measurement is performed at the next scheduled physician visit.
• the next scheduled dose is increased by 0.5 mcg/kg/day.
• the ANC is rechecked in 1 week.
• the next scheduled dose is kept the same.
• the ANC is rechecked in 1 week.
• the next ANC measurement is performed at the next scheduled physician visit. Physicians may decrease dosages as necessary due to severe bone pain. Once the ANC has been in the target range (40-50) on two consecutive measurements, monitoring is increased to the next scheduled physician visit. Physician or nurse coordinators review the CBC results and call the patient with any dosage change.
• Example 4
• This example shows the protocol for a further study of the method of the present invention using GM-CSF.
• Exclusion criteria 1) NSAID or ASA ingestion within two weeks of study entry.
• Liver disease with a prothrombin time > 2 second prolongation portal hypertension ; severe hypertension (systolic blood pressure >200 mmHg or a diastolic blood pressure >105 mmHg); renal failure requiring dialysis or a creatinine >2.5.
• Subjects are screened within 14 days of initiating the medication with a history, physical and recall estimation of a Crohn's disease activity index (CDAI). If the estimated CDAI is > 200 and ⁇ 450, subjects have a CBC drawn, beta-HCG if female and premenopausal) and complete a diary for 1 consecutive week within the next 14 days. The subject returns for initiation at day 0. If subject meets entry/exclusion criteria, blood is drawn for CBC, BUN, creatinine, liver enzymes
• LM injection a daily diary is completed throughout the period of administration of the medication. Telephone calls are performed weekly during the medication period through week 8 and monthly through six months to assess disease activity and adverse effects. At each visit, patients are provided a sufficient supply of medication in preloaded syringes to continue administration through the next physician visit. Dose adjustment
• CDAI is calculated with and without febrile episodes.
• the CDAI which includes fevers as one extra intestinal manifestation in the calculation of disease activity score, for calculating the index, is calculated with and without fevers assessed. Entry criteria are calculated including febrile episodes.
• Possible Adverse Events The principal concern is lack of effect or an exacerbation of disease.
• GM-CSF Sessionostim
• Patients receiving GM-CSF have experienced fever; chills; nausea; vomiting; diarrhea; fatigue; weakness; headache; decreased appetite; thrombosis; rapid or irregular heartbeat or other heart problems; feeling of faintness; facial flushing; pain in the bones, muscles, chest abdomen, or joints; local reaction at the site of injection; rashes; and kidney and liver dysfunction.

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