This report uses data available in Pathway Studio knowledgebase to find new therapeutic applications for anti-TNF antibody drug Humira

1. Humira repositioning
Prepared by Anton Yuryev, Professional Services, Elsevier Life Sciences Solutions
Disclaimer: The report is based on criteria suggested by Elsevier to showcase text-mining technology. Upon your
specifications other type of information and scores are possible to extract by Elsevier technology. Some scores can
be omitted from the final statistical model for simplicity or cost reduction.
Part I. Identifying Humira indications reported in the literature
Defining literature corpus
TargetInsights Enterprise document search system loaded with Pubmed, Pubmed Central and Elsevier
content was searched with semantic query “Humira inhibits Disease” to find 317 publication stating
Humira indications. “Humira” keyword is substituted by all known names of the drug automatically such
as “Adalimumab”, “Trudexa” etc. The results of the search are shown on Figure 1.
Extracting Humira indications mentioned in biomedical literature
Documents identified by semantic search at previous step were exported from TargetInsights Enterprise
and processed with MedScan Reader software using ChemEffect cartridge. We additionally processed
all articles from Pubmed Central and Elsevier and all Pubmed abstracts that mention “Humira” or it
synonyms as keywords. The effort has identified 53 Humira indications. 23 indications were supported
by more than one reference. Found indications are reported in Table 1 and shown on Figure 2.
Extracting Humira indications tested in clinical trials
We have used two approaches to find Humira indications with clinical trials. First, we used data from
DiseaseFX database for Pathway Studio to find diseases linked to Humira with “ClinicalTrial” relation
type. This relation type is generated by processing ClinicalTrials.gov with dedicated MedScan cartridge
to extract drug-disease indications. Second, we have downloaded all Pubmed abstracts that mention
Humira in the title and were classified as “Clinical trial” in Medline. We then extracted all diseases from
the titles of these clinical trials. The results of these two approaches are shown in Table 2 and shown on
Figure 2.
Extracting Humira indications from patents
188 patents mentioning Humira or Adalimumab in title, abstract or claims were found at
http://www.freepatentsonline.com/ using the following search query:
(TTL/humira OR TTL/Adalimumab OR ACLM/humira OR ACLM/Adalimumab ABST/humira OR ABST/Adalimumab) AND
(treatment OR treatments OR indication OR indications OR disease OR therapy OR Therapeutic OR application OR applications)
Found patents were processed with MedScan Reader to extract 36 diseases from their titles and
abstracts. Extracted diseases were scores by number of patents mentioning them. The result of this
approach is shown in Table 9.
Anton
Yuryev
Digitally signed by
Anton Yuryev
DN: cn=Anton Yuryev,
email=a.yuryev@elsev
ier.com, o=Elsevier,
l=Rockville, MD USA
Date: 2013.07.17
15:47:12 -04'00'

2. Part II. Predicting Humira indications from the literature data
Predicting indications from indications reported for other anti-TNF drugs
Five anti-TNF drugs were identified in Pathway Studio database with similar mechanism of action to
Humira: Afelimomab, Certolizumab, Golimumab, Infliximab, Etanercept. Pathway Studio ChemEffect
database contains all indications extracted by MedScan from all Pubmed abstracts and Elsevier full-text
content for all drugs. Indications reported in biomedical literature for anti-TNF drug were found using
the same methodology as described for Humira. The results are shown in Table 3 and Figure 3.
Indications tested in clinical trials for all anti-TNF drugs were found using the same methodology as
described for Humira. The results are shown in Table 4 and shown in Figure 4. The score for every
indication was calculated as a sum of all articles referencing the indication for all five anti-TNF drugs.
Predicting Humira indications from disease with contributing TNF activity
To identify diseases reported that have increased TNF activity as a contributing factor we have used data
from Pathway Studio Mammal database. Pathway Studio Mammal database contains all diseases linked
by MedScan to all proteins from all Pubmed abstracts and Elsevier full-text content. The same data can
be generated by processing all literature mentioning TNF using MedScan Reader Standard cartridge.
Pubmed finds 158,069 abstracts mentioning “TNF-alpha” keyword. The estimated time for processing
158,069 abstracts with MedScan Reader is about 5 minutes. After the import into Pathway Studio such
diseases can be identified as diseases downstream of TNF linked by Regulation relation type with Effect
positive or unknown. The results obtained in Pathway Studio Mammal database are shown in Figure 5
and Table 5.
Predicting Humira indications from disease with up-regulated TNF activity
To identify diseases reported that have increased TNF activity we have used data from Pathway Studio
DiseaseFX database. Pathway Studio DiseaseFX database contains all proteins reported up-regulated for
every disease. The data was extracted by MedScan to from all Pubmed abstracts and Elsevier full-text
content. The same data can be generated by processing all literature mentioning TNF using MedScan
reader DiseaseFX cartridge. Pubmed finds 158,069 abstracts mentioning “TNF-alpha” keyword. The
estimated time for processing 158,069 abstracts with MedScan Reader is about 5 minutes. After the
import into Pathway Studio such diseases can be identified as diseases upstream of TNF linked by
QuantitativeChange relation type with Effect positive or unknown. The results obtained in Pathway
Studio Mammal database are shown in Figure 6 and Table 6.

3. Part III. Predicting Humira indications from the literature data using
curated pathway data in Pathway Studio
We have used TNF expression targets pathways available in DiseaseFX database for Pathway Studio to
find diseases linked to TNF signaling. Six pathways used for the report are shown on Figure 4. All six
pathways were combined into one pathway and diseases were identified using sub-network enrichment
analysis (Sivachenko et al, 2007) with option Proteins/Chemicals Regulating Diseases. SNEA outputs top
100 diseases enriched with proteins from TNF pathways. The results of sub-network enrichment
analysis are shown in Table 7. The score for each disease was calculated as number of proteins from
TNF pathways contributing to disease in Pathway Studio normalized by the biggest score.
Combining individual scores for every disease into one score using Excel
The scores obtained from every text-mining method were normalized by dividing on the biggest score
for every method. Normalized scores were combined into one statistical score by summing individual
scores weighted by its confidence. Table 8 shows the weights for individual scores. Worksheet
“Master” in supplemental Excel file shows Humira indications sorted by the combined score. Master
table was manually curated to remove generic disease classes such as “Cancer” or “Inflammation”, to
remove end point and symptoms such as “Demyelination” or “leukocyte recruitment”, and to group
together related diseases. The curated results for 491 possible Humira indications are available in the
worksheet “Master curated” in supplemental Excel file.

4. Figure 1. Search results using semantic query “Humira inhibits Disease” in TargetInsights Enterprise. Left
panel shows diseases sorted by frequency of occurrence in found documents. Back to text.
Figure 2. Humira indications reported in clinical trials and biomedical literature as found in Pathway
Studio database and annotated in Pathway Studio interface

5. Table 1. Humira indications extracted by MedScan ChemEffect cartridge from biomedical literature.
Back to text
Indication # of References Normalized score
Arthritis, Rheumatoid 198 1
Crohn Disease 140 0.707071
Psoriasis 142 0.444444
Spondylitis, Ankylosing 64 0.323232
Arthritis, Psoriatic 55 0.277778
Uveitis 36 0.181818
Arthritis 22 0.060606
Colitis, Ulcerative 18 0.090909
Inflammatory Bowel Diseases 14 0.070707
Arthritis, Juvenile Rheumatoid 13 0.065657
Behcet Syndrome 13 0.065657
Fistula 12 0.060606
Spondylarthritis 11 0.055556
Hidradenitis Suppurativa 9 0.045455
Pyoderma Gangrenosum 7 0.035354
Sarcoidosis 7 0.035354
Uveitis, Anterior 7 0.035354
Bone Diseases, Metabolic 6 0.030303
Granuloma 4 0.020202
Enthesitis 7 0.035354
Scleritis 3 0.015152
Spondylarthritis 2 0.010101
Spondylarthropathies 2 0.010101
Pouchitis 2 0.010101
Polychondritis, Relapsing 1 0.005051
HIV Infections 1 0.005051
Choroidal Neovascularization 1 0.005051
Bronchiolitis Obliterans 1 0.005051
Wegener Granulomatosis 1 0.005051
Vesicovaginal Fistula 1 0.005051
Systemic Vasculitis 1 0.005051
Tendinopathy 1 0.005051
Coronary Artery Disease 1 0.005051

6. Cellulitis 1 0.005051
Fatty Liver 1 0.005051
Pancreatitis 1 0.005051
Hidradenitis 1 0.005051
Dermatitis 1 0.005051
Granuloma Annulare 1 0.005051
Enterocolitis 1 0.005051
Osteoarthritis 1 0.005051
Panuveitis 1 0.005051
Temporal Arteritis 1 0.005051
Osteoarthritis, Knee 1 0.005051
Corneal Ulcer 1 0.005051
Acne Vulgaris 1 0.005051
Multicentric reticulohistiocytosis 1 0.005051
Still's Disease, Adult-Onset 1 0.005051
Sjogren's Syndrome 1 0.005051
Acrodermatitis 1 0.005051
Ophthalmia, Sympathetic 1 0.005051
Table 2. Indications tested in Humira clinical trials. “Disease in title” source indicates Pubmed abstracts
classified as Clinical trial, “ClinicalTrial.gov” source indicate clinical trials reported on
www.ClinicalTrial.gov . Back to text
Indication Source # of References
Arthritis, Rheumatoid Disease in title 68
Arthritis, Rheumatoid ClinicalTrial.gov 72
Psoriasis Disease in title 39
Crohn Disease Disease in title 46
Psoriasis ClinicalTrial.gov 29
Spondylitis, Ankylosing Disease in title 21
Arthritis, Psoriatic Disease in title 17
Crohn Disease ClinicalTrial.gov 21
Uveitis Disease in title 7
Colitis, Ulcerative Disease in title 5
Hidradenitis Suppurativa Disease in title 5
Spondylarthritis Disease in title 2
Arthritis Disease in title 2
Arthritis, Juvenile Rheumatoid Disease in title 3
Arthritis, Psoriatic ClinicalTrial.gov 7
Colitis, Ulcerative ClinicalTrial.gov 7
Spondylarthritis ClinicalTrial.gov 7

7. Spondylitis, Ankylosing ClinicalTrial.gov 7
Sarcoidosis Disease in title 2
Uveitis ClinicalTrial.gov 6
Arthritis ClinicalTrial.gov 5
Arthritis, Juvenile Rheumatoid ClinicalTrial.gov 4
Hidradenitis Suppurativa ClinicalTrial.gov 4
Osteoarthritis ClinicalTrial.gov 4
Sarcoidosis ClinicalTrial.gov 4
Bone Diseases, Metabolic Disease in title 3
Fistula Disease in title 2
Glomerulosclerosis, Focal Segmental Disease in title 1
Sciatica Disease in title 2
Enthesitis Disease in title 1
Fatigue Disease in title 2
Glomerulosclerosis, Focal Segmental ClinicalTrial.gov 2
Pain Disease in title 2
Pyoderma Gangrenosum ClinicalTrial.gov 2
Ankylosis Disease in title 1
Arterial stiffness Disease in title 1
Arteritis Disease in title 1
Asthma ClinicalTrial.gov 1
Behcet Syndrome ClinicalTrial.gov 1
bone mineral density Disease in title 1
Colitis, Collagenous Disease in title 1
Cystitis, Interstitial ClinicalTrial.gov 1
Enthesitis ClinicalTrial.gov 1
Fistula ClinicalTrial.gov 1
Hermanski-Pudlak Syndrome ClinicalTrial.gov 1
Ileal Pouches Disease in title 1
Inflammatory Bowel Diseases Disease in title 1
Influenza, Human Disease in title 1
Intervertebral Disk Displacement ClinicalTrial.gov 1
Joint Diseases Disease in title 1
Langerhans cell density Disease in title 1
Lupus Erythematosus, Cutaneous Disease in title 1
Macular Degeneration ClinicalTrial.gov 1
Pouchitis Disease in title 1
Sciatica ClinicalTrial.gov 1
Spondylarthropathies ClinicalTrial.gov 1
Synovitis Disease in title 1
Systemic Vasculitis Disease in title 1

8. Temporal Arteritis ClinicalTrial.gov 1
Uveitis, Anterior Disease in title 1
Vitiligo Disease in title 1
Figure 3. Indications extracted by MedScan ChemEffect cartridge from biomedical literature for other
anti-TNF drugs as found in Pathway Studio database and annotated in Pathway Studio interface. Back to
text
Table 3. Indications extracted by MedScan ChemEffect cartridge from biomedical literature for other
anti-TNF drugs. The final score for each indication was calculated as a sum of “# of References” from all
anti-TNF drugs. Score calculations were performed in Excel. Back to text
Drug Indication # of References
Infliximab Arthritis, Rheumatoid 235
Infliximab Crohn Disease 211
Etanercept Arthritis, Rheumatoid 173
Infliximab Colitis, Ulcerative 127
Infliximab Spondylitis, Ankylosing 126
Etanercept Psoriasis 126
Etanercept Spondylitis, Ankylosing 84
Infliximab Inflammatory Bowel Diseases 76
Etanercept Arthritis, Psoriatic 75
Infliximab Arthritis, Psoriatic 75
Etanercept Arthritis, Juvenile Rheumatoid 65
Infliximab Uveitis 44
Infliximab Spondylarthropathies 40
Infliximab Behcet Syndrome 37
Infliximab Sarcoidosis 36

9. Infliximab Fistula 36
Etanercept Arthritis 35
Infliximab Psoriasis 34
Etanercept Inflammation 28
Golimumab Arthritis, Rheumatoid 28
certolizumab Crohn Disease 27
Infliximab Graft vs Host Disease 26
Infliximab Arthritis 25
certolizumab Arthritis, Rheumatoid 23
Etanercept Crohn Disease 20
Infliximab Granuloma 19
Infliximab Pyoderma Gangrenosum 19
Infliximab joint degeneration 18
Golimumab Spondylitis, Ankylosing 18
Etanercept Arthritis, Experimental 16
Etanercept joint degeneration 16
Etanercept Spondylarthropathies 14
Infliximab Rheumatic Diseases 13
Infliximab Inflammation 13
Infliximab Arthritis, Juvenile Rheumatoid 12
Infliximab Tuberculosis 12
Infliximab Pain 11
Etanercept Rheumatic Diseases 11
Infliximab Wegener Granulomatosis 11
Etanercept Cancer 10
Etanercept Lupus Erythematosus, Systemic 10
Etanercept Spondylarthritis 10
Infliximab Sjogren's Syndrome 10
Etanercept Hyperalgesia 10
Etanercept Inflammatory Bowel Diseases 10
Infliximab Hidradenitis Suppurativa 10
Golimumab Arthritis, Psoriatic 10
Infliximab Spondylarthritis 9
Infliximab Uveitis, Posterior 9
Infliximab Neoplasms 8
Infliximab Joint Diseases 8
Etanercept Allodynia 8
Etanercept Heart Failure 7
Etanercept blood pressure 7
Etanercept Hypertension 7
Etanercept Graft vs Host Disease 7
Etanercept Endometriosis 7

10. Etanercept Amyloidosis 7
Infliximab Autoimmune Diseases 7
Infliximab Scleritis 7
Infliximab Uveitis, Anterior 7
Etanercept Wounds and Injuries 7
Infliximab Dermatomyositis 7
Infliximab Still's Disease, Adult-Onset 7
Etanercept Uveitis 7
Infliximab Cancer 6
Etanercept Breast Neoplasms 6
Etanercept Neoplasms 6
Infliximab Vasculitis 6
Infliximab Pouchitis 6
Infliximab Enthesitis 6
Infliximab Constriction, Pathologic 6
certolizumab joint degeneration 6
Etanercept Pyoderma Gangrenosum 6
Etanercept Dermatomyositis 5
Etanercept Autoimmune Diseases 5
Infliximab Panuveitis 5
Etanercept Macrophage Activation Syndrome 5
Etanercept Ischemia 4
Etanercept Colitis 4
Etanercept kidney toxicity 4
Etanercept Diabetes Mellitus 4
Etanercept liver toxicity 4
Etanercept Hypersensitivity 4
Infliximab Acquired Hyperostosis Syndrome 4
Infliximab Eye Diseases 4
Infliximab Arthritis, Experimental 4
Etanercept Skin Diseases 4
Infliximab Lymphoma, T-Cell 4
Infliximab Intestinal Diseases 4
certolizumab Pain 4
certolizumab Inflammation 4
Etanercept Sjogren's Syndrome 4
Infliximab Polymyositis 4
Infliximab Hyperalgesia 4
certolizumab Fatigue 4
Infliximab Mucocutaneous Lymph Node Syndrome 4
Etanercept Hidradenitis Suppurativa 4
Infliximab Takayasu Arteritis 4

11. Golimumab Inflammation 4
Etanercept Sarcoidosis 4
Etanercept heart remodeling 3
Etanercept Asthma 3
Etanercept airway hyperreactivity 3
Infliximab Aneurysm 3
Infliximab Asthma 3
Infliximab Endometriosis 3
Infliximab Pneumonia, Pneumocystis 3
Infliximab Amyloidosis 3
Infliximab Hemorrhage 3
Etanercept Still's Disease, Adult-Onset 3
Infliximab Ileal Pouches 3
Infliximab Myelodysplastic Syndromes 3
Etanercept Enthesitis 3
Etanercept Choroidal Neovascularization 3
Etanercept Pancreatitis 3
Infliximab Nail Diseases 3
Etanercept Hepatitis C 3
Etanercept Hearing Loss 3
Infliximab Corneal Ulcer 3
Etanercept Juvenile-Onset Still Disease 3
Infliximab Infection 3
Etanercept Fatigue 3
Etanercept Pain 3
certolizumab Inflammatory Bowel Diseases 3
Infliximab Colitis 3
Etanercept Metabolic Syndrome X 2
Etanercept Ventricular Dysfunction, Left 2
Infliximab Wounds and Injuries 2
Etanercept Colorectal Neoplasms 2
Infliximab Ovarian Neoplasms 2
Etanercept Wounds 2
Infliximab Fatty Liver 2
Infliximab Carcinoma, Renal Cell 2
Infliximab Breast Neoplasms 2
Infliximab Neoplasm Metastasis 2
Infliximab Proteinuria 2
Etanercept neuron toxicity 2
Infliximab blood pressure 2
Infliximab Arthritis, Reactive 2
Infliximab Polymyalgia Rheumatica 2

12. Infliximab Infectious complications 2
Infliximab bone loss 2
Infliximab Hypersensitivity 2
Infliximab Complex Regional Pain Syndromes 2
Etanercept inflammatory lesions 2
Golimumab Psoriasis 2
Etanercept Ulcer 2
Infliximab lymphocyte count 2
Infliximab Choroidal Neovascularization 2
Etanercept Multiple Myeloma 2
Infliximab Sweet Syndrome 2
Etanercept body weight 2
Etanercept Polyarthritis 2
Infliximab Ischemia 2
Infliximab Osteoporosis 2
Infliximab joint space narrowing 2
Infliximab Lung Injury 2
Infliximab Necrosis 2
Infliximab Proctitis 2
Infliximab Neurologic Manifestations 2
Etanercept Primary Myelofibrosis 2
Infliximab Intervertebral Disk Displacement 2
Infliximab Gastrointestinal Hemorrhage 2
Infliximab Pityriasis Rubra Pilaris 2
Etanercept Pemphigoid, Bullous 2
Infliximab Myositis 2
Etanercept Graves Ophthalmopathy 2
Etanercept Low Back Pain 2
Infliximab Orbital Pseudotumor 2
Infliximab Dermatitis, Atopic 2
Etanercept Necrosis 2
Infliximab Arthralgia 2
Etanercept Brain Injuries 2
Afelimomab organ failure 2
Etanercept Hypertension, Pulmonary 2
Infliximab Rectovaginal Fistula 2
Infliximab Familial Mediterranean Fever 2
certolizumab Hepatitis C, Chronic 2
Infliximab Keratitis 2
Golimumab Hepatitis C, Chronic 2
Etanercept Hepatitis C, Chronic 2
Infliximab Hepatitis C, Chronic 2

13. Infliximab Lupus Erythematosus, Systemic 2
Etanercept Behcet Syndrome 2
Infliximab Heart Failure 2
Infliximab Polyarthritis 2
Etanercept Shock, Hemorrhagic 1
Etanercept hemodynamics 1
Infliximab Dislocations 1
Etanercept Fistula 1
Etanercept Dislocations 1
Etanercept intimal hyperplasia 1
Etanercept Abortion, Spontaneous 1
Etanercept Fetal Resorption 1
Etanercept fetal weight 1
Infliximab Fanconi Anemia 1
Etanercept Fanconi Anemia 1
Infliximab Pancytopenia 1
Etanercept Pancytopenia 1
Infliximab Carcinoma, Pancreatic Ductal 1
Infliximab Melanoma 1
Etanercept Melanoma 1
Etanercept Retinal Neovascularization 1
Etanercept microvessel density 1
Etanercept Carcinoma, Renal Cell 1
Infliximab Colorectal Neoplasms 1
Etanercept Ovarian Neoplasms 1
Etanercept Carcinoma, Pancreatic Ductal 1
Infliximab Liver Neoplasms 1
Etanercept Weight Loss 1
Infliximab Nerve Degeneration 1
Etanercept artery pressure 1
Etanercept urinary excretion 1
Infliximab Ascites 1
Infliximab Subarachnoid Hemorrhage 1
Etanercept Albuminuria 1
Infliximab macrophage infiltration 1
Etanercept Sepsis 1
Etanercept Bone Neoplasms 1
Etanercept Hypothermia 1
Golimumab Infection 1
Infliximab Mucopolysaccharidosis VI 1
Etanercept Diabetes Mellitus, Type 2 1
Etanercept Acute-Phase Reaction 1

14. Infliximab Pemphigoid, Benign Mucous Membrane 1
Infliximab Vesicovaginal Fistula 1
Infliximab Bone Diseases, Metabolic 1
Infliximab Autoimmune Response 1
Infliximab joint swelling 1
Infliximab Mycoses 1
Infliximab Pancreatitis 1
Infliximab Insulin Resistance 1
Infliximab Nephritis, Interstitial 1
Golimumab Nail Diseases 1
Etanercept Pericarditis, Constrictive 1
Infliximab Kidney Transplantation 1
Etanercept Leprosy, Lepromatous 1
Etanercept Shock, Septic 1
Etanercept macrophage infiltration 1
Infliximab Hyperthyroidism 1
Etanercept HIV Infections 1
Infliximab Coccidioidomycosis 1
Etanercept Osteoarthritis 1
Infliximab Dermatomycoses 1
Infliximab Granulomatous Disease, Chronic 1
Infliximab Glaucoma 1
Etanercept Arteritis 1
Etanercept Polymyalgia Rheumatica 1
Infliximab Thrombosis 1
Etanercept Temporal Arteritis 1
Etanercept Hyperimmunoglobulinemia D 1
Infliximab Osteitis 1
Infliximab Leprosy, Lepromatous 1
Etanercept Sarcoidosis, Pulmonary 1
Golimumab Enthesitis 1
Golimumab Dactylitis 1
Infliximab Mycobacterium avium-intracellulare Infection 1
Etanercept Meniere Disease 1
Etanercept Splenomegaly 1
Etanercept Communicable Diseases 1
Etanercept Aneurysm 1
Infliximab Fibrosis 1
Infliximab HIV Infections 1
Infliximab Cataract 1
Infliximab Brain Injuries 1
Infliximab Lupus Nephritis 1

15. Etanercept joint effusion 1
Etanercept Autoimmune Response 1
Infliximab Communicable Diseases 1
Etanercept Acquired Hyperostosis Syndrome 1
Etanercept Kidney Failure, Chronic 1
Infliximab Bronchitis 1
Etanercept Hypertrophy 1
Etanercept Virus Diseases 1
Infliximab Reiter Syndrome 1
Etanercept mdx dystrophy 1
Etanercept Vasculitis 1
Etanercept Drowsiness 1
Infliximab Myocarditis 1
Etanercept Multiple Organ Failure 1
Infliximab Liver Cirrhosis, Alcoholic 1
Infliximab leukocyte count 1
Infliximab Arteriosclerosis 1
Etanercept Pemphigus 1
Infliximab Scabies 1
Etanercept Pemphigoid, Benign Mucous Membrane 1
Etanercept Purpura, Thrombocytopenic, Idiopathic 1
Infliximab Failure to Thrive 1
Etanercept Lymphohistiocytosis, Hemophagocytic 1
Infliximab Uveomeningoencephalitic Syndrome 1
Etanercept nerve disease 1
Etanercept Sensation Disorders 1
Etanercept Dermatitis, Atopic 1
Etanercept Wegener Granulomatosis 1
Etanercept Bronchitis 1
Infliximab Macrophage Activation Syndrome 1
Etanercept skin thickness 1
Etanercept Hepatitis B, Chronic 1
Etanercept Pityriasis Rubra Pilaris 1
Etanercept Insulin Resistance 1
Infliximab Fibrosis, Liver 1
Infliximab Otitis Media 1
Infliximab mdx dystrophy 1
Infliximab Graft Rejection 1
Infliximab Psoas Abscess 1
Infliximab Ileitis 1
Etanercept Diabetic Retinopathy 1
Infliximab eosinophil infiltration 1

16. Infliximab Rhinitis, Allergic, Perennial 1
Infliximab Immune Reconstitution Inflammatory Syndrome 1
Etanercept Acrodermatitis 1
Infliximab Extravasation 1
Infliximab Vulvitis 1
Infliximab Drowsiness 1
Infliximab Heart Arrest 1
Etanercept Pain, Intractable 1
Infliximab Lymphoproliferative Disorders 1
Etanercept Epidermal Necrolysis, Toxic 1
Infliximab Hidradenitis 1
Etanercept liver abnormality 1
Infliximab Abdominal Pain 1
Infliximab Leukemia 1
Infliximab Dacryoadenitis 1
Infliximab Multicentric reticulohistiocytosis 1
Etanercept Xerostomia 1
Infliximab Hepatitis, Alcoholic 1
Etanercept Macular Edema 1
Etanercept Polychondritis, Relapsing 1
Infliximab lymphocyte reaction 1
Etanercept Hypertrophy, Left Ventricular 1
Infliximab Burns 1
Etanercept Pruritus 1
Etanercept Panuveitis 1
Etanercept Depression 1
Infliximab Lymphopenia 1
Infliximab Nephrotic Syndrome 1
Infliximab Pyoderma 1
Golimumab Sleep Disorders 1
Infliximab Myasthenia Gravis 1
Etanercept Scleritis 1
Etanercept Paraplegia 1
Infliximab Respiratory Distress Syndrome, Adult 1
Infliximab Macular Degeneration 1
Infliximab Hypertension, Portal 1
Infliximab Cystic Fibrosis 1
Etanercept Hepatitis, Alcoholic 1
Infliximab Xerostomia 1
Infliximab Enteritis 1
Etanercept Mixed Connective Tissue Disease 1
Infliximab Polyps 1

17. Etanercept Leukemia 1
Etanercept Corneal Ulcer 1
Infliximab Hypothyroidism 1
Infliximab Cutaneous Fistula 1
Infliximab Osteoarthritis 1
Etanercept neuroinflammation 1
Infliximab cartilage degeneration 1
Infliximab liver fibrosis 1
Infliximab Emphysema 1
Infliximab Reperfusion Injury 1
Infliximab Retinal Vasculitis 1
Etanercept Systemic Vasculitis 1
Etanercept Reperfusion Injury 1
certolizumab Scleritis 1
Infliximab Neuroretinitis 1
Infliximab Pneumonia 1
Etanercept Death 1
Etanercept Spinal Cord Injuries 1
Infliximab Latent Tuberculosis 1
Etanercept Glomerulonephritis 1
Infliximab Glomerulonephritis 1
Infliximab Enterocolitis 1
Golimumab Granuloma 1
Etanercept Exanthema 1
Etanercept Necrobiosis Lipoidica 1
Golimumab Uveitis 1
Infliximab Vitiligo 1
Etanercept Chorioretinitis 1
Golimumab Inflammatory Bowel Diseases 1
certolizumab Neoplasms 1
Etanercept joint space narrowing 1
Etanercept Recovery of Function 1
Etanercept Toxoplasmosis, Cerebral 1
Infliximab body weight 1
Infliximab Granuloma Annulare 1
Infliximab Exanthema 1
Infliximab Nephritis 1
Infliximab Chorioretinitis 1
Etanercept Acne Vulgaris 1
Infliximab Toxoplasmosis, Cerebral 1
Etanercept Uveitis, Anterior 1
Infliximab bone mineral density 1

18. Golimumab joint degeneration 1
Golimumab joint space narrowing 1
Etanercept Hyperplasia 1
Infliximab Acne Vulgaris 1
certolizumab Psoriasis 1
Infliximab artery rhythm 1
Golimumab Spondylarthritis 1
Infliximab Colitis, Collagenous 1
Infliximab Gastrointestinal Diseases 1
Etanercept Infection 1
Etanercept Fever 1
Etanercept bone loss 1
Etanercept Leg Ulcer 1
Figure 4. Indications tested in anti-TNF drug clinical trials as found in Pathway Studio. Back to text
Table 4. Indications tested in anti-TNF drug clinical trials. “Disease in title” source indicates Pubmed
abstracts classified as Clinical trial, “ClinicalTrial.gov” source indicate clinical trials reported on
www.ClinicalTrial.gov . The final score for each indication was calculated as a sum of “# of References”
from all anti-TNF drugs. Score calculations were performed in Excel. Back to text
Drug Indication Type # of References
Etanercept Psoriasis Disease in title 104
certolizumab Spondylitis, Ankylosing Disease in title 102

19. Etanercept Arthritis, Rheumatoid ClinicalTrial 65
Afelimomab Arthritis, Psoriatic Disease in title 58
Etanercept Psoriasis ClinicalTrial 45
Etanercept Colitis, Ulcerative Disease in title 40
certolizumab Arthritis, Rheumatoid ClinicalTrial 33
certolizumab Arthritis, Juvenile Rheumatoid Disease in title 26
certolizumab Crohn Disease ClinicalTrial 22
Etanercept Spondylitis, Ankylosing ClinicalTrial 18
Etanercept Spondylarthropathies Disease in title 16
Golimumab Arthritis, Rheumatoid ClinicalTrial 14
Etanercept Uveitis Disease in title 13
Afelimomab Arthritis Disease in title 10
Etanercept Inflammatory Bowel Diseases Disease in title 10
Etanercept Fistula Disease in title 9
Etanercept Sciatica Disease in title 9
Etanercept Behcet Syndrome Disease in title 8
Etanercept Graft vs Host Disease Disease in title 8
Etanercept Arthritis, Juvenile Rheumatoid ClinicalTrial 7
Etanercept Arthritis, Psoriatic ClinicalTrial 7
Etanercept Synovitis Disease in title 7
Golimumab Spondylarthritis Disease in title 7
Etanercept Graft vs Host Disease ClinicalTrial 6
Etanercept Sarcoidosis Disease in title 6
Etanercept Sjogren's Syndrome Disease in title 6
Etanercept Wegener Granulomatosis Disease in title 6
Golimumab Hidradenitis Suppurativa Disease in title 6
Infliximab Heart Failure Disease in title 6
Adalimumab Fatigue Disease in title 5
Afelimomab Enthesitis Disease in title 5
Afelimomab Hepatitis, Alcoholic Disease in title 5
Etanercept Leukemia ClinicalTrial 5
Etanercept bone mineral density Disease in title 5
Etanercept Mucocutaneous Lymph Node Syndrome Disease in title 5
Infliximab Myelodysplastic Syndromes Disease in title 5
Adalimumab Arterial stiffness Disease in title 4
Etanercept Diabetes Mellitus, Type 1 ClinicalTrial 4
Etanercept Intervertebral Disk Displacement Disease in title 4
Etanercept Polymyalgia Rheumatica Disease in title 4
Golimumab Spondylitis, Ankylosing ClinicalTrial 4
Adalimumab Sarcoidosis, Pulmonary Disease in title 3
Afelimomab Sepsis Disease in title 3
Afelimomab Temporal Arteritis Disease in title 3

20. Etanercept Alzheimer Disease ClinicalTrial 3
Etanercept Hidradenitis Suppurativa ClinicalTrial 3
Etanercept Lichen Planus ClinicalTrial 3
Etanercept Metabolic Syndrome X ClinicalTrial 3
Etanercept Spondylarthritis ClinicalTrial 3
Etanercept Diabetes Mellitus, Type 2 Disease in title 3
Etanercept joint degeneration Disease in title 3
Etanercept Joint Diseases Disease in title 3
Etanercept Neoplasms Disease in title 3
Etanercept Pouchitis Disease in title 3
Etanercept Pulmonary Disease, Chronic Obstructive Disease in title 3
Etanercept Systemic Vasculitis Disease in title 3
Etanercept Ulcer Disease in title 3
Golimumab Colitis, Ulcerative ClinicalTrial 3
Infliximab Rheumatic Diseases Disease in title 3
Etanercept Myasthenia Gravis Disease in title 3
Adalimumab Infection Disease in title 2
Adalimumab Juvenile-Onset Still Disease Disease in title 2
certolizumab Psoriasis ClinicalTrial 2
Etanercept Arthritis ClinicalTrial 2
Etanercept Asthma ClinicalTrial 2
Etanercept Dermatomyositis ClinicalTrial 2
Etanercept Infection ClinicalTrial 2
Etanercept Spondylarthropathies ClinicalTrial 2
Etanercept Arthralgia Disease in title 2
Etanercept Asthma Disease in title 2
Etanercept Brain Injuries Disease in title 2
Etanercept Cholangitis, Sclerosing Disease in title 2
Etanercept Edema Disease in title 2
Etanercept inflammatory lesions Disease in title 2
Etanercept Insulin Resistance Disease in title 2
Etanercept Lupus Erythematosus, Systemic Disease in title 2
Etanercept Necrosis Disease in title 2
Etanercept Pneumonia, Pneumocystis Disease in title 2
Etanercept Pyoderma Gangrenosum Disease in title 2
Etanercept Takayasu Arteritis Disease in title 2
Etanercept Tuberculosis Disease in title 2
Etanercept Uveitis, Posterior Disease in title 2
Etanercept Vasculitis Disease in title 2
Etanercept Weight Loss Disease in title 2
Golimumab Asthma ClinicalTrial 2
Golimumab Proctitis Disease in title 2

21. Infliximab Bone Diseases, Metabolic Disease in title 2
Infliximab Carcinoma, Renal Cell Disease in title 2
Infliximab Colitis Disease in title 2
Infliximab Constriction, Pathologic Disease in title 2
Etanercept Metabolic Syndrome X Disease in title 2
Etanercept Obesity Disease in title 2
Etanercept Pneumonia Disease in title 2
Etanercept Tenosynovitis Disease in title 2
Adalimumab Labyrinth Diseases Disease in title 1
Adalimumab skin lesion Disease in title 1
Adalimumab Stem Cell Transplantation Disease in title 1
Afelimomab Esophagitis Disease in title 1
Afelimomab Low Back Pain Disease in title 1
Afelimomab Spinal Stenosis Disease in title 1
Afelimomab Stroke Disease in title 1
certolizumab Arthritis, Juvenile Rheumatoid ClinicalTrial 1
certolizumab Colitis, Ulcerative ClinicalTrial 1
certolizumab Spondylarthropathies ClinicalTrial 1
certolizumab Lymphoma, Follicular Disease in title 1
certolizumab Osteolysis Disease in title 1
Etanercept Acute Lung Injury ClinicalTrial 1
Etanercept Amyloidosis ClinicalTrial 1
Etanercept Anorexia ClinicalTrial 1
Etanercept Behcet Syndrome ClinicalTrial 1
Etanercept Bronchitis ClinicalTrial 1
Etanercept Cardiovascular Diseases ClinicalTrial 1
Etanercept Enthesitis ClinicalTrial 1
Etanercept Fanconi Anemia ClinicalTrial 1
Etanercept Hernia, Inguinal ClinicalTrial 1
Etanercept Histiocytosis, Langerhans-Cell ClinicalTrial 1
Etanercept Inflammation ClinicalTrial 1
Etanercept Kidney Failure, Chronic ClinicalTrial 1
Etanercept Kidney Neoplasms ClinicalTrial 1
Etanercept Leukemia, Lymphocytic, Chronic, B-Cell ClinicalTrial 1
Etanercept Lung Neoplasms ClinicalTrial 1
Etanercept Lupus Erythematosus, Discoid ClinicalTrial 1
Etanercept Lupus Nephritis ClinicalTrial 1
Etanercept Mucocutaneous Lymph Node Syndrome ClinicalTrial 1
Etanercept Myelodysplastic Syndromes ClinicalTrial 1
Etanercept Myocardial Infarction ClinicalTrial 1
Etanercept Myositis, Inclusion Body ClinicalTrial 1
Etanercept Neoplasms ClinicalTrial 1

22. Etanercept Osteoporosis, Postmenopausal ClinicalTrial 1
Etanercept Pancreatic Neoplasms ClinicalTrial 1
Etanercept Pemphigus ClinicalTrial 1
Etanercept Pneumonia ClinicalTrial 1
Etanercept Polymyalgia Rheumatica ClinicalTrial 1
Etanercept Pulmonary Disease, Chronic Obstructive ClinicalTrial 1
Etanercept Pulmonary Fibrosis ClinicalTrial 1
Etanercept Radiculopathy ClinicalTrial 1
Etanercept Respiratory Distress Syndrome, Adult ClinicalTrial 1
Etanercept Sciatica ClinicalTrial 1
Etanercept Sjogren's Syndrome ClinicalTrial 1
Etanercept Stomatitis ClinicalTrial 1
Etanercept Synovitis ClinicalTrial 1
Etanercept Temporomandibular Joint Disorders ClinicalTrial 1
Etanercept Urticaria ClinicalTrial 1
Etanercept Vasculitis ClinicalTrial 1
Etanercept Vitiligo ClinicalTrial 1
Etanercept Wegener Granulomatosis ClinicalTrial 1
Etanercept Alopecia Areata Disease in title 1
Etanercept Alzheimer Disease Disease in title 1
Etanercept Amyloidosis Disease in title 1
Etanercept Anorexia Disease in title 1
Etanercept Aphasia Disease in title 1
Etanercept Bacteremia Disease in title 1
Etanercept body weight Disease in title 1
Etanercept bone loss Disease in title 1
Etanercept Breast Neoplasms Disease in title 1
Etanercept Dactylitis Disease in title 1
Etanercept Depression Disease in title 1
Etanercept Dermatomyositis Disease in title 1
Etanercept Diabetes Mellitus, Type 1 Disease in title 1
Etanercept Drowsiness Disease in title 1
Etanercept Familial Mediterranean Fever Disease in title 1
Etanercept Granuloma Annulare Disease in title 1
Etanercept Graves Ophthalmopathy Disease in title 1
Etanercept Hepatitis C, Chronic Disease in title 1
Etanercept Hepatitis, Autoimmune Disease in title 1
Etanercept Hernia, Inguinal Disease in title 1
Etanercept Hypersensitivity, Delayed Disease in title 1
Etanercept Hypertrophy Disease in title 1
Etanercept Idiopathic Pulmonary Fibrosis Disease in title 1
Etanercept Keloid Disease in title 1

23. Etanercept Kidney Diseases Disease in title 1
Etanercept Leukemia, Lymphocytic, Chronic, B-Cell Disease in title 1
Etanercept Lymphoma, T-Cell, Cutaneous Disease in title 1
Etanercept Mycoses Disease in title 1
Etanercept Osteitis Disease in title 1
Etanercept Pain Disease in title 1
Etanercept Pain, Postoperative Disease in title 1
Etanercept Pancreatic Neoplasms Disease in title 1
Etanercept Panuveitis Disease in title 1
Etanercept Pemphigus Disease in title 1
Etanercept Primary Myelofibrosis Disease in title 1
Etanercept Pulmonary Fibrosis Disease in title 1
Etanercept Rectovaginal Fistula Disease in title 1
Etanercept Scleritis Disease in title 1
Etanercept Scleroderma, Diffuse Disease in title 1
Etanercept Sleep Disorders Disease in title 1
Etanercept Smoking Disease in title 1
Etanercept Spinal Diseases Disease in title 1
Etanercept Systemic Inflammatory Response
Syndrome
Disease in title 1
Etanercept Uveitis, Anterior Disease in title 1
Etanercept Vascular Diseases Disease in title 1
Etanercept vascular stiffness Disease in title 1
Etanercept Yellow Fever Disease in title 1
Golimumab Arthritis ClinicalTrial 1
Golimumab Arthritis, Juvenile Rheumatoid ClinicalTrial 1
Golimumab Arthritis, Psoriatic ClinicalTrial 1
Golimumab Labyrinth Diseases ClinicalTrial 1
Golimumab Sarcoidosis ClinicalTrial 1
Golimumab Spondylarthritis ClinicalTrial 1
Golimumab Macular Edema Disease in title 1
Golimumab Nail Diseases Disease in title 1
Golimumab Orbital Myositis Disease in title 1
Golimumab Orbital Pseudotumor Disease in title 1
Golimumab Postoperative Complications Disease in title 1
Infliximab Abscess Disease in title 1
Infliximab Acute Coronary Syndrome Disease in title 1
Infliximab Acute-Phase Reaction Disease in title 1
Infliximab Beryllium Disease Disease in title 1
Infliximab Cachexia Disease in title 1
Infliximab Carcinoma, Non-Small-Cell Lung Disease in title 1
Infliximab collagen Disease in title 1

24. Infliximab Dermatitis, Atopic Disease in title 1
Infliximab Dermatitis, Exfoliative Disease in title 1
Infliximab Diabetic Retinopathy Disease in title 1
Infliximab endothelial cell dysfunction Disease in title 1
Infliximab Gonarthritis Disease in title 1
Infliximab Hepatitis B, Chronic Disease in title 1
Infliximab Ileitis Disease in title 1
Infliximab Intestinal Diseases Disease in title 1
Infliximab joint space narrowing Disease in title 1
Infliximab left ventricular ejection fraction Disease in title 1
Infliximab Leukemia Disease in title 1
Infliximab leukocyte count Disease in title 1
Infliximab lupus erythematosus Disease in title 1
Infliximab Myositis Disease in title 1
Infliximab Osteoarthritis Disease in title 1
Etanercept Myositis, Inclusion Body Disease in title 1
Etanercept Optic Neuritis Disease in title 1
Etanercept Ovarian Neoplasms Disease in title 1
Etanercept Radiculopathy Disease in title 1
Etanercept Sleep Apnea Syndromes Disease in title 1

25. Figure 5. 820 diseases, syndromes, physiological effects and toxicities reported to have TNF-alpha up-
regulation contributing to disease progression found by graph search in Pathway Studio database. Color
intensity of the Regulation link indicates the number of references supporting the observation. Back to
text

26. Table 5. 820 diseases, syndromes, physiological effects and toxicities reported to have TNF-alpha up-
regulation contributing to disease progression found by graph search in Pathway Studio database. “#
References” column indicates number of report supporting the observation. Back to text
Indication # of References Normalized score
Inflammation 810 1
Psoriasis 114 0.342342
Arthritis, Rheumatoid 219 0.405109
Wounds and Injuries 316 0.385645
Granuloma 110 0.19708
Insulin Resistance 120 0.153285
Neoplasms 101 0.153285
Death 117 0.147202
Crohn Disease 116 0.143552
Arthritis 115 0.143552
Inflammatory Bowel Diseases 117 0.142336
liver toxicity 113 0.138686
Infection 107 0.132603
Cancer 108 0.131387
Necrosis 108 0.131387
Shock, Septic 100 0.131387
Sepsis 100 0.13017
Bone Diseases, Metabolic 106 0.128954
Atherosclerosis 105 0.128954
Tuberculosis 104 0.126521
Autoimmune Diseases 102 0.125304
Cachexia 102 0.124088
Fever 102 0.124088
Heart Failure 102 0.124088
Diabetes Mellitus 98 0.124088
Hepatitis 101 0.122871
joint degeneration 101 0.122871
Obesity 101 0.122871
Lung Injury 100 0.121655
endothelial cell dysfunction 92 0.115572
kidney toxicity 92 0.115572
Reperfusion Injury 91 0.115572
Acute-Phase Reaction 94 0.114355
neuron toxicity 91 0.114355
Fibrosis 93 0.113139
Graft vs Host Disease 90 0.110706
Arthritis, Experimental 86 0.104623

27. Pneumonia 83 0.100973
Pain 82 0.099757
Hyperalgesia 80 0.097324
Anorexia 78 0.096107
Mycobacterium Infections 76 0.092457
Colitis 72 0.087591
Asthma 67 0.086375
neutrophil recruitment 66 0.080292
Osteoarthritis 64 0.077859
Hypotension 63 0.076642
Ischemia 63 0.076642
Neurotoxicity Syndromes 61 0.074209
Bacteremia 43 0.074209
Glomerulonephritis 31 0.072993
Encephalomyelitis 59 0.071776
Weight Loss 59 0.071776
Autoimmunity 42 0.071776
Muscular Atrophy 58 0.07056
Neoplasm Metastasis 58 0.07056
Endotoxemia 57 0.07056
leukocyte recruitment 56 0.068127
Edema 55 0.06691
Heart Diseases 55 0.06691
Brain Injuries 52 0.06691
Hypertrophy 54 0.065693
Myocarditis 51 0.062044
endothelial hyperpermeability 47 0.062044
Arthritis, Psoriatic 50 0.060827
Multiple Sclerosis 50 0.060827
Anemia 49 0.059611
Cardiovascular Diseases 49 0.059611
neutrophil infiltration 48 0.058394
Spondylitis, Ankylosing 47 0.058394
Breast Neoplasms 47 0.057178
Pulmonary Fibrosis 46 0.057178
Hypothermia 45 0.054745
Nerve Degeneration 45 0.054745
Diabetes Mellitus, Type 2 44 0.053528
airway hyperreactivity 43 0.052311
Demyelination 43 0.052311
Fatty Liver 42 0.051095
Myocardial Infarction 42 0.051095

28. Dermatitis 41 0.049878
Uveitis 41 0.049878
Hypersensitivity 40 0.048662
leukocyte infiltration 40 0.048662
Neuralgia 40 0.048662
vascular endothelial damage 39 0.047445
Liver Diseases 37 0.047445
Multiple Organ Failure 36 0.046229
Melanoma 37 0.045012
Virus Diseases 37 0.045012
Graft Rejection 36 0.043796
Malaria, Cerebral 36 0.043796
vascular hyperpermeability 35 0.043796
Allodynia 35 0.042579
Diabetes Mellitus, Type 1 35 0.042579
Intestinal Diseases 34 0.042579
Hemorrhage 34 0.041363
Hypertension 34 0.041363
Thrombosis 34 0.041363
Pancreatitis 32 0.041363
Acute Lung Injury 33 0.040146
Endometriosis 33 0.040146
Hypersensitivity, Contact 33 0.040146
Infarction 32 0.040146
muscle injury 31 0.040146
Cardiomyopathies 32 0.038929
Kidney Failure, Acute 31 0.038929
Lung Diseases 31 0.038929
Fibrosarcoma 31 0.037713
Sarcoma 30 0.036496
Atrophy 26 0.036496
atrial depression 29 0.03528
HIV Infections 29 0.03528
Hyperplasia 29 0.03528
Osteolysis 29 0.03528
Liver Neoplasms 27 0.03528
Extravasation 28 0.034063
Heart Injuries 28 0.034063
Leukemia 28 0.034063
Pulmonary Edema 28 0.034063
blood pressure 26 0.034063
Skin Diseases 27 0.032847

29. Systemic Inflammatory Response Syndrome 27 0.032847
Adenocarcinoma 26 0.03163
Colitis, Ulcerative 26 0.03163
heart remodeling 26 0.03163
Pulmonary Disease, Chronic Obstructive 26 0.03163
Alzheimer Disease 25 0.030414
Liver Failure 25 0.030414
Pathologic Processes 25 0.030414
Stroke 25 0.030414
Synovitis 25 0.030414
Behcet Syndrome 24 0.029197
bone loss 24 0.029197
Lung Neoplasms 24 0.029197
Respiratory Distress Syndrome, Adult 24 0.029197
Shock 24 0.029197
Wounds 23 0.029197
cartilage degeneration 23 0.027981
hemodynamics 23 0.027981
neutrophil accumulation 23 0.027981
Mucositis 22 0.026764
Osteoporosis 22 0.026764
Prostatic Neoplasms 20 0.026764
Skin Neoplasms 20 0.026764
Cystic Fibrosis 13 0.026764
Bacterial Infections 21 0.025547
Hypoglycemia 21 0.025547
Kidney Diseases 20 0.025547
Brain Ischemia 20 0.024331
Hypersensitivity, Delayed 20 0.024331
Liver Failure, Acute 20 0.024331
Lymphoma 19 0.024331
Renal Insufficiency 19 0.024331
Encephalomyelitis, Autoimmune, Experimental 19 0.023114
Hepatitis, Alcoholic 19 0.023114
Joint Diseases 19 0.023114
organ failure 19 0.023114
systemic toxicity 19 0.023114
Ventricular Dysfunction, Left 19 0.023114
Liver Diseases, Alcoholic 16 0.023114
Bone Marrow Transplantation 18 0.021898
Cardiomegaly 18 0.021898
Emphysema 18 0.021898

30. Metabolic Syndrome X 18 0.021898
Bronchial Hyperreactivity 17 0.020681
Carcinoma, Squamous Cell 17 0.020681
Fibrosis, Liver 17 0.020681
neuroinflammation 17 0.020681
Peritonitis 17 0.020681
Hypertriglyceridemia 16 0.020681
Leukemia, Myeloid 16 0.020681
Encephalitis 16 0.019465
Ileitis 14 0.019465
Stomach Neoplasms 14 0.019465
Vasculitis 9 0.019465
Acquired Immunodeficiency Syndrome 15 0.018248
anemia of chronic disease 15 0.018248
Carcinoma 15 0.018248
Multiple Myeloma 15 0.018248
Neurodegenerative Diseases 15 0.018248
Severe Combined Immunodeficiency 15 0.018248
Spinal Cord Injuries 13 0.018248
artery pressure 14 0.017032
Cardiomyopathy, Dilated 14 0.017032
Colonic Neoplasms 14 0.017032
Fatigue 14 0.017032
Hyperlipidemias 14 0.017032
Spondylarthritis 14 0.017032
Spondylarthropathies 14 0.017032
Thrombocytopenia 14 0.017032
Vascular Diseases 14 0.017032
Arthritis, Juvenile Rheumatoid 13 0.015815
astrogliosis 13 0.015815
Cardiomyopathy, Hypertrophic 13 0.015815
Communicable Diseases 13 0.015815
Diabetes, Autoimmune 13 0.015815
Diarrhea 13 0.015815
vascular resistance 13 0.015815
liver fibrosis 12 0.015815
Carcinoma, Renal Cell 12 0.014599
Leukemia, Myeloid, Acute 12 0.014599
Lung Diseases, Interstitial 12 0.014599
macrophage infiltration 12 0.014599
Meningitis 12 0.014599
Nasal Polyps 12 0.014599

31. Ovarian Neoplasms 12 0.014599
Parkinson Disease 12 0.014599
Shock, Hemorrhagic 12 0.014599
Nephritis 11 0.014599
Alveolitis, Extrinsic Allergic 11 0.013382
Cytomegalovirus Infections 11 0.013382
Hypertension, Pulmonary 11 0.013382
Metabolic Diseases 11 0.013382
Obstetric Labor, Premature 11 0.013382
Proteinuria 11 0.013382
skin lesion 11 0.013382
vascular remodeling 11 0.013382
Vasospasm, Intracranial 11 0.013382
Wegener Granulomatosis 11 0.013382
capillary hyperpermeability 10 0.012165
Cholestasis 10 0.012165
Choroidal Neovascularization 10 0.012165
Chronic Disease 10 0.012165
Demyelinating Diseases 10 0.012165
Hyperinsulinism 10 0.012165
intimal hyperplasia 10 0.012165
joint swelling 10 0.012165
Listeriosis 10 0.012165
Lymphopenia 10 0.012165
Mucocutaneous Lymph Node Syndrome 10 0.012165
Myositis 10 0.012165
Pre-Eclampsia 10 0.012165
Wasting Syndrome 10 0.012165
Brain Edema 9 0.012165
Acute Coronary Syndrome 9 0.010949
Burns 9 0.010949
cardiovascular calcification 9 0.010949
Colorectal Neoplasms 9 0.010949
Drowsiness 9 0.010949
Glioma 9 0.010949
Immune System Diseases 9 0.010949
inflammatory lesions 9 0.010949
Keratitis 9 0.010949
liver degeneration 9 0.010949
Malnutrition 9 0.010949
neutrophil depletion 9 0.010949
Osteoporosis, Postmenopausal 9 0.010949

32. Ventricular Dysfunction 9 0.010949
kidney fibrosis 8 0.010949
bronchoconstriction 8 0.009732
cardiovascular tone 8 0.009732
cognitive impairment 8 0.009732
Fatty Streak, Arterial 8 0.009732
Hepatitis C, Chronic 8 0.009732
kidney ischemia 8 0.009732
Leukocytosis 8 0.009732
Leukopenia 8 0.009732
Lupus Nephritis 8 0.009732
Lymphoma, Large B-Cell, Diffuse 8 0.009732
Middle Cerebral Artery Occlusion 8 0.009732
Muscle Weakness 8 0.009732
Myelodysplastic Syndromes 8 0.009732
Neurologic Manifestations 8 0.009732
Pancreatic Neoplasms 8 0.009732
Paralysis 8 0.009732
Polycystic Ovary Syndrome 8 0.009732
Recovery of Function 8 0.009732
Sarcoma, Kaposi 8 0.009732
Sjogren's Syndrome 8 0.009732
T-cell infiltration 8 0.009732
tissue compatibility 8 0.009732
Urinary Bladder Neoplasms 8 0.009732
vascular reactivity 7 0.009732
Arrhythmias, Cardiac 7 0.008516
Carcinoma, Hepatocellular 7 0.008516
cardiovascular passage 7 0.008516
Central Nervous System Diseases 7 0.008516
Corneal Neovascularization 7 0.008516
Cryptococcosis 7 0.008516
Dementia 7 0.008516
Diabetic Nephropathies 7 0.008516
Dyslipidemias 7 0.008516
Fetal Death 7 0.008516
Gastroparesis 7 0.008516
Glioblastoma 7 0.008516
graft-vs-leukemia effect 7 0.008516
heart rate 7 0.008516
hemodynamic abnormalities 7 0.008516
Hepatitis C 7 0.008516

33. hepatocyte dysfunction 7 0.008516
Hyperglycemia 7 0.008516
Hypoalbuminemia 7 0.008516
Leishmaniasis, Cutaneous 7 0.008516
Leukemia, Lymphocytic, Chronic, B-Cell 7 0.008516
Mycobacterium avium-intracellulare Infection 7 0.008516
myocyte hypertrophy 7 0.008516
nerve disease 7 0.008516
Nervous System Diseases 7 0.008516
Neuroblastoma 7 0.008516
Periodontal Diseases 7 0.008516
Polyarthritis 7 0.008516
Rhinitis, Allergic, Perennial 7 0.008516
Sarcopenia 7 0.008516
Silicosis 7 0.008516
lymphocyte infiltration 6 0.008516
Abortion, Spontaneous 6 0.007299
Allergic Reaction 6 0.007299
Amyloidosis 6 0.007299
beta cell dysfunction 6 0.007299
Eye Diseases 6 0.007299
Glucose Intolerance 6 0.007299
Hematologic Diseases 6 0.007299
Hypertrophy, Left Ventricular 6 0.007299
Immunologic Deficiency Syndromes 6 0.007299
Kidney Failure, Chronic 6 0.007299
Latent Tuberculosis 6 0.007299
Leukemia, Promyelocytic, Acute 6 0.007299
Lymphoproliferative Disorders 6 0.007299
Metaplasia 6 0.007299
neutrophil count 6 0.007299
Osteosarcoma 6 0.007299
Pancytopenia 6 0.007299
Premature Birth 6 0.007299
Salmonella Infections 6 0.007299
Scleroderma, Systemic 6 0.007299
Splenomegaly 6 0.007299
Ulcer 6 0.007299
Wallerian Degeneration 6 0.007299
Liver Transplantation 5 0.007299
Periodontitis 5 0.007299
Optic Nerve Diseases 4 0.007299

34. Aortic Aneurysm, Abdominal 5 0.006083
Arthritis, Reactive 5 0.006083
Ascites 5 0.006083
Blood Coagulation Disorders 5 0.006083
Brain Neoplasms 5 0.006083
Carcinoma, Non-Small-Cell Lung 5 0.006083
Central Nervous System Infections 5 0.006083
Chromosome Aberrations 5 0.006083
connective tissue cell degeneration 5 0.006083
Coronary Occlusion 5 0.006083
Cystitis 5 0.006083
Dermatitis, Contact 5 0.006083
Dermatomyositis 5 0.006083
Diabetes Complications 5 0.006083
Diabetes, Gestational 5 0.006083
Diabetic Retinopathy 5 0.006083
Disseminated Intravascular Coagulation 5 0.006083
Dysentery, Bacillary 5 0.006083
Encephalopathy 5 0.006083
eosinophil infiltration 5 0.006083
Fetal Resorption 5 0.006083
Gastritis 5 0.006083
Gliosis 5 0.006083
Graves Ophthalmopathy 5 0.006083
Hearing Loss, Sensorineural 5 0.006083
Heart Rupture 5 0.006083
Hepatitis, Chronic 5 0.006083
Influenza, Human 5 0.006083
Intervertebral Disk Displacement 5 0.006083
Intracranial Aneurysm 5 0.006083
Leukemia, T-Cell 5 0.006083
lupus erythematosus 5 0.006083
lymph node morphology 5 0.006083
Lymphatic Diseases 5 0.006083
lymphocyte reaction 5 0.006083
Lymphoma, Non-Hodgkin 5 0.006083
Melanoma, Experimental 5 0.006083
Meningitis, Bacterial 5 0.006083
monocyte infiltration 5 0.006083
motor complications 5 0.006083
Neutropenia 5 0.006083
Otitis Media 5 0.006083

35. Otitis Media with Effusion 5 0.006083
Papilloma 5 0.006083
Plasmacytoma 5 0.006083
Pleural Effusion, Malignant 5 0.006083
Polyps 5 0.006083
Respiration Disorders 5 0.006083
Shwartzman Phenomenon 5 0.006083
Thyroiditis, Autoimmune 5 0.006083
Toxoplasmosis, Cerebral 5 0.006083
Ureteral Obstruction 5 0.006083
Uterine Cervical Neoplasms 5 0.006083
coronary flow 4 0.006083
Enthesitis 4 0.006083
experimental autoimmune uveoretinitis 4 0.006083
Dengue Hemorrhagic Fever 3 0.006083
Abscess 4 0.004866
Acne Vulgaris 4 0.004866
AIDS Dementia Complex 4 0.004866
Allergic Airway Disease 4 0.004866
Amebiasis 4 0.004866
Amyotrophic Lateral Sclerosis 4 0.004866
androgen-independent prostate cancer 4 0.004866
Anemia, Aplastic 4 0.004866
Bronchiolitis Obliterans 4 0.004866
Candidiasis 4 0.004866
cardiovascular risk 4 0.004866
Cholesteatoma 4 0.004866
Constriction, Pathologic 4 0.004866
Cysts 4 0.004866
Dermatosclerosis 4 0.004866
Diabetic Neuropathies 4 0.004866
Disorders of Excessive Somnolence 4 0.004866
Enzootic Bovine Leukosis 4 0.004866
Eosinophilia 4 0.004866
epithelial cell cancer 4 0.004866
Euthyroid Sick Syndromes 4 0.004866
gestational age 4 0.004866
Glaucoma 4 0.004866
Guillain-Barre Syndrome 4 0.004866
heart index 4 0.004866
Hepatitis, Autoimmune 4 0.004866
Hepatoblastoma 4 0.004866

36. Herpes Zoster 4 0.004866
Hyperandrogenism 4 0.004866
Hypercalcemia 4 0.004866
Infertility 4 0.004866
Inflammatory Stress 4 0.004866
Leishmaniasis, Visceral 4 0.004866
leukocyte count 4 0.004866
Leukostasis 4 0.004866
lung volume 4 0.004866
Mesothelioma 4 0.004866
Metabolic acidosis 4 0.004866
Myasthenia Gravis 4 0.004866
myelosuppression 4 0.004866
Nausea 4 0.004866
Opportunistic Infections 4 0.004866
Polymyositis 4 0.004866
Respiratory Syncytial Virus Infections 4 0.004866
Schistosomiasis 4 0.004866
Schizophrenia 4 0.004866
Septicemia 4 0.004866
steatohepatitis 4 0.004866
Stomach Ulcer 4 0.004866
Systemic Vasculitis 4 0.004866
Tachycardia 4 0.004866
Thyroid Neoplasms 4 0.004866
Uveitis, Anterior 4 0.004866
vascular leak syndrome 4 0.004866
Vascular lesions 4 0.004866
Ventilator-Induced Lung Injury 4 0.004866
Viremia 4 0.004866
Vitreoretinopathy, Proliferative 4 0.004866
Warm Ischemia 4 0.004866
Celiac Disease 3 0.004866
Endomyocardial Fibrosis 3 0.004866
Myeloproliferative Disorders 3 0.004866
Nephrotic Syndrome 3 0.004866
Pregnancy Complications 3 0.004866
Acquired Hyperostosis Syndrome 3 0.00365
Adenoviridae Infections 3 0.00365
Agranulocytosis 3 0.00365
Alveolar Bone Loss 3 0.00365
Anaphylaxis 3 0.00365

37. Anorexia Nervosa 3 0.00365
Anoxia 3 0.00365
Anxiety 3 0.00365
Aortic Aneurysm 3 0.00365
Aortitis 3 0.00365
Arterial stiffness 3 0.00365
Arteriosclerosis 3 0.00365
bone marrow dysfunction 3 0.00365
Brain Diseases 3 0.00365
Bronchitis, Chronic 3 0.00365
Brucellosis 3 0.00365
Brucellosis, Bovine 3 0.00365
Carcinoma, Lewis Lung 3 0.00365
Cholangiocarcinoma 3 0.00365
Cholestasis, Intrahepatic 3 0.00365
Churg-Strauss Syndrome 3 0.00365
Cicatrix, Hypertrophic 3 0.00365
Cognition Disorders 3 0.00365
Coronary Artery Disease 3 0.00365
Dengue 3 0.00365
Diabetic Angiopathies 3 0.00365
Eclampsia 3 0.00365
Ehrlichiosis 3 0.00365
Emaciation 3 0.00365
Enteritis 3 0.00365
Enterocolitis, Necrotizing 3 0.00365
Erectile Dysfunction 3 0.00365
Erythema 3 0.00365
Escherichia coli Infections 3 0.00365
eye pressure 3 0.00365
Failure to Thrive 3 0.00365
Familial Mediterranean Fever 3 0.00365
Fanconi Anemia 3 0.00365
Fetal Growth Retardation 3 0.00365
Fistula 3 0.00365
fracture healing 3 0.00365
Gastrointestinal Diseases 3 0.00365
gastrointestinal system damage 3 0.00365
Glomerulonephritis, IGA 3 0.00365
Graves Disease 3 0.00365
Hematologic Neoplasms 3 0.00365
Hemorrhagic Fever with Renal Syndrome 3 0.00365

38. Hepatitis B, Chronic 3 0.00365
Hepatomegaly 3 0.00365
Histiocytosis, Langerhans-Cell 3 0.00365
Hodgkin Disease 3 0.00365
Hyperemia 3 0.00365
Hypertension, Portal 3 0.00365
Infectious complications 3 0.00365
Intervertebral Disk Degeneration 3 0.00365
Intraoperative Complications 3 0.00365
Juvenile-Onset Still Disease 3 0.00365
Lichen Planus 3 0.00365
Liver Cirrhosis 3 0.00365
lung lesion 3 0.00365
lung size 3 0.00365
lung toxicity 3 0.00365
Lupus Erythematosus, Cutaneous 3 0.00365
Lyme Disease 3 0.00365
Lymphohistiocytosis, Hemophagocytic 3 0.00365
Lymphoma, T-Cell 3 0.00365
Malabsorption Syndromes 3 0.00365
Malaria, Falciparum 3 0.00365
Memory Disorders 3 0.00365
Meningococcal Infections 3 0.00365
Migraine Disorders 3 0.00365
monocyte accumulation 3 0.00365
muscle mass 3 0.00365
Muscular Diseases 3 0.00365
Muscular Disorders, Atrophic 3 0.00365
Muscular Dystrophies 3 0.00365
Nephrosis, Lipoid 3 0.00365
Pancreatitis, Acute Necrotizing 3 0.00365
Pemphigus 3 0.00365
Pneumococcal Infections 3 0.00365
Pneumoconiosis 3 0.00365
Pneumonia, Bacterial 3 0.00365
Pneumonia, Pneumocystis 3 0.00365
podocyte disease 3 0.00365
Poisoning 3 0.00365
Polymyalgia Rheumatica 3 0.00365
Pulmonary Emphysema 3 0.00365
Respiratory Failure 3 0.00365
Respiratory Tract Infections 3 0.00365

39. Retinal Degeneration 3 0.00365
Retinoblastoma 3 0.00365
Sclerosis 3 0.00365
skin reaction 3 0.00365
skin thickness 3 0.00365
Sleep Apnea, Obstructive 3 0.00365
stable disease 3 0.00365
T cell hyporesponsiveness 3 0.00365
Takayasu Arteritis 3 0.00365
Trichinellosis 3 0.00365
Trypanosomiasis, African 3 0.00365
vascular integrity 3 0.00365
Vitiligo 3 0.00365
Vomiting 3 0.00365
Glomerulosclerosis, Focal Segmental 2 0.00365
Mouth Neoplasms 2 0.00365
Acantholysis 2 0.002433
Acidosis 2 0.002433
Acute Disease 2 0.002433
Adverse Drug Reaction 2 0.002433
Albuminuria 2 0.002433
alpha 1-Antitrypsin Deficiency 2 0.002433
Aneurysm 2 0.002433
Aortic Diseases 2 0.002433
Aortic Valve Insufficiency 2 0.002433
Aortic Valve Stenosis 2 0.002433
Arthritis, Infectious 2 0.002433
Aspergillosis 2 0.002433
Astrocytoma 2 0.002433
Atrial Fibrillation 2 0.002433
Bites and Stings 2 0.002433
blood vessel invasion 2 0.002433
Bone Diseases 2 0.002433
Bone Neoplasms 2 0.002433
Callosities 2 0.002433
Carcinoma, Ductal 2 0.002433
Carcinoma, Merkel Cell 2 0.002433
cardiac output 2 0.002433
Cell Transformation, Neoplastic 2 0.002433
Cerebral Hemorrhage 2 0.002433
Cerebral Infarction 2 0.002433
Chagas Cardiomyopathy 2 0.002433

40. Chagas Disease 2 0.002433
Chills 2 0.002433
chondrocyte hypertrophy 2 0.002433
Complex Regional Pain Syndromes 2 0.002433
Congenital Abnormalities 2 0.002433
Contracture 2 0.002433
Corneal Diseases 2 0.002433
corneal endothelium permeability 2 0.002433
Coronary Aneurysm 2 0.002433
Delayed onset muscle soreness 2 0.002433
Dental Caries 2 0.002433
Dermatitis, Allergic Contact 2 0.002433
Dermatitis, Atopic 2 0.002433
Duodenal Ulcer 2 0.002433
Dysmenorrhea 2 0.002433
endothelial cell viability 2 0.002433
endothelioma 2 0.002433
Enterocolitis 2 0.002433
Epidermal Necrolysis, Toxic 2 0.002433
Fetal Diseases 2 0.002433
genotoxicity 2 0.002433
Giardiasis 2 0.002433
Glomerulonephritis, Membranous 2 0.002433
Gout 2 0.002433
Graft Occlusion, Vascular 2 0.002433
Graft vs Host Reaction 2 0.002433
Granulomatous Disease, Chronic 2 0.002433
Head Injuries, Closed 2 0.002433
Headache 2 0.002433
Heart Arrest 2 0.002433
Helicobacter Infections 2 0.002433
Helminthiasis 2 0.002433
hematocrit 2 0.002433
Hematuria 2 0.002433
Hemochromatosis 2 0.002433
Hepatic Encephalopathy 2 0.002433
hepatocyte viability 2 0.002433
Hypercalciuria 2 0.002433
Hypergammaglobulinemia 2 0.002433
Hypersomnia 2 0.002433
Hypertension, Pregnancy-Induced 2 0.002433
Hypertension, Renal 2 0.002433

41. Hypophosphatemia 2 0.002433
Hypovolemic Shock 2 0.002433
Hypoxia-Ischemia, Brain 2 0.002433
influenza-like illness 2 0.002433
Insulinoma 2 0.002433
Intussusception 2 0.002433
Jaundice, Obstructive 2 0.002433
Keloid 2 0.002433
Kidney Tubular Necrosis, Acute 2 0.002433
Legionellosis 2 0.002433
Leishmaniasis 2 0.002433
Leprosy, Lepromatous 2 0.002433
Lethargy 2 0.002433
Leukemia, Hairy Cell 2 0.002433
Leukemia, Myelomonocytic, Chronic 2 0.002433
Leukemia, Myelomonocytic, Juvenile 2 0.002433
Lichen Planus, Oral 2 0.002433
Liver Cirrhosis, Biliary 2 0.002433
Low Back Pain 2 0.002433
Low Birth Weight 2 0.002433
Lung Diseases, Fungal 2 0.002433
Lymphoma, B-Cell 2 0.002433
Lymphoma, T-Cell, Cutaneous 2 0.002433
Macrophage Activation Syndrome 2 0.002433
Macular Degeneration 2 0.002433
muscle dysfunction 2 0.002433
Myxoma 2 0.002433
Nematode Infections 2 0.002433
Nephrosis 2 0.002433
Neuritis, Autoimmune, Experimental 2 0.002433
neuron dysfunction 2 0.002433
neuron viability 2 0.002433
Neurotic Disorders 2 0.002433
Niemann-Pick Diseases 2 0.002433
night sweats 2 0.002433
Osteitis 2 0.002433
Otosclerosis 2 0.002433
Panniculitis 2 0.002433
Paraneoplastic Syndromes 2 0.002433
Paraparesis, Tropical Spastic 2 0.002433
Parasitic Diseases 2 0.002433
peripheral nerve dysfunction 2 0.002433

42. Pheochromocytoma 2 0.002433
Pleurisy 2 0.002433
Polyneuropathies 2 0.002433
Precursor Cell Lymphoblastic Leukemia-Lymphoma 2 0.002433
Pruritus 2 0.002433
Pterygium 2 0.002433
Purpura, Schoenlein-Henoch 2 0.002433
Pyoderma Gangrenosum 2 0.002433
Q Fever 2 0.002433
Radiculopathy 2 0.002433
Reflex Sympathetic Dystrophy 2 0.002433
Respiratory Sounds 2 0.002433
Retinal Diseases 2 0.002433
Retinal Hemorrhage 2 0.002433
Retinal Neovascularization 2 0.002433
rhabdomyocyte dysfunction 2 0.002433
Rhabdomyosarcoma 2 0.002433
Rheumatic Fever 2 0.002433
Sarcoma, Ewing's 2 0.002433
Schistosomiasis mansoni 2 0.002433
Skin Manifestations 2 0.002433
Sleep Apnea Syndromes 2 0.002433
Small Cell Lung Carcinoma 2 0.002433
Smoking 2 0.002433
Starvation 2 0.002433
Still's Disease, Adult-Onset 2 0.002433
Substance-Related Disorders 2 0.002433
Sweet Syndrome 2 0.002433
T-cell dysfunction 2 0.002433
Thrombophilia 2 0.002433
Toxoplasmosis 2 0.002433
Trypanosomiasis 2 0.002433
ventricle remodeling 2 0.002433
Aggression 1 0.001217
akinesia 1 0.001217
Alcohol Drinking 1 0.001217
Aneuploidy 1 0.001217
Anhedonia 1 0.001217
Aphasia 1 0.001217
Arteritis 1 0.001217
artery diameter 1 0.001217
artery rhythm 1 0.001217

43. Arthus Reaction 1 0.001217
Ataxia Telangiectasia 1 0.001217
Autoimmune Response 1 0.001217
Barrett Esophagus 1 0.001217
blood gas 1 0.001217
Bronchitis 1 0.001217
Bronchopulmonary Sequestration 1 0.001217
Carcinoma, Pancreatic Ductal 1 0.001217
Carotid Artery Injuries 1 0.001217
Catalepsy 1 0.001217
Cellulitis 1 0.001217
Chlamydia Infections 1 0.001217
Chondrosarcoma 1 0.001217
Chorioamnionitis 1 0.001217
Cicatrix 1 0.001217
Cold Ischemia 1 0.001217
Corneal Opacity 1 0.001217
Cystinosis 1 0.001217
Depression 1 0.001217
Diabetes Mellitus, Experimental 1 0.001217
diabetic cardiomyopathy 1 0.001217
Dry Eye Syndromes 1 0.001217
Dyspnea 1 0.001217
Eales disease 1 0.001217
Endometrioma 1 0.001217
eosinophil viability 1 0.001217
erythrocyte turnover 1 0.001217
Esophageal Neoplasms 1 0.001217
evoked potential 1 0.001217
fetal weight 1 0.001217
Genotoxic Stress 1 0.001217
Graft failure 1 0.001217
hair cell loss 1 0.001217
Hashimoto Disease 1 0.001217
hematotoxicity 1 0.001217
hepatocyte degeneration 1 0.001217
Hepatopulmonary Syndrome 1 0.001217
Hyperimmunoglobulinemia D 1 0.001217
Hyperlipoproteinemia Type II 1 0.001217
Hyperparathyroidism 1 0.001217
Hypesthesia 1 0.001217
Hypoalgesia 1 0.001217

44. Hypoventilation 1 0.001217
Intestinal Polyps 1 0.001217
Iron Overload 1 0.001217
Leukemia, Basophilic, Acute 1 0.001217
Leukemia, Feline 1 0.001217
Leukemia, Myelogenous, Chronic, BCR-ABL Positive 1 0.001217
liver mass 1 0.001217
lung uptake 1 0.001217
lymphocyte response 1 0.001217
major adverse cardiac events 1 0.001217
Mastocytosis 1 0.001217
microscopic polyangiitis 1 0.001217
Mixed Connective Tissue Disease 1 0.001217
Mucolipidoses 1 0.001217
Mumps 1 0.001217
muscle fatigue 1 0.001217
Muscle Hypotonia 1 0.001217
myalgia 1 0.001217
Neoplasms, Experimental 1 0.001217
Neurofibromatoses 1 0.001217
Neuroma 1 0.001217
Neuromyelitis Optica 1 0.001217
neuron network morphology 1 0.001217
Osteogenesis Imperfecta 1 0.001217
Osteomyelitis 1 0.001217
Pancreatic Diseases 1 0.001217
Parkinsonian Disorders 1 0.001217
Peritoneal Neoplasms 1 0.001217
placenta abnormality 1 0.001217
Placenta Diseases 1 0.001217
placenta weight 1 0.001217
Pleuropneumonia 1 0.001217
podocyte infiltration 1 0.001217
portal pressure 1 0.001217
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma 1 0.001217
Prion Diseases 1 0.001217
Prolapse 1 0.001217
Respiratory Insufficiency 1 0.001217
Retinal Detachment 1 0.001217
Reye Syndrome 1 0.001217
Rheumatoid Vasculitis 1 0.001217
Rickettsia Infections 1 0.001217

45. salivary gland dysfunction 1 0.001217
Schistosomiasis japonica 1 0.001217
Schwann cell disease 1 0.001217
Sinusitis 1 0.001217
Skin Diseases, Infectious 1 0.001217
Skin Ulcer 1 0.001217
Smoke Inhalation Injury 1 0.001217
Subacute Cutaneous lupus erythematosus 1 0.001217
subarachnoid pressure 1 0.001217
systolic blood pressure 1 0.001217
tachypnea 1 0.001217
Teratocarcinoma 1 0.001217
Tetanus 1 0.001217
Thrombocytosis 1 0.001217
Tics 1 0.001217
tooth eruption 1 0.001217
Trachoma 1 0.001217
Tularemia 1 0.001217
Tumor Escape 1 0.001217
Underweight 1 0.001217
urinary excretion 1 0.001217
Vasculitis, Hemorrhagic 1 0.001217
Vasoplegia 1 0.001217
vein tone 1 0.001217
Venous Thrombosis 1 0.001217
Wounds, Gunshot 1 0.001217

46. Figure 6. 559 diseases, syndromes, physiological effects and toxicities reported to have up-regulated
TNF-alpha were found by graph search in Pathway Studio database. Color intensity of the
QuantitativeChange link indicates the number of references supporting the observation. Back to text
Table 6. 559 diseases, syndromes, physiological effects and toxicities reported to have up-regulated
TNF-alpha were found by graph search in Pathway Studio database. “# References” column indicates
number of report supporting the observation. Back to text

47. Indication # References Normalized score
Infection 107 1
Obesity 101 0.943925
Heart Failure 99 0.925234
Diabetes Mellitus 87 0.813084
Wounds and Injuries 75 0.700935
Sepsis 54 0.504673
Ischemia 51 0.476636
Arthritis, Rheumatoid 46 0.429907
Inflammation 44 0.411215
Diabetes Mellitus, Type 2 43 0.401869
Insulin Resistance 38 0.35514
Neoplasms 37 0.345794
Myocardial Infarction 33 0.308411
Hemorrhage 31 0.28972
Tuberculosis 31 0.28972
Colitis 24 0.233645
Pre-Eclampsia 23 0.214953
Shock, Septic 22 0.205607
Weight Loss 22 0.205607
Arthritis 21 0.196262
Asthma 21 0.196262
Cancer 21 0.196262
Crohn Disease 21 0.196262
Kidney Failure, Chronic 20 0.186916
Pulmonary Disease, Chronic Obstructive 20 0.186916
Fatty Liver 19 0.17757
Sleep Apnea, Obstructive 19 0.17757
Inflammatory Bowel Diseases 17 0.158879
Endotoxemia 16 0.149533
HIV Infections 16 0.149533
Liver Diseases 16 0.149533
liver toxicity 16 0.149533
Lupus Erythematosus, Systemic 16 0.149533
Multiple Sclerosis 15 0.140187
Psoriasis 15 0.140187
Bone Marrow Transplantation 14 0.130841
Fever 14 0.130841
Graft Rejection 14 0.130841
Diabetes Mellitus, Type 1 13 0.121495
Malaria 13 0.121495
Pancreatitis 13 0.121495

48. Virus Diseases 13 0.121495
Alzheimer Disease 12 0.11215
Arthritis, Experimental 12 0.11215
Brain Injuries 12 0.11215
Endometriosis 12 0.11215
Hyperglycemia 12 0.11215
Reperfusion Injury 12 0.11215
Shock, Hemorrhagic 12 0.11215
Stroke 12 0.11215
Behcet Syndrome 11 0.102804
Cardiomyopathy, Dilated 11 0.102804
Encephalomyelitis 11 0.102804
Infarction 11 0.102804
Liver Cirrhosis 11 0.102804
Peritonitis 11 0.102804
Wounds 11 0.102804
Acquired Immunodeficiency Syndrome 10 0.093458
Brain Ischemia 10 0.093458
Colitis, Ulcerative 10 0.093458
Graft vs Host Disease 10 0.093458
Granuloma 10 0.093458
Malaria, Cerebral 10 0.093458
Middle Cerebral Artery Occlusion 10 0.093458
Mycobacterium Infections 10 0.093458
Cachexia 9 0.084112
Eclampsia 9 0.084112
Fibrosis 9 0.084112
Hypothermia 9 0.084112
Myelodysplastic Syndromes 9 0.084112
Polycystic Ovary Syndrome 9 0.084112
Smoking 9 0.084112
Aortic Aneurysm, Abdominal 8 0.074766
Atherosclerosis 8 0.074766
Burns 8 0.074766
Cystic Fibrosis 8 0.074766
Hepatitis, Alcoholic 8 0.074766
Pneumonia 8 0.074766
Sleep Apnea Syndromes 8 0.074766
Dementia 7 0.065421
Diarrhea 7 0.065421
Hepatitis C, Chronic 7 0.065421
Parkinson Disease 7 0.065421

49. Scleroderma, Systemic 7 0.065421
Liver Failure, Acute 6 0.056075
Mucocutaneous Lymph Node Syndrome 6 0.056075
Myocardial Ischemia 6 0.056075
Ovarian Neoplasms 6 0.056075
Severe Combined Immunodeficiency 6 0.056075
Anemia 5 0.046729
Carcinoma, Hepatocellular 5 0.046729
Central Nervous System Diseases 5 0.046729
endothelial cell dysfunction 5 0.046729
Glomerulonephritis 5 0.046729
Heart Diseases 5 0.046729
hemodynamics 5 0.046729
Hemolytic-Uremic Syndrome 5 0.046729
Hepatitis 5 0.046729
Hepatitis C 5 0.046729
Hyperhomocysteinemia 5 0.046729
Hyperinsulinism 5 0.046729
Hypoxia-Ischemia, Brain 5 0.046729
Infertility 5 0.046729
Kidney Diseases 5 0.046729
Kidney Failure, Acute 5 0.046729
Leukemia, Myeloid, Acute 5 0.046729
Liver Diseases, Alcoholic 5 0.046729
Lung Injury 5 0.046729
Malnutrition 5 0.046729
Meningitis 5 0.046729
Multiple Myeloma 5 0.046729
muscle injury 5 0.046729
Osteoarthritis 5 0.046729
Pulmonary Fibrosis 5 0.046729
Renal Insufficiency, Chronic 5 0.046729
Respiratory Distress Syndrome, Adult 5 0.046729
Sarcoidosis 5 0.046729
Sjogren's Syndrome 5 0.046729
Spinal Cord Injuries 5 0.046729
Abortion, Spontaneous 4 0.037383
Acne Vulgaris 4 0.037383
Amyotrophic Lateral Sclerosis 4 0.037383
Breast Neoplasms 4 0.037383
Cerebral Hemorrhage 4 0.037383
Cholestasis 4 0.037383

50. Coronary Artery Disease 4 0.037383
Diabetes, Gestational 4 0.037383
Fistula 4 0.037383
Hypersensitivity 4 0.037383
Hypertension 4 0.037383
kidney ischemia 4 0.037383
kidney toxicity 4 0.037383
Lipodystrophy 4 0.037383
Liver Failure 4 0.037383
Lung Diseases 4 0.037383
Lupus Nephritis 4 0.037383
Pancreatic Neoplasms 4 0.037383
Periodontitis 4 0.037383
Pneumonia, Pneumocystis 4 0.037383
Porcine Reproductive and Respiratory Syndrome 3 0.037383
Seizures 2 0.037383
Severe Acute Respiratory Syndrome 4 0.037383
skin lesion 4 0.037383
Skin Neoplasms 4 0.037383
Stress, Psychological 4 0.037383
Subarachnoid Hemorrhage 4 0.037383
Ulcer 4 0.037383
AIDS Dementia Complex 3 0.028037
Angina, Unstable 3 0.028037
Anorexia 3 0.028037
Anoxia 3 0.028037
Arthritis, Infectious 3 0.028037
Arthritis, Juvenile Rheumatoid 3 0.028037
Arthritis, Psoriatic 3 0.028037
Bacterial Infections 3 0.028037
Barrett Esophagus 3 0.028037
Bone Diseases 3 0.028037
Carcinoma 3 0.028037
Carcinoma, Renal Cell 3 0.028037
Cardiovascular Diseases 3 0.028037
Chagas Disease 3 0.028037
Cytomegalovirus Infections 3 0.028037
Dengue Hemorrhagic Fever 3 0.028037
Disseminated Intravascular Coagulation 3 0.028037
Dry Eye Syndromes 3 0.028037
Enterocolitis, Necrotizing 3 0.028037
Fanconi Anemia 3 0.028037

51. Glomerulonephritis, Membranous 3 0.028037
Guillain-Barre Syndrome 3 0.028037
heart remodeling 3 0.028037
Herpes Simplex 3 0.028037
Hyperalgesia 3 0.028037
Hypertrophy 3 0.028037
Hypoglycemia 3 0.028037
Influenza, Human 3 0.028037
Jaundice, Obstructive 3 0.028037
Joint Diseases 3 0.028037
Kwashiorkor 3 0.028037
Liver Neoplasms 3 0.028037
Lung Diseases, Interstitial 3 0.028037
Lymphohistiocytosis, Hemophagocytic 3 0.028037
Lymphoma 3 0.028037
Metabolic Syndrome X 3 0.028037
Metaplasia 3 0.028037
Migraine Disorders 3 0.028037
Muscular Atrophy 3 0.028037
Muscular Dystrophy, Duchenne 3 0.028037
Mycobacterium avium-intracellulare Infection 3 0.028037
Myocarditis 3 0.028037
Nephritis 3 0.028037
neuron toxicity 3 0.028037
Overweight 3 0.028037
Paratuberculosis 3 0.028037
Premature Birth 3 0.028037
Renal Insufficiency 3 0.028037
Spondylitis, Ankylosing 3 0.028037
Underweight 3 0.028037
Uveitis 3 0.028037
Vascular Diseases 3 0.028037
Vitamin B 12 Deficiency 3 0.028037
Wegener Granulomatosis 3 0.028037
Acidosis 2 0.018692
Acidosis, Lactic 2 0.018692
Acrocephalosyndactylia 2 0.018692
Acute Coronary Syndrome 2 0.018692
Acute Lung Injury 2 0.018692
Acute-Phase Reaction 2 0.018692
Adenocarcinoma 2 0.018692
adipocyte deposition 2 0.018692

52. Adrenoleukodystrophy 2 0.018692
Airway Obstruction 2 0.018692
Alcohol Drinking 2 0.018692
Anemia, Aplastic 2 0.018692
Anemia, Sickle Cell 2 0.018692
Aneurysm 2 0.018692
Anorexia Nervosa 2 0.018692
Arrhythmias, Cardiac 2 0.018692
artery stenosis 2 0.018692
Arthus Reaction 2 0.018692
Atrial Fibrillation 2 0.018692
Autoimmune Diseases 2 0.018692
Bacteremia 2 0.018692
blood pressure 2 0.018692
Borna Disease 2 0.018692
Bronchiolitis Obliterans 2 0.018692
Candidiasis 2 0.018692
Carcinoma, Squamous Cell 2 0.018692
Cardiomyopathies 2 0.018692
Cholangitis 2 0.018692
cognitive impairment 2 0.018692
Colonic Neoplasms 2 0.018692
Common Variable Immunodeficiency 2 0.018692
Communicable Diseases 2 0.018692
Contusions 2 0.018692
Coronavirus Infections 2 0.018692
Critical Illness 2 0.018692
Demyelinating Diseases 2 0.018692
Dengue 2 0.018692
Dermatitis, Atopic 2 0.018692
Diabetes Mellitus, Experimental 2 0.018692
Diabetic Nephropathies 2 0.018692
Diabetic Retinopathy 2 0.018692
Drowsiness 2 0.018692
Dyslipidemias 2 0.018692
Emphysema 2 0.018692
Endocarditis 2 0.018692
Endometritis 2 0.018692
Escherichia coli Infections 2 0.018692
Fibromyalgia 2 0.018692
gestational age 2 0.018692
Glaucoma 2 0.018692

53. Glomerulonephritis, IGA 2 0.018692
Graves Ophthalmopathy 2 0.018692
Heart Arrest 2 0.018692
heart rate 2 0.018692
heart stress 2 0.018692
Heat Stroke 2 0.018692
Helicobacter Infections 2 0.018692
Hepatitis B, Chronic 2 0.018692
Hepatitis D 2 0.018692
Hernia, Diaphragmatic 2 0.018692
Histiocytosis, Langerhans-Cell 2 0.018692
Hyperaldosteronism 2 0.018692
Hyperandrogenism 2 0.018692
Hypercholesterolemia 2 0.018692
Hyperemesis Gravidarum 2 0.018692
Hyperlipidemia, Familial Combined 2 0.018692
Hyperlipidemias 2 0.018692
Hyperparathyroidism, Primary 2 0.018692
Hypersensitivity, Contact 2 0.018692
Hypersensitivity, Delayed 2 0.018692
Hypertension, Portal 2 0.018692
Hypertension, Pulmonary 2 0.018692
Immunologic Deficiency Syndromes 2 0.018692
Infectious Mononucleosis 2 0.018692
Influenza in Birds 2 0.018692
joint degeneration 2 0.018692
Keratoconjunctivitis, Vernal 2 0.018692
left ventricular pressure 2 0.018692
Leprosy, Lepromatous 2 0.018692
Leukemia 2 0.018692
Lichen Planus, Oral 2 0.018692
Listeriosis 2 0.018692
Liver Cirrhosis, Biliary 2 0.018692
Low Back Pain 2 0.018692
Lung Neoplasms 2 0.018692
Lymphoproliferative Disorders 2 0.018692
Macular Degeneration 2 0.018692
Melanoma 2 0.018692
Meningitis, Bacterial 2 0.018692
Metabolic Diseases 2 0.018692
Mucositis 2 0.018692
Multiple Organ Failure 2 0.018692

54. Myasthenia Gravis 2 0.018692
Myositis 2 0.018692
Necrosis 2 0.018692
Neoplasm Metastasis 2 0.018692
Neurodegenerative Diseases 2 0.018692
Neurotoxicity Syndromes 2 0.018692
Neutropenia 2 0.018692
Obstetric Labor, Premature 2 0.018692
Opportunistic Infections 2 0.018692
Orchitis 2 0.018692
Osteolysis 2 0.018692
Osteoporosis 2 0.018692
Otitis Media 2 0.018692
Pain 2 0.018692
Pancreatitis, Acute Necrotizing 2 0.018692
Parasitemia 2 0.018692
Pemphigoid, Bullous 2 0.018692
Postpoliomyelitis Syndrome 2 0.018692
Prostatic Neoplasms 2 0.018692
Pulmonary Edema 2 0.018692
Respiratory Sounds 2 0.018692
Respiratory Syncytial Virus Infections 2 0.018692
Sleep Deprivation 2 0.018692
Sleep Fragmentation 2 0.018692
Stomach Neoplasms 2 0.018692
Systemic Inflammatory Response Syndrome 2 0.018692
Takayasu Arteritis 2 0.018692
Tibial Fractures 2 0.018692
Typhoid Fever 2 0.018692
Uremia 2 0.018692
Ureteral Obstruction 2 0.018692
vascular leak syndrome 2 0.018692
Vasculitis 2 0.018692
Abruptio Placentae 1 0.009346
Acute Disease 1 0.009346
Adenoviridae Infections 1 0.009346
Adiponectin deficiency 1 0.009346
Allodynia 1 0.009346
Alphavirus Infections 1 0.009346
Amyloidosis 1 0.009346
Anaphylaxis 1 0.009346
androgen-independent prostate cancer 1 0.009346

55. anemia of chronic disease 1 0.009346
Anemia, Iron-Deficiency 1 0.009346
Anemia, Refractory 1 0.009346
Anti-Glomerular Basement Membrane Disease 1 0.009346
Anxiety Disorders 1 0.009346
Arterial Occlusive Diseases 1 0.009346
Arteriosclerosis 1 0.009346
Arteritis 1 0.009346
artery impedance 1 0.009346
artery ischaemia 1 0.009346
Arthritis, Reactive 1 0.009346
Astrocytoma 1 0.009346
Avian Leukosis 1 0.009346
Beryllium Disease 1 0.009346
Blister 1 0.009346
body weight 1 0.009346
Bone Diseases, Metabolic 1 0.009346
Borderline Personality Disorder 1 0.009346
Bovine Virus Diarrhea-Mucosal Disease 1 0.009346
Brain Edema 1 0.009346
Bronchitis 1 0.009346
bronchoconstriction 1 0.009346
bronchus lavage 1 0.009346
Brucellosis 1 0.009346
Brucellosis, Bovine 1 0.009346
Burns, Chemical 1 0.009346
Carcinoma, Non-Small-Cell Lung 1 0.009346
Cardiac Output, Low 1 0.009346
cardiovascular risk 1 0.009346
Celiac Disease 1 0.009346
Chagas Cardiomyopathy 1 0.009346
Cholesteatoma 1 0.009346
Chorioamnionitis 1 0.009346
Chronic Disease 1 0.009346
Cognition Disorders 1 0.009346
Cold Ischemia 1 0.009346
colorectal distension 1 0.009346
Colorectal Neoplasms 1 0.009346
Complex Regional Pain Syndromes 1 0.009346
Coronary Disease 1 0.009346
Coronary Occlusion 1 0.009346
Cough 1 0.009346

56. Craniocerebral Trauma 1 0.009346
Cryoglobulinemia 1 0.009346
Cytochrome-c Oxidase Deficiency 1 0.009346
Delayed onset muscle soreness 1 0.009346
Dementia, Vascular 1 0.009346
Demyelination 1 0.009346
Dermatitis Herpetiformis 1 0.009346
Dermatosclerosis 1 0.009346
diabetic cardiomyopathy 1 0.009346
Diabetic Ketoacidosis 1 0.009346
Ductus Arteriosus, Patent 1 0.009346
Dysentery, Bacillary 1 0.009346
Eales disease 1 0.009346
Embolism, Air 1 0.009346
Encephalitis, Tick-Borne 1 0.009346
Encephalopathy 1 0.009346
Endometrial Neoplasms 1 0.009346
Endophthalmitis 1 0.009346
Eosinophilia 1 0.009346
Epilepsy 1 0.009346
Epstein-Barr Virus Infections 1 0.009346
Erectile Dysfunction 1 0.009346
Eye Diseases 1 0.009346
Fatty Streak, Arterial 1 0.009346
Femoral Fractures 1 0.009346
Fetal Growth Retardation 1 0.009346
Fetal Membranes, Premature Rupture 1 0.009346
Fibrosis, Liver 1 0.009346
Food Deprivation 1 0.009346
Fungemia 1 0.009346
Gaucher Disease 1 0.009346
Glaucoma, Open-Angle 1 0.009346
Glioma 1 0.009346
glomerular filtration rate 1 0.009346
Glucose Intolerance 1 0.009346
Graft failure 1 0.009346
Graft Occlusion, Vascular 1 0.009346
Gram-Negative Bacterial Infections 1 0.009346
Granulomatous Disease, Chronic 1 0.009346
Headache 1 0.009346
Hearing Loss, Sensorineural 1 0.009346
Heart Transplantation 1 0.009346

57. Hemophilia A 1 0.009346
Hemorrhagic Fever, Crimean 1 0.009346
Hemorrhagic Fevers, Viral 1 0.009346
Hepatitis B 1 0.009346
Hepatitis, Chronic 1 0.009346
Hepatopulmonary Syndrome 1 0.009346
Hidradenitis Suppurativa 1 0.009346
HIV-Associated Lipodystrophy Syndrome 1 0.009346
Hydrocephalus 1 0.009346
Hydrocephalus, Normal Pressure 1 0.009346
Hypercalcemia 1 0.009346
Hyperimmunoglobulinemia D 1 0.009346
Hyperlipoproteinemia Type II 1 0.009346
Hypertension, Renal 1 0.009346
Hypertrichosis 1 0.009346
Hypogonadism 1 0.009346
Hypokalemia 1 0.009346
Hyponatremia 1 0.009346
Hypotension 1 0.009346
Immune Reconstitution Inflammatory Syndrome 1 0.009346
impaired fasting glucose 1 0.009346
Inhalation Exposure 1 0.009346
Intracranial Hemorrhage, Hypertensive 1 0.009346
Keratoconus 1 0.009346
Kidney Cortex Necrosis 1 0.009346
Leishmaniasis 1 0.009346
Leishmaniasis, Visceral 1 0.009346
Leprosy 1 0.009346
Leukemia, B-Cell 1 0.009346
Leukemia, Myeloid, Chronic-Phase 1 0.009346
Leukemia, Myelomonocytic, Chronic 1 0.009346
Leukemia, T-Cell 1 0.009346
leukocyte count 1 0.009346
lung lesion 1 0.009346
Lyme Disease 1 0.009346
Lyme Neuroborreliosis 1 0.009346
Lymphatic Diseases 1 0.009346
Lymphoma, Follicular 1 0.009346
Macrophage Activation Syndrome 1 0.009346
Malaria, Falciparum 1 0.009346
Malaria, Vivax 1 0.009346
Melanoma, Experimental 1 0.009346

58. Melioidosis 1 0.009346
Meningitis, Meningococcal 1 0.009346
Meningitis, Pneumococcal 1 0.009346
Miller Fisher Syndrome 1 0.009346
Mitral Valve Insufficiency 1 0.009346
Mixed Connective Tissue Disease 1 0.009346
Molluscum Contagiosum 1 0.009346
Mononeuropathies 1 0.009346
Motor Neuron Disease 1 0.009346
Multiple Sclerosis, Chronic Progressive 1 0.009346
Multiple Trauma 1 0.009346
Murine Acquired Immunodeficiency Syndrome 1 0.009346
Myofascial Pain Syndromes 1 0.009346
Narcolepsy 1 0.009346
Nasopharyngeal Neoplasms 1 0.009346
Nervous System Autoimmune Disease, Experimental 1 0.009346
Nervous System Diseases 1 0.009346
Neuritis 1 0.009346
Neurofibroma, Plexiform 1 0.009346
neuron dysfunction 1 0.009346
night sweats 1 0.009346
Obesity, Morbid 1 0.009346
Oophoritis 1 0.009346
Papilloma 1 0.009346
Parkinsonian Disorders 1 0.009346
Pelvic Pain 1 0.009346
Pemphigoid, Benign Mucous Membrane 1 0.009346
Pemphigus 1 0.009346
Periodontal Diseases 1 0.009346
Periodontal Pocket 1 0.009346
platelet count 1 0.009346
Pleural Effusion, Malignant 1 0.009346
Pneumoconiosis 1 0.009346
Pneumonia, Bacterial 1 0.009346
Pneumonia, Staphylococcal 1 0.009346
Polymyalgia Rheumatica 1 0.009346
Polymyositis 1 0.009346
Post-Traumatic Headache 1 0.009346
Pregnancy, Ectopic 1 0.009346
Prostatitis 1 0.009346
Proteinuria 1 0.009346
Pseudomonas Infections 1 0.009346

59. Pulmonary Eosinophilia 1 0.009346
Purpura, Schoenlein-Henoch 1 0.009346
Pyoderma Gangrenosum 1 0.009346
Relapsing Fever 1 0.009346
Renal Artery Obstruction 1 0.009346
Residual Tumor 1 0.009346
Retinal Detachment 1 0.009346
Retinal Diseases 1 0.009346
Retinitis 1 0.009346
Rheumatic Fever 1 0.009346
Rotavirus Infections 1 0.009346
Salmonella Infections 1 0.009346
Sarcoma 1 0.009346
Schistosomiasis haematobia 1 0.009346
Scleroderma, Diffuse 1 0.009346
Scleroderma, Localized 1 0.009346
Sclerosis 1 0.009346
Seizures, Febrile 1 0.009346
Septicemia 1 0.009346
Shock 1 0.009346
Silicosis 1 0.009346
Skin Diseases 1 0.009346
Small Cell Lung Carcinoma 1 0.009346
Spinal Cord Diseases 1 0.009346
Splenomegaly 1 0.009346
Spondylitis 1 0.009346
Stem Cell Transplantation 1 0.009346
Still's Disease, Adult-Onset 1 0.009346
Stomach Ulcer 1 0.009346
Streptococcal Infections 1 0.009346
Substance Abuse, Intravenous 1 0.009346
Sunburn 1 0.009346
Superinfection 1 0.009346
Thalassemia 1 0.009346
Thrombocytopenia 1 0.009346
Thrombophilia 1 0.009346
Thrombosis 1 0.009346
thymus involution 1 0.009346
Tourette Syndrome 1 0.009346
Toxemia 1 0.009346
Trachoma 1 0.009346
Trypanosomiasis 1 0.009346

60. Tuberculosis, Multidrug-Resistant 1 0.009346
Tuberculosis, Pulmonary 1 0.009346
Urticaria 1 0.009346
Uterine Cervical Neoplasms 1 0.009346
Uveitis, Intermediate 1 0.009346
Vasospasm, Intracranial 1 0.009346
Ventricular Dysfunction 1 0.009346
Viremia 1 0.009346
Vulvar Vestibulitis 1 0.009346
Wallerian Degeneration 1 0.009346
Warts 1 0.009346
Weight Gain 1 0.009346
Werner Syndrome 1 0.009346
Xanthomatosis 1 0.009346

61. Figure 7A. TNF/CREB Expression Targets pathways is shown with links between pathway components
and Atherosclerosis. Atherosclerosis was identified as a top disease linked to TNF pathways. The color
intensity of the links is proportionate to the number of references supporting the relation. Back to text
Figure 7B. TNF/STAT Expression Targets pathways is shown with links between pathway components
and Atherosclerosis. Atherosclerosis was identified as a top disease linked to TNF pathways. The color
intensity of the links is proportionate to the number of references supporting the relation. Back to text

63. Figure 7C. TNF/TP53/ATF Expression Targets pathways is shown with links between pathway
components and Atherosclerosis. Atherosclerosis was identified as a top disease linked to TNF
pathways. The color intensity of the links is proportionate to the number of references supporting the
relation. Back to text

64. Figure 7D. TNF/ELK-SRF Expression Targets pathways is shown with links between pathway components
and Atherosclerosis. Atherosclerosis was identified as a top disease linked to TNF pathways. The color
intensity of the links is proportionate to the number of references supporting the relation. Back to text

65. Figure 7E. TNF/NF-B Expression Targets pathways is shown with links between pathway components
and Atherosclerosis. Atherosclerosis was identified as a top disease linked to TNF pathways. The color
intensity of the links is proportionate to the number of references supporting the relation. Back to text
Figure 7F. TNF/AP-1 Expression Targets pathways is shown with links between pathway components
and Atherosclerosis. Atherosclerosis was identified as a top disease linked to TNF pathways. The color
intensity of the links is proportionate to the number of references supporting the relation. Back to text
Table 7. Results of sub-network enrichment analysis to find diseases enriched with components of TNF
pathways. Total # of Neighbors – number of proteins contributing to diseases in Pathway Studio

66. database. Overlap – number of protein components of TNF pathways contributing to disease. Percent
Overlap = 100* Overlap/ Total # of Neighbors. p-value - is calculated as Fisher test between unified
TNF pathway and proteins contributing to diseases. Normalized score = Overlap/209. Back to text
Name Total # of
Neighbors
Overlap Percent
Overlap
p-value Normalized
score
Inflammation 4154 196 4 1.35E-137 0.94
Atherosclerosis 1971 148 7 1.32E-121 0.71
Neoplasm Metastasis 2666 161 6 3.72E-120 0.77
Wounds and Injuries 4228 182 4 1.05E-115 0.87
Arthritis, Rheumatoid 1155 118 10 2.13E-108 0.56
Infection 4001 171 4 4.46E-105 0.82
Fibrosis 1745 129 7 6.01E-102 0.62
Pulmonary Fibrosis 893 99 11 1.62E-92 0.47
Arthritis 1211 108 8 1.37E-91 0.52
Cancer 5302 176 3 6.02E-91 0.84
Neoplasms 8954 209 2 4.33E-90 1.00
Carcinoma, Squamous Cell 1364 111 8 4.49E-90 0.53
Hypertrophy 1769 120 6 3.62E-89 0.57
Diabetes Mellitus 2800 138 4 8.25E-87 0.66
Lung Neoplasms 2203 127 5 1.32E-86 0.61
Hyperplasia 1522 112 7 3.73E-86 0.54
Pathologic Processes 674 86 12 1.04E-84 0.41
vascular remodeling 757 89 11 1.19E-84 0.43
Breast Neoplasms 3353 145 4 1.43E-84 0.69
Colitis 1098 99 9 1.55E-83 0.47
Prostatic Neoplasms 2033 121 5 2.46E-83 0.58
Glomerulonephritis 623 83 13 3.78E-83 0.40
Reperfusion Injury 1537 109 7 8.64E-82 0.52
Melanoma 1760 114 6 9.71E-82 0.55
Arthritis, Experimental 908 92 10 1.04E-81 0.44
Graft Rejection 632 82 12 4.21E-81 0.39
Cardiomegaly 1089 93 8 9.08E-76 0.44
Colorectal Neoplasms 1896 112 5 9.91E-76 0.54
Stomach Neoplasms 1270 97 7 9.90E-75 0.46
Insulin Resistance 1322 98 7 2.42E-74 0.47
liver toxicity 2265 118 5 2.51E-74 0.56
Wounds 1287 97 7 3.52E-74 0.46
Vascular Diseases 671 78 11 4.53E-73 0.37
Asthma 1592 103 6 1.12E-72 0.49
kidney toxicity 1659 104 6 4.21E-72 0.50
Autoimmune Diseases 878 84 9 6.46E-72 0.40
Pneumonia 1240 94 7 7.30E-72 0.45

67. leukocyte infiltration 464 69 14 8.47E-72 0.33
Encephalomyelitis 791 81 10 1.49E-71 0.39
Heart Failure 1377 97 7 2.16E-71 0.46
Autoimmunity 721 78 10 1.35E-70 0.37
Lung Injury 1095 89 8 2.64E-70 0.43
Endometriosis 443 67 15 3.86E-70 0.32
Carcinoma, Hepatocellular 1514 99 6 6.23E-70 0.47
Brain Injuries 1144 90 7 6.47E-70 0.43
Inflammatory Bowel Diseases 624 74 11 9.41E-70 0.35
Osteoarthritis 629 74 11 1.72E-69 0.35
intimal hyperplasia 559 71 12 6.14E-69 0.34
Pancreatic Neoplasms 1201 90 7 4.74E-68 0.43
Sepsis 1016 85 8 6.49E-68 0.41
Myocardial Infarction 1330 93 6 7.91E-68 0.44
Brain Ischemia 1046 85 8 7.45E-67 0.41
Kidney Diseases 1200 89 7 7.92E-67 0.43
macrophage infiltration 429 64 14 1.78E-66 0.31
Ovarian Neoplasms 1323 91 6 1.40E-65 0.44
Liver Neoplasms 2099 106 5 3.61E-64 0.51
Skin Neoplasms 848 77 9 9.33E-64 0.37
Adenocarcinoma 1304 89 6 1.06E-63 0.43
Fatty Streak, Arterial 427 62 14 1.45E-63 0.30
heart remodeling 444 62 13 1.80E-62 0.30
Ischemia 2303 108 4 2.62E-62 0.52
Acute Lung Injury 663 70 10 3.35E-62 0.33
Carcinoma, Non-Small-Cell
Lung
892 77 8 4.44E-62 0.37
Multiple Sclerosis 612 68 11 7.41E-62 0.33
Lymphatic Metastasis 482 63 13 1.20E-61 0.30
Fibrosis, Liver 596 67 11 3.01E-61 0.32
Cardiomyopathy, Hypertrophic 852 75 8 5.47E-61 0.36
Virus Diseases 1041 80 7 1.05E-60 0.38
Diabetic Nephropathies 592 66 11 4.73E-60 0.32
joint degeneration 254 51 20 1.27E-59 0.24
Scleroderma, Systemic 293 53 18 2.01E-59 0.25
Multiple Myeloma 832 73 8 3.71E-59 0.35
kidney fibrosis 457 60 13 9.91E-59 0.29
Infarction 1591 91 5 1.42E-58 0.44
Obesity 1553 90 5 2.40E-58 0.43
Necrosis 2072 100 4 3.73E-58 0.48
Coronary Artery Disease 550 63 11 5.86E-58 0.30
endothelial cell dysfunction 800 71 8 8.65E-58 0.34

68. Nerve Degeneration 1349 85 6 1.01E-57 0.41
Graft vs Host Disease 488 60 12 5.61E-57 0.29
Heart Diseases 987 75 7 2.79E-56 0.36
Extravasation 806 70 8 2.80E-56 0.33
Demyelination 425 57 13 3.00E-56 0.27
Lupus Erythematosus, Systemic 748 68 9 6.41E-56 0.33
Lung Diseases 623 64 10 7.30E-56 0.31
Glioblastoma 784 69 8 7.99E-56 0.33
Carcinoma 1424 85 5 8.19E-56 0.41
Neurotoxicity Syndromes 1715 91 5 9.12E-56 0.44
Allergic Airway Disease 303 51 16 1.91E-55 0.24
muscle injury 798 69 8 2.67E-55 0.33
Cardiovascular Diseases 1142 78 6 3.42E-55 0.37
cartilage degeneration 235 47 19 8.49E-55 0.22
neuron toxicity 1781 91 5 2.31E-54 0.44
Severe Combined
Immunodeficiency
603 62 10 4.52E-54 0.30
neutrophil infiltration 611 62 10 1.02E-53 0.30
Stroke 1375 82 5 1.25E-53 0.39
Colonic Neoplasms 1394 82 5 3.64E-53 0.39
Diabetes Mellitus, Type 1 727 65 8 7.19E-53 0.31
Alzheimer Disease 1229 78 6 8.38E-53 0.37
Table 8. Weights for individual normalized scores obtained by different text-mining efforts. Back to text
Normalized Score Weight
# Clinical trials linking to Humira 1
# References linking to Humira 7/8
# Clinical trials for other anti-TNF therapies 6/8
# References linking to other anti-TNF therapies 5/8
# Humira Patents mentioning the disease 4/8
# References reporting TNF-alpha contribution to disease progression 3/8
# References reporting TNF-alpha up-regulation in disease 2/8
# of protein components of TNF pathways contributing to disease progression 1/8
Table 9. Disease extracted from 188 Humira patents. The score for every disease was calculated as
number of patents mentioning the disease in the title or abstract. Back to text
Disease Patent
Alzheimer Disease US20060111316
Amyloidosis US20060111316
Arthritis US20050197293

69. Arthritis, Juvenile Rheumatoid US20050197293
Arthritis, Psoriatic US20050197293
Arthritis, Rheumatoid US20110150871
Arthritis, Rheumatoid WO/2010/020593A1
Arthritis, Rheumatoid US20090035315
Arthritis, Rheumatoid WO/2005/123193A2
Arthritis, Rheumatoid US20050197293
Atopy US20050163778
Autoimmune Diseases US20050163778
Autoimmune Diseases US20110150871
Autoimmune Diseases WO/2010/020593A1
Autoimmune Diseases WO/2012/074980A2
Autoimmune Diseases WO/2012/019015A2
Cancer WO/2013/036232A2
Cancer US20120225057
Cardiovascular Diseases WO/2010/120345A1
Cardiovascular Diseases US20100260825
Colitis US20110160085
Colitis, Ulcerative US20110160085
Coronary Disease US20100260825
Coronary Disease WO/2010/120345A1
Cystitis, Interstitial US20110287018
Cystitis, Interstitial US20110150891
Cystitis, Interstitial WO/2011/075578A1
Cystitis, Interstitial WO/2011/146727A1
Demyelinating Diseases WO/2008/049053A2
Demyelinating Diseases WO/2008/049053A3
Disease Patent
Graft vs Host Disease US20050163778
Hepatitis C US20100040576
Hepatitis C WO/2009/082448A2
Hepatitis C WO/2009/082448A3
Inflammatory Bowel Diseases US20110150871
Inflammatory Bowel Diseases WO/2010/020593A1
Joint Diseases US20090035315
Joint Diseases WO/2005/123193A2
Liver Diseases WO/2012/074980A2
Melanoma WO/2013/036232A2
Multiple Sclerosis WO/2008/049053A2
Multiple Sclerosis WO/2008/049053A3
Myeloproliferative Disorders WO/2012/019015A2
Myeloproliferative Disorders US20120225057

70. Myeloproliferative Disorders WO/2013/036232A2
Neoplasms US20100260825
Osteoarthritis US20090035315
Osteoarthritis WO/2005/123193A2
Osteoarthritis US20050197293
Pain US20120076791
Pain WO/2012/050944A2
Pain WO/2005/123193A2
Pain US20110150891
Pain WO/2011/075578A1
Pain US20090035315
Pain WO/2011/146727A1
Pain US20110287018
Pelvic Pain US20120076791
Pelvic Pain WO/2012/050944A2
Polymyalgia Rheumatica WO/2006/076673A2
Pregnancy, Tubal WO/2010/120345A1
Pregnancy, Tubal US20100260825
Prostatitis US20120076791
Prostatitis WO/2012/050944A2
Spondylitis, Ankylosing US20050197293
Stroke WO/2010/120345A1
Stroke US20100260825
Temporal Arteritis WO/2006/076673A2
Virus Diseases US20100040576
Virus Diseases WO/2009/082448A2
Virus Diseases WO/2009/082448A3