Catastrophizing

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Nada Lukkahatai, PhD, RN

Co-authors : B. Majors, BS; S. Reddy, PhD; B. Walitt, MD; L. Saligan, PhD

Conflict of Interest

There is no conflict of interest to report.

Study Objective and Questions

Objective:

To examine differential expression of genes from fatigued fibromyalgia women with different levels of pain and catastrophizing.

Specific Research Questions:

Does the gene expression profile different in fatigued fibromyalgia women with high and low pain severities?

Does the gene expression profile different in fatigued fibromyalgia women with high and low catastrophizing?

Fibromyalgia

 Fibromyalgia (FM) is characterized by prolonged widespread muscle pain, profound fatigue, and sleep disturbance.

 An estimated 10 million Americans and 200-400 million adults worldwide suffer from FM.

 Prevalence: 3 times higher among women than men.

 5.5 million FM patients visit the ambulatory care per year.

 The etiology of the fibromyalgia is unknown.

Diagnostic Criteria for FM

1990 American College of

Rheumatology (ACR)

Criteria

1. History of chronic widespread pain

2. Pain in at least 11/18 tender point sites on digital palpation.

Diagnostic Criteria for FM

2010 ACR Criteria

1 . Widespread Pain

Index (WPI) > 7 and

Symptom Severity

(SS) Scale score > 5 or

2. WPI = 3-6 and SS > 9

3. Symptoms present at similar level for > 3 months

4. No other disorder explaining the pain .

Catastrophizing

 Catastrophizing is an exaggerated negative attention to symptoms.

 Pain catastrophizing significantly predicts pain severity, chronic illness-related disability & emotional distress.

 High fatigue catastrophizing is associated with high fatigue severity in breast cancer patients and predicts post cancer treatment fatigue.

 Cognitive behavioral intervention focus on addressing maladaptive thinking improve fatigue severity and depression in chronic fatigue syndrome.

Gaps in Knowledge

 No study has explored the role of catastrophizing in influencing possible biologic correlates of pain and fatigue in

FM.

 Little is known about the mechanisms that can explain both pain and fatigue symptoms experienced by FM patients.

 Few studies have looked at possible genomic correlates of

FM.

Study

Actively recruiting MedStar Research Institute protocol.

Women diagnosed with FM based on the 1990 and 2010 diagnostic criteria are currently enrolled in this study.

Methods

Questionnaires:

 Pain severity subscale of Brief Pain Inventory (BPI)

4-item subscale; the mean subscale score ranged from

0 to 10. The cutoff score that is clinically significant is 5.

 General fatigue subscale - Multidimensional Fatigue

Inventory (MFI) 4-item subscale; score range from 4-20.

The score of ≥ 13 is significant fatigue.

 Pain Catastrophizing Scale (PCS) = 13-item questionnaire; scores ranged from 0 - 52. Suggested clinical cut point is 16.

Gene Expression

Biological sample collection and analysis:

 Microarray technology using

Affymetrix GeneChip ® human genome U133 Plus 2.0 array was used on blood collected using Paxgene ® tubes.

Whole blood

Collected using

Paxgene tubes

Microarray

 Differential gene expression was analyzed using Partek software.

 Gene selection criteria: over 2fold increase or decrease, p <

0.05.

 Network analyses by Ingenuity® software.

Extracted RNA

U133 Plus 2.0

Sample Characteristics

9 Caucasian, female, diagnosed with FM, 26-64 years old

Min Max Mean (SD) Clinical

Cut-off

General Fatigue 13 20 17.1 (2.7) >13

Pain severity 0.5

6.3

4.1 (1.9)

Catastrophizing 4.0

36.0

17.0 (9.8)

>5

>16

Categories of Pain and Catastrophizing

N = 9

Pain:

- Low pain (pain severity < 5) n = 6

High pain (pain severity ≥ 5) n = 3

Catastrophizing:

- Low catastrophizing (PCS < 16) n = 4

High catastrophizing (PCS ≥ 16) n = 5

High Pain Severity vs. Low Pain Severity (112 genes)

Up- regulated genes Down- regulated genes

Gene

Symbol

BATF2

Gene Title Function pvalue

Fold-

Change basic leucine zipper transcription factor, ATFlike 2

Protein binding/ protein dimerization activity

0.0002

2.1

CASP5 caspase 5, apoptosisrelated cysteine peptidase

Cyteine-type endopeptidase activity

0.0003

2.7

CCR1 chemokine

(C-C motif) receptor 1

CEACAM1 carcinoembry onic antigenrelated cell adhesion molecule 1

Molecular function, protein binding

0.001

2.4

COMMD6

COMM domain containing 6

C-C chemokine binding, chemokine (C-C motif) activity

0.0004

2.2

NF-kappa-B binding/ protein binding

0.001

4.1

Gene

Symbol

RPL7

SH2D1B

SIGLEC1 sialic acid binding Iglike lectin 1, sialoadhesin

UQCRB

ZCCHC2

Gene Title ribosomal protein L7

SH2 domain containing 1B ubiquinolcytochrome c reductase binding protein zinc finger,

CCHC domain containing 2

Function protein dimerization activity

Immune responses

Carbonydrate binding ubiquinolcytochrome-c reductase activity

Nucleic acid binding pvalue

Fold-

Change

0.02

0.04

0.04

0.05

0.05

-2.9

-2.8

-2.7

-2.6

-2.6

Network Analysis for high pain vs. low pain

High Catastrophizing vs. Low Catastrophizing (63 genes)

Up- regulated genes Down- regulated genes

Gene

Symbol

Gene Title function pvalue

Fold-

Change

SPP1 secreted phosphoprotein 1

Cytokine activity

0.01

2.1

TMTC1 transmembrane and

Integral to tetratricopeptide repeat containing membrane

1

0.02

2.5

SLC6A8 solute carrier family 6

(neurotransmitter transporter activity/ transporter,

Creatine molecular creatine), function member 8

0.03

2.4

NPRL3 nitrogen permease regulator-like 3

(S. cerevisiae)

Molecular function

0.04

2.1

HEMGN hemogen

Protein binding

0.04

2.2

Gene

Symbol

USP46

SEPT10

Gene Title ubiquitin specific peptidase 46 septin 10 function p-value

Fold-

Change

Ubiquitinspecific protease activity

GTP binding

0.001

0.002

-2.2

-2.0

CLEC4D

C-type lectin domain family 4, member D

Carbonydrate binding

0.005

-2.3

ZDHHC2 zinc finger,

DHHC-type containing 2

Zinc ion binding

0.005

-2.2

FAS

Fas (TNF receptor superfamily, member 6)

Identical protein binding/ signal transducer activity

0.010

-2.0

Network Analysis high vs. low catastrophizing

Differentially Expressed Genes of Interest

High vs Low Pain

 Basic leucine zipper protein

(BATF2) is regulated by interferon and serves as a suppressor of activating protein-1

(AP-1).

 Caspase 5, apoptosisrelated cysteine peptidase

(CASP5) and chemokine (C-C motif) receptor 1 (CCR1) are associated with immune response and inflammation in musculoskeletal disorders.

High vs Low Catastrophizing

 Secreted phosphoprotein 1

(SPP1 or Osteopontin) is upregulated during inflammation and associated with muscular dystrophies.

 Ubiquitin specific peptidase

46 (USP46) is a GABA regulation gene. In animal study, deletion of

USP46 is associated with depression-like behaviors in mice and rats.

STRESSOR

Inflammation

Inflammatory Cells: Leukocytes,

Lymphocytes, Platelets, Mast

Cells, Macrophages

CASP5

CCR1

BATF2

SPP1

Cytokines, Nerve Growth factor, prostaglandins,

Thromboxanes,

Leukotrienes, Serotonin

Discussion

Hypothalamic-pituitary-adrenal (HPA) axis

Hypothalamus

Corticotropin releasing factors (CRF)

Anterior pituitary

Pituitary adrenocorticotropin

(ACTH)

Adrenal cortex

Physiological responses:

Pain and fatigue

USP46

Glucocorticoids

Fibromyalgia

Sympathetic nervous system

Adrenal gland:

Medulla

Acetylcholine (Ach) epinephrine norepinephrine

Bloodstream

Lymphoid organs

Behavioral responses:

Catastrophizing, depression

Conclusion of Preliminary Study

Differentially expressed genes may delineate mechanisms between pain and fatigue.

Catastrophizing may serve as a behavioral correlate in FM.

Differentially expressed genes may serve as a biological correlate for catastrophizing.

Acknowledgements

Leorey N. Saligan, PhD, CRNP

Tenure-Track Investigator

National Institute of Nursing Research, Intramural Research Program

Brian Walitt, MD, MPH, FACR

Associate Professor of Medicine

Georgetown University Medical Center

Benjamin Majors, BS

National Institute of Nursing Research, Intramural Research Program

Swarnalatha Reddy, PhD

National Institute of Nursing Research, Intramural Research Program

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