Horvath v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 15-260V

Filed: December 20, 2018

To be Published

*************************************

S.E.H., *

*

Petitioner, *

* Influenza (“flu”) vaccine; mixed

v. * connective tissue disease (“MCTD”);

* failure to provide a persuasive

SECRETARY OF HEALTH * medical theory of causation

AND HUMAN SERVICES, *

*

Respondent. *

*

*************************************

Michael A. Firestone, San Mateo, CA, for petitioner.

Linda S. Renzi, Washington, DC, for respondent.

MILLMAN, Special Master

DECISION1

On March 13, 2015, petitioner filed a petition pro se under the National Childhood

Vaccine Injury Act, 42 U.S.C. § 300aa-10-34 (2012), alleging that influenza (“flu”) vaccine

administered in her left deltoid on September 20, 2012 caused her mixed connective tissue

disease (“MCTD”) whose onset was October 3, 2012 with joint pains. Pet. Preamble and ¶¶ 2, 4;

Pet. Tab 2.

On August 11, 2015, petitioner retained counsel. On January 4, 2016, petitioner filed an

amended petition, alleging in the alternative that her September 20, 2012 flu vaccination caused

significant aggravation of an underlying autoimmune disease that was asymptomatic until early

October 2012. Am. Pet. at ¶ 20.

1

Vaccine Rule 18(b) states that all decisions of the special masters will be made available to the public unless they

contain trade secrets or commercial or financial information that is privileged and confidential, or medical or similar

information whose disclosure would constitute a clearly unwarranted invasion of privacy. This means the decision

will be available to anyone with access to the Internet. When such a decision is filed, petitioner has 14 days to

identify and move to redact such information prior to the document’s enclosure. If the special master, upon review,

agrees that the identified material fits within the banned categories listed above, the special master shall redact such

material from public access. Petitioner filed a motion to redact on December 27, 2018 which the undersigned

granted on December 28, 2018.

A hearing was held on August 29, 2017. Testifying for petitioner were petitioner,

petitioner’s husband, and Dr. S. Sohail Ahmed. Testifying for respondent was Dr. Mehrdad

Matloubian.

On April 27, 2018, petitioner filed her post-hearing brief.

On August 31, 2018, respondent filed his post-hearing brief.

On November 16, 2018, petitioner filed her reply to respondent’s post-hearing brief.

Because the undersigned finds petitioner has failed to present a persuasive scientific or

medical theory to associate causally her September 20, 2012 flu vaccination with MCTD or, in

the alternative, to prove flu vaccine significantly aggravated her prior rheumatologic disease, the

undersigned dismisses this case.

FACTS

Prevaccination Records

Petitioner was born on July 17, 1955.

On October 7, 1999, petitioner received flu vaccine2 in her left deltoid. Med. recs. Ex.

16, at 1.

On February 8, 2000, petitioner saw Dr. Anjali Sagdeo, and gave a history that she

received a flu vaccination in her left arm and, since then, had pain in her left arm and difficulty

raising it.3 Med. recs. Ex. 12, at 1 (same record filed as Ex. 69, at 1). She saw a worker’s

compensation doctor. On physical examination, petitioner had tenderness in her left upper arm

2

In the 1999-2000 flu vaccine season, the trivalent flu vaccine contained A/Sydney/5/97-like virus (H3N2),

A/Beijing/262/95-like virus (H1N1), and B/Beijing/184/93-like (Yamagata lineage) virus. Update: Influenza

Activity – United States and Worldwide, 1998-99 Season, and Composition of the 1999-2000 Influenza Vaccine, 48

MORBIDITY AND MORTALITY WEEKLY REPORT (MMWR) 18:374-78 (May 14, 1999),

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4818a2.htm.

3

Petitioner’s description of left arm pain and difficulty raising her left arm a day after vaccination may have been

SIRVA (shoulder injury related to vaccine administration), which became a Table injury after March 21, 2017.

National Vaccine Injury Compensation Program: Revisions to the Vaccine Injury Table; Delay of Effective Date, 82

Fed. Reg. 34:11321 (Feb. 22, 2017). The Vaccine Injury Table is at 42 C.F.R. § 100.3(a). The Qualifications and

aids to interpretation, § 100.3(c)(10), state “SIRVA manifests as shoulder pain and limited range of motion

occurring after administration of a vaccine intended for intramuscular administration in the upper arm. The

symptoms are thought to occur as a result of unintended injection of vaccine antigen or trauma from the needle into

and around the underlying bursa of the shoulder resulting in an inflammatory reaction. SIRVA is caused by an

injury to the musculoskeletal structures of the shoulders (e.g. tendons, ligaments, bursae, etc.).” One of the

manifestations of SIRVA is “(iii) Pain and reduced range of motion … limited to the shoulder in which the

intramuscular vaccine was administered….” Id. The Vaccine Injury Table requires onset of SIRVA within 48 hours

of vaccination. Id. at (a). Petitioner’s description of her left arm pain and difficulty raising her left arm a day after

vaccination may have been SIRVA.

2

and decreased abduction. Dr. Sagdeo’s diagnosis was tendinitis4 – inflammation secondary to

injury from an intramuscular injection. Petitioner was right-handed. Dr. Sagdeo suggested she

follow up with the worker’s compensation doctor. Id.

On February 29, 2000, petitioner saw Dr. Dinesh N. Bhuva, giving a history that she

received flu vaccine in her left arm in November 1999 and, the next day, had a punched arm.

She could not sleep on the shoulder or abduct her arm. She could not pull up her pants. Her

range of motion declined. The doctor diagnosed petitioner with tendinitis. An examination for

her left shoulder pain revealed tenderness at the supraspinatus5 insertion. X-ray revealed

calcification of the supraspinatus.6 Med. recs. Ex. 69, at 2.

On March 9, 2000, petitioner saw Dr. Sagdeo, to rule out food and alcohol allergies.

Petitioner states her face got red with [the following word was redacted]. This also happened

with certain foods. Dr. Sagdeo referred petitioner to an allergist. He also diagnosed her with

hypothyroidism.7 Med. recs. Ex. 12, at 4 (same record filed as Ex. 69, at 4).

On March 29, 2000, petitioner saw Dr. Bhuva for a recheck of her left shoulder. Id. at 4.

Petitioner’s last injection helped a lot for three weeks, but now her left shoulder hurt again. It

4

Tendinitis is “inflammation of tendons and of tendon-muscle attachments. . . .” DORLAND’S ILLUSTRATED

MEDICAL DICTIONARY 1881 (32nd ed. 2012) [hereinafter “Dorland’s”].

5

Supraspinatus tendinitis or painful arc syndrome occurs in the shoulder. The shoulder joint owes its stability to the

rotator cuff muscles—which are four small muscles located around the shoulder joint which help with movement,

but importantly their tendons stabilize the head of the humerus within the joint capsule. The tendon of one of these

muscles—the supraspinatus--commonly impinges on the acromion (the bone forming the tip of the shoulder) as it

passes between the acromion and the humeral head. The supraspinatus muscles help abduct (lift up sideways) the

arm. Any friction between the tendon and the acromion is normally reduced by the subacromial bursa—a fluid

filled sac between the supraspinatus tendon and the acromion. Arthritis can cause painful arc syndrome.

Supraspinatus tendinitis is very common and typically seen in people aged 25-60. It can also result from gradual

degeneration with wear and tear or other inflammatory disorders, such as rheumatoid arthritis. An x-ray may show

calcification. Chronic trauma and impingement may lead to osteoarthritis of the shoulder. Supraspinatus tendinitis

(painful arc syndrome), MYVMCVIRTUALMEDICALCENTRE, https://www.myvmc.com/diseases/supraspinatus-

tendinitis-painful-arc-syndrome/ (last visited November 26, 2018). The humerus is “the bone that extends from the

shoulder to the elbow.” Dorland’s at 873. “The humeral head is the ‘ball’ part of the ball and socket” making up the

shoulder. Anatomy of the shoulder (glenohumeral joint/scapulo-thoracic joint), MYVMCVIRTUALMEDICALCENTRE,

https://www.myvmc.com/anatomy/anatomy-of-the-shoulder-glenohumeral-jointscapulo-thoracic-joint/ (last visited

November 26, 2018). Painful arc syndrome is “shoulder pain occurring at a particular portion of the arc described

when the arm is abducted from the side to the fully raised position, as in inflammation of the tendons of the

supraspinatus muscle.” Dorland’s at 1842.

6

“Supraspinatus tendon calcification is thought to be due to the deposition of calcium hydroxyapatite crystals inside

the supraspinatus tendon near the greater tuberosity of the humerus insertion point, and the calcium deposits in the

supraspinatus tendon may be due to fibrosis, necrosis, tendon degeneration, or systemic non-degenerative causes.

[citation omitted].” David C. Riley et al., Emergency department diagnosis of supraspinatus tendon calcification

and shoulder impingement syndrome using bedside ultrasonography, 5 CRIT ULTRASOUND J 1-4, at 2-3 (2013).

7

Hypothyroidism is “a deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and

lethargy. . . .” Dorland’s at 907. The most common cause of hypothyroidism is Hashimoto’s thyroiditis or

autoimmune hypothyroidism, but Hashimoto’s is not the sole cause of hypothyroidism. Eren Berber, MD, Causes of

Hypothyroidism. Hashimoto’s thyroiditis is the most common cause, ENDOCRINEWEB,

https://www.endocrineweb.com/conditions/hypothyroidism/causes-hypothyroidism (last visited November 2, 2018).

3

hurt with overhead reaching. Id.

On April 4, 2000, petitioner filled out an Allergy Questionnaire for Dr. Clayton A.

Feldman. Med. recs. Ex. 12, at 1 (same record filed as Ex. 69, at 6). She said she had seasonal

hay fever, food allergy, and drug allergy. She complained of nasal congestion, itchy eyes,

swollen eyelids, dark circles under her eyes, and a sinus headache. Med. recs. Ex. 12, at 1. She

said 20 years previously, she broke out in hives after receiving sulfa. Id. at 8. She told Dr.

Feldman that she had years of sinus problems. Id. at 15. She had been getting erythema8 of the

face, nausea, and headaches in the past year. Id. at 16. Dr. Feldman’s impression was that

petitioner did not have a conventional food allergy, but food intolerances without food allergy.

Id. Her symptoms sounded like a vascular reaction, such as migraine,9 and he recommended she

eliminate foods for which she had no tolerance. Id. at 12-13 (same record filed as Ex. 69, at 16-

17).

On April 7, 2000, Dr. Feldman wrote a consultation report. Med. recs. Ex. 9, at 11.

Petitioner said she had several years of minor sinus and seasonal allergy symptoms. In the past

year, she had some concern about food allergy. She had been getting erythema of her face,

nausea, and headaches from almost any kind of alcoholic beverage. She experimented with red

and white wines, gin and tonic, and beer, and got reactions approximately 20 minutes after each.

She had a similar reaction after a mushroom omelet one month ago, but this occurred only once.

A few weeks earlier, she went on the Atkins diet for weight control, and since then her sinus

headaches disappeared. She ate meat, fish, and limited carbohydrates, and took supplements, but

no fruits, bread, pasta or sugars. She had a history of sulfa sensitivity. She had good relief from

mild seasonal hay fever with antihistamines, Sudafed,10 and topical steroids. Her physical

examination was unremarkable except for slightly thickened red nasal membranes. The RAST11

allergy testing was negative for fruits that she eliminated from her diet, including banana, lemon

apple, orange, peach, strawberry, and melon. Dr. Feldman’s impression was food intolerance

without food allergy, and minimal seasonal and perennial allergic rhinitis. Id. Dr. Feldman

stated petitioner really did not have a conventional food allergy. Her symptoms sounded like a

vascular reaction, something like a migraine. Id. at 11, 13.

On May 3, 2000, petitioner went to Dr. Bhuva for a recheck of her left shoulder. Med.

recs. Ex. 12, at 14 (same record filed as Ex. 69, at 18). She still had pain and could not do her

hair. Id.

8

Erythema is “redness of the skin produced by congestion of the capillaries.” Dorland’s at 643.

9

Migraine is “an often familial symptom complex of periodic attacks of vascular headache, usually temporal and

unilateral in onset, commonly associated with irritability, nausea, vomiting, constipation or diarrhea, and often

photophobia. Attacks are preceded by constriction of the cranial arteries, often with resultant prodromal sensory

(especially ocular) symptoms and the spreading depression of Leão; the migraines themselves commence with the

vasodilation that follows.” Dorland’s at 1166.

10

Sudafed is “trademark for preparations containing pseudoephedrine hydrochloride.” Dorland’s at 1796. It is used

as a nasal decongestant. Id. at 1542.

11

RAST is an acronym for “radioallergosorbent test.” Dorland’s at 1593.

4

On May 15, 2000, petitioner’s TSH12 of 6.16 was consistent with hypothyroidism. Med.

recs. Ex. 9, at 5.

On May 30, 2000, petitioner had an MRI to rule out rotator cuff tear as the cause of her

left shoulder pain. Id. at 9.

On June 2, 2000, petitioner saw Dr. Michael W. Su for migraine headaches. Med. recs.

Ex. 12, at 18. She had migraines triggered by certain foods: smoked foods and almonds. She

thought she had some nausea with photophobia. She also had a urinary tract infection. Id.

On October 31, 2000, petitioner saw Dr. Gary Lee to have her thyroid checked. Med.

recs. Ex. 16, at 24. She told Dr. Lee she felt exhausted over the prior week. Dr. Lee diagnosed

petitioner with hypothyroidism. Id.

On January 24, 2001, petitioner saw Dr. Joel S. Saal for an orthopedic consultation.

Med. recs. Ex. 11, at 1. Petitioner complained of low back pain and right leg hypesthesia.13 The

onset was December 15, 2000 while she was working as a nurse. She was using a slideboard to

help a patient transfer when the patient’s foot caught on the edge of the board and she reached

over to pull it up and support the foot. She went to Urgent Care and received a Demerol14

injection, Vicodin,15 and Flexeril.16 She was prescribed physical therapy twice a week and

placed on work restrictions of no bending, twisting, or lifting. She described no improvement

and each day when she would work, her pain became worse and was not relieved until she lay

down at night. She stopped working for a number of days and her symptoms improved

somewhat but still persisted and increased with any bending, lifting, or sitting for prolonged

periods of time. Petitioner was taking Flexeril and Naprosyn.17 Id. Dr. Saal diagnosed

petitioner with probable annulus18 tear, L4-L5 vs. L5-S1. Id. at 2. He suggested she supplant the

anti-inflammatory medicine with exercises. Id.

12

TSH stands for “thyroid-stimulating hormone.” Dorland’s at 1902.

13

Hypesthesia or hypoesthesia is “a dysesthesia consisting of abnormally decreased sensitivity, particularly to

touch.” Dorland’s at 901.

14

Demerol is “trademark for preparations of meperidine hydrochloride.” Dorland’s at 485. Meperidine

hydrochloride is “a synthetic opioid analgesic, used as an analgesic to relieve moderate to severe pain. . . .” Id. at

1136.

15

Vicodin is “trademark for combination preparations of hydrocodone bitartrate and acetaminophen.” Dorland’s at

2055. Hydrocodone is “a semisynthetic opioid analgesic derived from codeine but having more powerful sedative

and analgesic effects.” Id. at 878.

16

Flexeril is “trademark for a preparation of cyclobenzaprine hydrochloride.” Dorland’s at 717. Cyclobenzaprine

hydrochloride is “a compound structurally related to the tricyclic antidepressants, used as a skeletal muscle relaxant

for relief of painful muscle spasms. . . .” Id. at 455.

17

Naprosyn is “trademark for preparations of naproxen.” Dorland’s at 1232. Naproxen is “a nonsteroidal anti-

inflammatory drug that is a propionic acid derivative, used in the treatment of pain, inflammation, osteoarthritis,

rheumatoid arthritis, gout, calcium pyrophosphate deposition disease, fever, and dysmenorrhea and in the

prophylaxis and suppression of vascular headache. . . .” Id.

18

Annulus is “a ring or ringlike structure. . . .” Dorland’s at 94.

5

On April 3, 2001, Dr. Saal performed a lumbar transforaminal19 selective epidural block,

in the left L5 position. Id. at 5.

On April 23, 2001, petitioner returned to Dr. Saal. Id. at 7. She had marked relief for a

short period of time following the epidural injection, but no significant change in her symptoms.

Her MRI showed only minor degenerative changes at L4-L5 with a slight annular bulge, but no

evidence of significant abnormality. Dr. Saal’s impression was probable discogenic pain, most

likely from the L4-L5 segment. Id. He suggested petitioner change where she received physical

therapy or, if that were unsuccessful, have a repeat epidural injection. In addition, he wanted

petitioner to start acupuncture. Id.

On July 26, 2001, petitioner saw Dr. Su, complaining of coughing for one month. Med.

recs. Ex. 16, at 26.

On September 21, 2001, Dr. Saal performed a lumbar intradiscal electrothermal

annuloplasty (“IDET”) on petitioner. Med. recs. Ex. 11, at 17.

On September 25, 2001, petitioner saw Dr. Harley B. Negin, complaining of headache,

and palpitations for months. Med. recs. Ex. 69, at 29.

On October 18, 2001, Dr. Saal reevaluated petitioner. Med. recs. Ex. 11, at 20. She had

no further leg pain after her IDET, but her back pain was the same. Id.

On November 29, 2001, Dr. Saal reevaluated petitioner. Id. at 21. She said she felt about

30 percent better. She had difficulty with long standing. Dr. Saal recommended a pool program.

Id. She was to remain on temporary total disability through January 30, 2002. Id.

On January 3, 2002, Dr. Saal reevaluated petitioner. Id. at 22. She was markedly

improved but still significantly symptomatic and limited. Her abdominal muscles were

extremely weak. Dr. Saal recommended progression in her physical rehabilitation program. She

was to remain on temporary total disability through March 30, 2002. Id.

On January 29, 2002, petitioner saw Dr. Su, complaining of problems with her back.

Med. recs. Ex. 69, at 30. She was continuing to undergo therapy for her back. Id.

On February 28, 2002, Dr. Saal reevaluated petitioner. Med. recs. Ex. 11, at 24. She was

improving somewhat from her flare up. The symptoms were unchanged, mostly in her back.

She took Prednisone20 and then went on Vioxx. Her physical examination showed painful

lumbar flexion and extension. Dr. Saal prescribed acupuncture and extended her total temporary

disability through April 20, 2002. Id.

19

Transforaminal is “through or across a foramen.” Dorland’s at 1952. Foramen is “a natural opening or passage,

especially one into or through a bone.” Id. at 729.

20

Prednisone is “a synthetic glucocorticoid derived from cortisone, administered orally as an anti-inflammatory and

immunosuppressant in a wide variety of disorders.” Dorland’s at 1509.

6

On April 24, 2002, Dr. Saal reevaluated petitioner. Id. at 25. She described persistent

symptoms: pressure in her low back and some symptoms in her right leg. Overall, she described

herself as 50-60 percent improved. Dr. Saal injected Marcaine21 and Decadron22 into the soft

tissue region in the right L5-S1 interspace because it was tender. Id. This decreased petitioner’s

leg pain but had no effect on the pressure sensation in her low back. Id.

On June 27, 2002, Dr. Saal reevaluated petitioner. Id. at 26. Petitioner said she was

progressively improving. She had daily symptoms, but could tolerate them. Id. She remained

on total temporary disability through August 30, 2002. Id.

On July 11, 2002, Dr. Saal gave petitioner soft tissue injections with Marcaine, Depo-

Medrol,23 and Decadron after she complained about a slight increase in symptoms when she

reduced her dosage of Vioxx. Id. at 27, 28. Her disability status remained unchanged. Id. at 27.

On August 20, 2002, Dr. Saal reevaluated petitioner. She said she did not get a good

response from the intramuscular and deep paraspinal soft tissue injections, and did not receive

lasting relief from corticosteroids. Id. at 29. Her symptoms were now back to her baseline. She

tolerated the increased level of exercise from three months ago. Dr. Saal hoped to increase her

exercise tolerance and if that did not succeed, move toward a lumbar epidural. Id.

On October 15, 2002, Dr. Saal reevaluated petitioner. Id.at 30. Petitioner said she had a

little flare up of ankle pain and secondarily back pain, worse on the right than on the left. It

occurred while she was exercising more aggressively using the treadmill and doing squatting

exercises. It was similar to what she experienced at the early onset of her low back pain

syndrome. She was concerned that this was extremity referral pain from the lumbar spine. On

physical examination, however, she had some swelling in the retro-Achilles bursa and there was

marked tenderness over this on the right greater than on the left. Dr. Saal’s impression was that

her extremity pain was secondary to pre-Achilles bursitis and her back pain flare up was due to

increasing stress from her exercises. Dr. Saal’s plan was to carry out an intensive and focused

rehabilitation program. Petitioner remained on temporary total disability until November 30,

2002. Id.

21

Marcaine is “trademark for preparations of bupivacaine hydrochloride.” Dorland’s at 1105. Bupivacaine

hydrochloride is “a homologue of mepivacaine, chemically related to lidocaine, used as a local anesthetic for

infiltration, peripheral nerve block, retrobulbar block, subarachnoid block, sympathetic block, and caudal and

epidural anesthesia.” Id. at 261.

22

Decadron is “trademark for a preparation of dexamethasone.” Dorland’s at 474. Dexamethasone is “a synthetic

glucocorticoid, 25 times as potent as cortisol: used topically on the skin and conjunctiva as an anti-inflammatory and

administered orally in replacement therapy for adrenocortical insufficiency, as an anti-inflammatory and

immunosuppressant in a wide variety of disorders, and as an antiemetic in cancer chemotherapy.” Id. at 504.

23

Depo-Medrol is “trademark for preparations of methyl-prednisolone acetate.” Dorland’s at 492. Methyl-

prednisolone is “a synthetic glucocorticoid derived from progesterone, used in replacement therapy for

adrenocortical insufficiency and as an anti-inflammatory and immunosuppressant in a wide variety of disorders.”

Id. at 1154.

7

On November 7, 2002, Dr. Saal reevaluated petitioner. Id. at 31. Petitioner’s low back

had a slight flare up from doing some hamstring strengthening exercise, but overall she was

doing fairly well. Her ankle was significantly better although somewhat symptomatic after a

local injection. Dr. Saal recommended orthotics and strengthening exercises. Petitioner

remained on temporary total disability through December 30, 2002. Id.

On January 6, 2003, petitioner filled out a medical history for a chiropractor K. Robyn

Kubo-Manley at Willow Chiropractic, stating she had the following medical history: neck pain,

pain in her arms and legs, thyroid problems, and a lower back injury since 2000. Med. recs. Ex.

15, at 16.

On January 7, 2003, Dr. Saal reevaluated petitioner. Med. recs. Ex. 11, at 32. Petitioner

said her symptoms persisted. Her exercise tolerance had improved, but she had a persistent

limitation and inability to carry out any hip or leg extension. This caused increased back pain.

She described a 50 percent reduction in symptom level. Dr. Saal pondered the etiology of

petitioner’s persistent low back pain and thought it could be residual discogenic pain at the L5-

S1 vs. posterior element pain. He thought diagnostic therapeutic facet blocks were indicated.

Petitioner remained on full temporary disability through March 3, 2003. Id.

On January 9, 2003, petitioner saw Dr. Su, complaining of continuing problems with her

back. Med. recs. Ex. 12, at 29 (filed also as Ex. 69, at 33).

On January 28, 2003, petitioner had an MRI of her lumbar spine, to be compared to one

done March 23, 2001 which had revealed mild disc disease at the L3-L4 and L5-S1 disc levels

without evidence for herniation or transligamentous disc extrusion. Med. recs. Ex. 11, at 33. Dr.

Murray A. Solomon’s findings were there were no significant interval changes from the previous

MRI. There was mild disc disease at the L4-L5 and L5-S1 disc levels without evidence for large

herniation or transligamentous disc extrusion at either level. Id.

On February 7, 2003, petitioner saw Dr. Saal and told him she had a flare up with back

pain centrally and bilaterally from doing scissor kicks in the pool. Id. at 23. Dr. Saal increased

her Vioxx.24 Id.

On February 11, 2003, petitioner saw Dr. Su, stating that Zoloft helped her somewhat and

elevated her mood to some degree. She had an underactive thyroid. Dr. Su increased

petitioner’s dosage of Synthroid.25 Med. recs. Ex. 69, at 34.

On February 13, 2003, petitioner saw Dr. Saal complaining of low back pain. Med. recs.

24

Vioxx is “trademark for a preparation of rofecoxib.” Dorland’s at 2057. Rofecoxib is “a nonsteroidal anti-

inflammatory drug of the COX-2 inhibitors groups, used in treatment of osteoarthritis, acute pain, and

dysmenorrhea. . . .” Id. at 1652.

25

Synthroid is “trademark for a preparation of levothyroxine sodium.” Dorland’s at 1856. Levothyroxine sodium is

“the monosodium salt of L-thyroxine, the naturally occurring form of thyroxine, obtained from the thyroid gland of

domesticated food animals or prepared synthetically. It is used as replacement therapy for hypothyroidism and in

the prophylaxis and treatment of goiter and of thyroid carcinoma. . . .” Id. at 1032.

8

Ex. 11, at 35. Dr. Saal writes that her MRI scan showed no significant change compared to the

one in 2001. She had degenerative changes only at L5-S1, which had not progressed. However,

she had significant facet degenerative changes at those levels. On physical examination,

petitioner had painful extension, worse on the right than on the left as well as in the center. Dr.

Saal planned to carry out lumbar facet injections. Petitioner remained on temporary total

disability through April 30, 2003. Id.

On March 7, 2003, Dr. Saal performed a lumbar intra-articular facet block on the right

and left of L4-L5 and L5-S1. Id. at 36.

On April 3, 2003, Dr. Saal reevaluated petitioner. Id. at 39. Petitioner said she was 30

percent improved. She had marked dramatic improvement the day of the facet blocks which

lasted approximately six hours following the anesthetic injection. This strongly suggested to Dr.

Saal that facet symptoms and facet irritation played a role in generating her present pain. He

proposed advancement in physical rehabilitation. Petitioner remained on temporary total

disability through May 30, 2003. Id.

On April 24, 2003, Dr. Saal reevaluated petitioner. Id. at 40. She reported that her

marked improvement in back pain and increased exercise tolerance had begun to wear off and

she was approximately 40 percent worse than the best she had felt after the facet injections. Her

symptoms were localized across her lower back and increased with extension, which was limited

approximately 80 percent that day. Dr. Saal’s impression was that petitioner had facet-related

pain and would benefit from a median branch rhizotomy26 if median branch diagnostic blocks

were helpful. Id.

On May 23, 2003, Dr. Saal performed lumbar median nerve root blocks on the right and

left of L3, L4, and L5. Id. at 41.

On June 19, 2003, Dr. Saal reevaluated petitioner. Id. at 43. Despite her marked relief in

the corticosteroid and anesthetic phases with an intra-articular facet block, she had no or minimal

response during the anesthetic phase of the median branch block. Dr. Saal considered whether

petitioner had relative intolerance to local anesthetics since this was a low dose and volume vs. a

non-discrete facet source of her symptoms. He considered this somewhat paradoxical. His

recommendation was to repeat the median branch block with both short- and long-acting

anesthetic and with a slightly higher volume, being careful of nonspecific spread. If the block

were negative again, then petitioner was not a candidate for facet rhizotomy. However, she

could be a candidate for further discogenic treatment considering her partially significant

improvement, which was inadequate for carrying out full and usual work. Id.

On October 14, 2003, Dr. Saal performed lumbar intra-articular facet blocks on the right

and left of L4-L5 and L5-S1. Id. at 44.

On November 13, 2003, Dr. Saal reevaluated petitioner. Id. at 47. Petitioner was

26

Rhizotomy is “interruption of a cranial or spinal nerve root. . . .” Dorland’s at 1641.

9

significantly improved from where she first started but was still limited compared to normal.

She could carry out light housework and cook dinner and eat it, but she still could not do any

heavy housework, repetitive bending, stooping or lifting. Her symptoms remained in her low

back. On physical examination, she had limited lumbar extension by 50 percent and limited

forward flexion by 50 percent. Dr. Saal’s impression was that internal disc disruption and

discogenic pain were the persistent source of her symptoms. He recommended she live with

what she had or do a repeat discography. He prescribed a Lidoderm27 patch. Id. Petitioner

remained on temporary total disability through December 30, 2003. It was clear that she would

not be able to return to her full and usual job duties as a nurse. Id.

On January 8, 2004, Dr. Saal reevaluated petitioner. Id. at 48. Dr. Saal suggested a

lumbar discography to determine if the L4-L5 disc were painful or if the problem were the L5-S1

level. If that fails, she would be a candidate for a disc replacement or lumbar interbody fusion.

He prescribed four treatments of acupuncture. Petitioner was on temporary total disability

through March 1, 2004. Id.

On February 26, 2004, Dr. Saal reevaluated petitioner. Id. at 49. She reported continued

symptoms. Dr. Saal’s impression was internal disc disruption. Petitioner would continue on

temporary total disability through March 30, 2004. Id.

On March 25, 2004, petitioner saw Dr. Saal to discuss her course to date. Id. at 50. She

was somewhat worse and less functional. Dr. Saal thought petitioner was a candidate for either

disc replacement or fusion. Id. Petitioner was on temporary total disability through May 30,

2004. Id.

On May 6, 2004, Dr. Saal reevaluated petitioner. Id. at 51. She was still waiting for a

surgical consultation. Lumbar flexion on physical examination was 60 percent of normal.

Lumbar extension was 20 percent of normal. Bilateral side bending was guarded at 75 percent of

normal. Dr. Saal’s impression was internal disc disruption at multiple levels. Petitioner was

released to modified duties of no lifting greater than 10 pounds, a required posture change every

30 minutes, and no pushing or pulling greater than 50 pounds. Id.

On June 22, 2004, Dr. Saal saw petitioner for a long discussion after her consultation

with Dr. Hsu. Id. at 52. Dr. Hsu recommended she have lumbar discography to determine what

levels are painful and if there were a disc that could be treated with an IDET and if so to carry

that out. If that procedure failed, she was a candidate for lumbar disc replacement surgery.

Petitioner continued to have functionally limiting, impairing discogenic pain. Low back pain

daily limited her ability to sit, stand, walk, or do any lifting or carrying. She remained on

temporary total disability through August 1, 2004. Id.

On December 23, 2004, Dr. Saal wrote what he called his final report. Id. at 53.

27

Lidoderm is “trademark for a preparation of lidocaine.” Dorland’s at 1034. Lidocaine is “a drug having

anesthetic, sedative, analgesic, anticonvulsant, and cardiac depressant activities, used as a local anesthetic, applied

topically to the skin and mucous membranes.” Id.

10

Petitioner decided against aggressive surgery. Id. Petitioner described constant minimal to

slight pain that became moderate with prolonged sitting of longer than 20 to 30 minutes, standing

in one spot for longer than 15 minutes, or doing repetitive bending, stooping, or heavy lifting.

Id. at 54. Rest and ice offered relief as did anti-inflammatory medication. Physical examination

showed a 25 percent decrease in lumbar forward flexion and a 50 percent decrease in lumbar

extension. She had full bilateral lateral side bending. She could carry out her duties as a nurse if

accommodations were made for postural changes and she was precluding from heavy lifting and

repetitive bending. Id.

On February 3, 2005, Dr. Saal reevaluated petitioner. Id. at 56. She decided she did not

want to live with her back condition and needed to do something else. Dr. Saal’s impression was

discogenic pain. Petitioner was ready to undergo surgery. Id.

On March 24, 2005, Dr. Saal reevaluated petitioner. Id. at 57. She reported her

symptoms unchanged. Id. He recommended another IDET. Id. at 58.

On June 7, 2005, Dr. Saal reevaluated petitioner. Id. at 61. Her symptoms were

unchanged. He recommended a lumbar discography. Id. Petitioner was to be off work until

August 10, 2005. Id. at 62.

On August 9, 2005, Dr. Saal reevaluated petitioner. Id. at 63. She continued to complain

of functionally limiting low back pain. A recent MRI of her bilateral ankles showed evidence of

adhesion of the peritendinous sheath around the Achilles tendon with a recommendation of

treatment with saline by Dr. Fred Orcutt or potentially surgery. Dr. Saal recommended

discography. Id. Petitioner was off work until October 1, 2005. Id. at 64.

On September 20, 2005, Dr. Saal reevaluated petitioner. Id. at 65. Her symptoms

remained the same. She still had sitting and bending pain and had difficulty carrying out

intensive therapeutic exercises because of a flare up of her symptoms. He recommended she

return to modified duty with no lifting greater than 25 pounds and no repetitive bending,

stooping, or twisting. She required postural changes every 30 minutes. She could push only 100

pounds and pull only 50 pounds. Id.

On December 13, 2005, Dr. Saal reevaluated petitioner. Id. at 67. She reported her

symptoms were somewhat worse. They were in her low back and bilateral heels. A new MRI

scan did not show significant abnormalities. She had undergone a number of laboratory tests so

that Dr. Orcutt28 could exclude the possibility that she had rheumatic disease or multiple

myeloma.29 She had a loss of thigh circumference. Id. Petitioner was to be off work until

28

The undersigned cannot find any records from Dr. Orcutt filed in this case. On November 5, 2018, the

undersigned ordered petitioner to file them, but petitioner filed a status report on November 15, 2018, stating that

Dr. Fred Orcutt, an orthopedic surgeon, retired and all reports from 2010 and earlier were unavailable. Petitioner

filed exhibit 120, a statement from the medical group to which Dr. Orcutt previously belonged, to that effect.

29

Multiple myeloma is “a disseminated type of plasma cell dyscrasia characterized by multiple bone marrow tumor

foci and secretion of an M component, associated with widespread osteolytic lesions resulting in bone pain,

pathologic fractures, hypercalcemia, and normochromic normocytic anemia. . . .” Dorland’s at 1219.

11

January 30, 2006. Id. at 68.

On February 9, 2006, Dr. Saal reevaluated petitioner. Id. at 69. She reported a marked

increase in the level of pain in her legs, worse in the past two weeks. She had difficulty sleeping

at night. She underwent a new MRI scan and an EMG study. On physical examination, positive

straight leg raising on both sides at 60 degrees caused leg and back pain. Dr. Saal’s impression

was referred pain into the lower extremities related to a degenerative painful disc that has disc

disruption/annulus tear at L5-S1. Id. Petitioner was to be off work until April 1, 2006. Id. at 70.

On March 9, 2006, Dr. Saal reevaluated petitioner. Id. at 71. She had improvement in

her leg pain with use of Lyrica.30 Id.

On March 29, 2006, petitioner noted neck and arm pain intermittently with numbness in

her right hand three fingers (3rd, 4th, and 5th digits) since 2003. Med. recs. Ex. 15, at 18. She

had had neck and arm pain for six months. Id. at 15.

On March 30, 2006, Dr. Saal reevaluated petitioner. Med. recs. Ex. 11, at 72. Her

symptoms remained the same. She was on total temporary disability through May 5, 2006. Id.

On April 25, 2006, Dr. Saal reevaluated petitioner. Id. at 73. She continued to complain

of the same symptoms. She went off Lyrica because of weight gain. She had returned to work

with no lifting greater than 20 pounds, no pushing or pulling greater than 40 pounds and only

occasional bending, no climbing, and no prolonged standing. Postural changes were required

every thirty minutes. Id.

On April 3, 2007, Dr. Saal reevaluated petitioner. Id. at 75. Petitioner said she had made

a 75-80 plus percent improvement. She could tolerate sitting and standing for hours. Her back

pain was less intense. Dr. Saal opined she could return to her full and usual work duties. Id.

On November 21, 2007, petitioner complained of left shoulder pain that had been

bothering her for 2-3 months. Med. recs. Ex. 14, at 49. It was not getting better despite

chiropractic treatment, upper body strengthening, anti-inflammatories, and swimming two to

four times a week. On physical examination, petitioner was tender anteriorly overlying the

biceps tendon. The doctor sent petitioner to another doctor for an injection. Id.

On March 3, 2008, petitioner saw Dr. Mary Regan at Samaritan Family Practice,

complaining of one month of aching in her fingers and thumbs bilaterally and head and chest

congestion for three days. Id. at 45. Petitioner needed a work note since she missed the last

several days due to cold/flu. Petitioner was seeing a chiropractor but that seemed to be making

her worse. Petitioner had intermittent pain on her right side. Dr. Regan questioned whether

30

Lyrica is “trademark for a preparation of pregabalin.” Dorland’s at 1088. Pregabalin is “a derivative of ƴ-

aminobutyric acid (GABA) having anticonvulsant and antinociceptive effects, used in the treatment of neuropathic

pain in diabetic neuropathy and postherpetic neuralgia. . . .” Id. at 1509. “Antinociceptive” means “blocking or

reducing sensitivity to painful stimuli. . . .” Id. at 108.

12

petitioner’s fingers were slightly swollen. She noted that petitioner had a family history of

rheumatoid arthritis in her grandmother. Id. Petitioner’s physical examination was

unremarkable except for mild nasal congestion. Dr. Regan diagnosed petitioner with upper

respiratory infection, cervical pain, and hand pain. She referred petitioner for testing to see if she

had a positive ANA31 and rheumatoid factor (“RF”).32 Id. Petitioner had a positive ANA of

1:160. Id. at 20. Dr. Regan noted petitioner might have a rheumatic disorder, discussed this with

petitioner, and referred her to a rheumatologist.33 Id.

On that same date, March 3, 2008, Dr. Keith Fraker did x-rays on petitioner’s cervical

spine for persistent neck pain. Id. at 2. Petitioner had degenerative change at the C5-C6 level

with anterior and posterior spurring and disc space narrowing. C6 and C7 appeared to be fused,

which Dr. Fraker assumed to be a congenital anomaly. He noted degenerative changes over the

facet joints and joints of Luschka.34 There might be some neural foraminal encroachment at the

C5 level, especially on the right. He noted calcification within the ligamentum nuchae and some

reversal of the normal cervical curve. Id.

On March 5, 2008, petitioner’s erythrocyte sedimentation rate (“ESR”)35 was normal, her

rheumatoid factor serum was negative, but her antinuclear antibody (“ANA”) was positive at

1:160 with a homogeneous pattern.36 Id. at 20.

31

Antinuclear antibodies (ANA) are “antibodies directed against nuclear antigens; ones against a variety of different

antigens are almost invariably found in systemic lupus erythematosus and are frequently found in rheumatoid

arthritis, scleroderma (systemic sclerosis), Sjögren syndrome, and mixed connective tissue disease. Antinuclear

antibodies may be detected by immunofluorescent staining. Serologic tests are also used to determine antibody

titers against specific antigens.” Dorland’s at 101.

32

Rheumatoid factor (“RF”) are “antibodies directed against antigenic determinants, i.e., Gm, in the Fc region of the

IgG class of immunoglobulins; these are found in the serum of about 80 percent of persons with classical or definite

rheumatoid arthritis, but only about 20 percent of those with juvenile rheumatoid arthritis. Rheumatoid factors may

be of the IgM, IgG, or IgA classes of immunoglobulins, although serologic tests measure only IgM. Rheumatoid

factors also occur in other connective tissue diseases and infectious diseases, such as Sjögren syndrome, systemic

lupus erythematosus, sarcoidosis, subacute bacterial endocarditis, hepatitis A, and leprosy.” Dorland’s at 676.

33

The undersigned cannot find any rheumatology records from 2008. In an Order dated November 5, 2018, the

undersigned ordered petitioner to file them, but petitioner filed a status report on November 15, 2018, stating the

rheumatologist, Dr. Carter V. Multz of the Arthritis Care Center in San Jose, was dead. Petitioner filed as exhibit

119 an obituary of Dr. Multz, stating his date of death was August 7, 2013.

34

Joints of Luschka are “a series of jointlike structures at the lateral edges of the vertebral bodies from vertebra C3

to T1, forming small spurlike lips at the upper surface, covered with cartilage, and containing a capsule filled with

fluid. They are considered by some to be true diarthrodial joints, and by others to be degenerative spaces of the

intervertebral disks filled with extracellular fluid and lined by a membrane formed by fibrocytes. They are frequent

sites of spur formation. Called also uncovertebral j’s.” Dorland’s at 973.

35

Erythrocyte sedimentation rate (“ESR”) is “the rate at which erythrocytes precipitate out from a well-mixed

specimen of venous blood, measured by the distance the top of the column of erythrocytes falls in a given time

interval under specified conditions; an increase in rate is usually due to elevated levels of plasma proteins, especially

fibrinogen and immunoglobulins, which decrease the zeta potential on erythrocytes by dielectric shielding and thus

promote rouleau formation. It is increased in monoclonal gammopathy, hypergammaglobulinemia due to

inflammatory disease, hyperfibrinogenemia, active inflammatory disease, and anemia.” Dorland’s at 1594. Rouleau

formation is “the aggregation of erythrocytes in structures resembling piles of coins, caused by adhesion of their flat

surfaces.” Id. at 733.

36

“ANAs are used to diagnose systemic lupus erythematosus (SLE) and other autoimmune diseases.” Kathleen D.

13

On March 12, 2008, petitioner saw MR (presumably “Mary Regan”) at Samaritan Family

Practice, complaining that her head and ear congestion persisted. Id. at 44. Petitioner said she

could not “shake this cold.” Id. Dr. Regan diagnosed petitioner with sinusitis and prescribed

Augmentin.37 Id.

On May 20, 2009, Dr. Saal reevaluated petitioner. Med. recs. Ex. 11, at 77. Petitioner

was taking Cymbalta38 and discontinued Zoloft.39 She lived a full and active lifestyle. Id.

On September 22, 2009, petitioner saw a doctor (“TK”) at Samaritan Family Practice,

stating she fell in the lobby of a Las Vegas hotel on September 18, 2009 and landed on her right

hip and right elbow and arm. Med. recs. Ex. 14, at 37. She had a stiff neck and lower back with

slight numbness in her arms and legs, but no weakness. The doctor diagnosed cervical and

lumbar strain, recommended rest, ice, and heat, and referred petitioner for physical therapy. Id.

On October 14, 2009, petitioner received flu vaccine40 in her left deltoid from Dr.

Joceliza G. Chaudhary at Samaritan Family Practice. Id. at 35. This occurred during petitioner’s

office visit for a urinary tract infection and allergic rhinitis. Id. at 36. Petitioner did not have a

reaction to the October 14, 2009 flu vaccination.

On November 20, 2009, petitioner saw a doctor (“MR” presumably Mary Regan) at

Samaritan Family Practice, complaining of a sore throat and bilateral ear pain for three days, and

99.4 degree temperature two hours previously. Id. at 34. One week earlier, she developed body

Pagana & Timothy J. Pagana, MOSBY’S MANUAL OF DIAGNOSTIC AND LABORATORY TESTS, ch. 2, at 80 (6th ed.

2018). ANA has fluorescent patterns in cells. Id. at 82. “Different patterns are associated with a variety of

autoimmune disorders.” Id. MOSBY’S states a positive ANA with a homogeneous pattern is associated with SLE

and MCTD. Id. It also says that a positive ANA with a speckled pattern is associated with SLE, scleroderma, RA,

MCTD, Sjögren syndrome, and polymyositis (“PM”). Id. As for anti-RNP antibodies, they are associated with

MCTD, SLE, and progressive systemic sclerosis (scleroderma). Id. at 81. MCTD is associated with ANA, anti-

RNP antibodies, RF, and ssDNA. Id. Petitioner tested negative in 2008 and 2012 for RF. Petitioner tested negative

in 2012 for ssDNA.

37

Augmentin is “trademark for combination preparations of amoxicillin and clavulanate potassium.” Dorland’s at

179. Amoxicillin is “a semisynthetic derivative of ampicillin effective against a broad spectrum of gram-positive

and gram-negative bacteria; used especially in the treatment of infections due to susceptible strains of Haemophilus

influenzae, Escherichia coli, Proteus mirabilis, Neisseria gonorrhoeae, streptococci (including Streptococcus

faecalis and S. pneumonia), and nonpenicillinase-producing staphylococci.” Id. at 65.

38

Cymbalta is “trademark for a preparation of duloxetine hydrochloride.” Dorland’s at 457. Duloxetine

hydrochloride is “a serotonin-norepinephrine reuptake inhibitor, used for the treatment of major depressive disorder

and the relief of pain in diabetic neuropathy. . . .” Id. at 572.

39

Zoloft is “trademark for preparations of sertraline hydrochloride.” Dorland’s at 2092. Sertraline hydrochloride is

“a selective serotonin reuptake inhibitor, used to treat depressive, obsessive-compulsive, and panic disorders. . . .”

Id. at 1699.

40

In the 2009-2010 flu season, the trivalent flu vaccine contained A/Brisbane/59/2007-like virus (H1N1),

A/Brisbane/10/2007-like virus (H3N2), and B/Brisbane/60/2008-like virus (B/Victoria lineage). Update: Influenza

Activity – United States, September 28, 2008—April 4, 2009, and Composition of the 2009—10 Influenza Vaccine,

58 MORBIDITY AND MORTALITY WEEKLY REPORT (MMWR) 14:369-74 (April 17, 2009),

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5814a4.htm.

14

aches, and fever which resolved in 3-4 days. Three days earlier, she developed sinus pain with

discharge, sore throat, and hoarseness. She wanted Vicodin for sleep. Dr. Regan diagnosed

petitioner with an upper respiratory infection and pharyngitis. She prescribed Vicodin. Id.

On March 11, 2010, petitioner saw a doctor (“JH”) at Samaritan Family Practice,

complaining of hot flashes and sweating. Id. at 29. She stated she was ready to stop smoking.

She wanted to stop taking Cymbalta, which she had taken for back pain which had now resolved.

On January 20, 2011, petitioner saw a doctor (“TK”) at Samaritan Family Practice to

evaluate her thyroid. Id. at 28. She had been fatigued for 1-2 months. She had had right

shoulder pain and trouble lifting her arm for 2-3 months. She had trouble sleeping on her right

side. She requested physical therapy and the doctor referred her for it. Id.

On March 17, 2011, petitioner saw a doctor at Samaritan Family Practice, complaining of

foot and shoulder pain. Med. recs. Ex. 14, at 27. She needed a referral for physical therapy

again. She did not go to physical therapy when referred before and the last referral expired. Her

palpitations resolved and she discontinued Sudafed. The doctor diagnosed petitioner with right

foot pain, right shoulder strain, hypothyroidism, and neuropathy. Id.

On April 8, 2011, petitioner saw a doctor (“TH”) at Samaritan Family Practice because

she had a rash on her stomach since the day before and a burning sensation. Id. at 26. The

doctor diagnosed dermatitis, probably due to sitting in a hot tub while wearing an old swimsuit.

Id.

On June 15, 2011, petitioner saw a doctor (“TK”) at Samaritan Family Practice for two

reasons: (1) she had sliced her pinkie finger the prior evening, and (2) her right shoulder had

been painful for nine months. Id. at 25.

On January 26, 2012, petitioner saw Dr. Jing Qing Xu as a new patient. Med. recs. Ex. 3,

at 1. Dr. Xu was at Kaiser Permanente Medical Group in San Jose, CA. Id. Petitioner had

chronic pain syndrome and shoulder joint pain. Dr. Xu prescribed Cymbalta for chronic pain

syndrome. Id. at 3. Petitioner had chronic left shoulder pain. Id. Petitioner was on

levothyroxine for hypothyroidism, Benicar,41 and Cymbalta. Id.

On March 16, 2012, Dr. Xu called petitioner. Id. at 20. She said over the prior three to

four days, she had been feeling acid reflux, burped a lot, and felt something stuck in her

esophagus. She had been taking ranitidine.42 Dr. Xu diagnosed petitioner with GERD43 and

prescribed Omeprazole,44 told her to avoid citrus, and advised walking and stress reduction. Id.

41

Benicar is “trademark for a preparation of olmesartan medoxomil.” Dorland’s at 208. Olmesartan medoxomil is

“a selective angiotensin receptor antagonist used as an antihypertensive . . . .” Id. at 1319.

42

Ranitidine is “a histamine H2 receptor antagonist, which inhibits gastric secretion.” Dorland’s at 1592.

43

GERD is “gastroesophageal reflux disease.” Dorland’s at 772.

44

Omeprazole is “a proton pump inhibitor used in the treatment of dyspepsia, gastroesophageal reflux disease, and

gastric hypersecretory conditions. . . .” Dorland’s at 1319.

15

On August 13, 2012, petitioner saw Dr. Xu, telling Dr. Xu that she had pain in her left

arm and right shoulder intermittently for a long time. Id. at 33. Dr. Xu diagnosed petitioner with

impingement syndrome of the shoulder. Id. In Dr. Xu’s progress notes, the doctor says that

petitioner has complained of pain intermittently in both shoulders. Id. at 34. Petitioner had

positive kiss elbow signs. Id. Petitioner worked as a registered nurse at the Intensive Care Unit,

pushing carts around. Dr. Xu’s diagnosis was impingement syndrome of the shoulders. Id.

Postvaccination Records

On September 20, 2012, petitioner received flu vaccine45 in her left deltoid. Med. recs.

Ex. 16, at 2.

On October 3, 2012, petitioner saw Dr. Xu complaining of still having pain in her joints,

knees, hands, and lower back, but her shoulder pain was improving. Med. recs. Ex. 3, at 37. Dr.

Xu diagnosed petitioner with chronic sinusitis and osteoarthritis of the hand. Id. at 36. Both her

hands had slight swelling. Id. at 37. Cyclic citrullinated peptide (“CCP”)46 for rheumatoid

arthritis was negative at 5 (being less than 20). Id. at 40. RF factor was negative at 10.3

(reference range less than 14.0). Id. C-reactive protein (“CRP”)47 was negative at 0.4 (reference

range less than 0.5). Id. at 41. Petitioner’s Nuclear AB Panel testing on October 3, 2012 (Ex. 3,

at 41) was negative for all of the following: dsDNA antibody48; Sjögrens49-A (anti-SS-A)

antibody and –B (anti-SS-B) antibody; Smith IgG; chromatin (nucleosomal) antibody;

ribosomal P antibody; centromere antibody; Sm antibody+RNP antibody; Scl-70 antibody; and

Jo-1 antibody. Id. Her RNP antibody was positive at 1.2 (when the normal result is less than

1.0). Id.

On October 15, 2012, petitioner had a positive ANA of 2+ with homogeneous staining

45

In the 2012-2013 flu season, the trivalent flu vaccine contained A/California/7/2009-like virus (pH1N1),

A/Victoria/361/2011-like virus (H3N2), and B/Wisconsin/1/2010-like virus (B/Yamagata lineage). Update:

Influenza Activity – United States, 2011-12 Season and Composition of the 2012-13 Influenza Vaccine, 61

MORBIDITY AND MORTALITY WEEKLY REPORT (MMWR) 22:414-20 (June 8, 2012),

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6122a4.htm. The “p” before the “H” (hemagglutinin) stands

for “pandemic.” Robert P. de Vries et al., Evolution of the Hemagglutinin Protein of the New Pandemic H1N1

Influenza Virus: Maintaining Optimal Receptor Binding by Compensatory Substitutions, 87 J VIROL 24: 13868-877,

13868 (2013).

46

Cyclic citrullinated peptide (“CCP”) is “a synthetic, citrulline-containing peptide with a cyclic structure, used in

assays for rheumatoid arthritis; the presence of antibodies to this peptide is highly specific for rheumatoid arthritis.”

Dorland’s at 1408.

47

C-reactive protein (“CRP”) is “a globulin that forms a precipitate with the somatic C-polysaccharide of the

pneumococcus in vitro; it is the most predominant of the acute phase proteins.” Dorland’s at 1532.

48

Anti-dsDNA antibody is “a type of antinuclear antibody specific for double-stranded DNA, found in the serum of

patients with systemic lupus erythematosus.” Dorland’s at 100.

49

Sjögren syndrome is “a symptom complex of unknown etiology, usually occurring in middle-aged or older

women, marked by the triad of keratoconjunctivitis sicca with or without lacrimal gland enlargement, xerostomia

with or without salivary gland enlargement, and the presence of a connective tissue disease, usually rheumatoid

arthritis but sometimes systemic lupus erythematosus, scleroderma, or polymyositis. An abnormal immune response

has been implicated.” Dorland’s at 1848.

16

and a titer of 1:320. Id. at 45. Her ESR was normal. Id. at 46.

On October 31, 2012, petitioner saw Dr. Jan Jingyang Lin, a rheumatologist, complaining

of joint pain in her hands, knees, and toes with prolonged morning stiffness for many months.50

(This would place onset of petitioner’s pain and prolonged morning stiffness before the flu

vaccination which was just six weeks earlier than petitioner’s October 31, 2012 visit to Dr. Lin.)

Med. recs. Ex. 13, at 96-99. Dr. Lin was at Kaiser Permanente Medical Group in San Jose, CA.

Med. recs. Ex. 3, at 48. Petitioner had a history of redness of face and nasal bridge and chin, dry

eyes and mouth, and extreme fatigue. On physical examination, she had bilateral proximal-

interphalangeal (“PIP”) and metacarpal-phalangeal (“MCP”) joint tenderness, ulnar deviation,

and bilateral knee tenderness. Dr. Lin’s diagnosis was MCTD.51 She started petitioner on

hydroxychloroquine52 and prednisone. Id. at 47-64. Dr. Lin tested petitioner for cardiolipin

antibody53 and for lupus anticoagulant, both of which were negative. Id. at 62. However,

petitioner’s cardiolipin IgG was 28, which was high since the normal range is 1-14, and her

cardiolipin IgM was 15, which was also high since the normal range is 1-11. Id. at 63. Dr. Lin

had petitioner undergo chest x-rays to look for interstitial lung disease, and the result was

normal. Id. at 64. Her ESR and CRP on October 31, 2012 were normal. Id. at 58, 59.

Petitioner’s C3 and C4 complement levels were normal. Id. at 60.

On January 7, 2013, petitioner saw Dr. Lin. Her joint symptoms had resolved on

steroids, but returned while she was on hydroxychloroquine. She complained of muscle pains.

Her joint tenderness remained. She mentioned her joints were swollen. Dr. Lin prescribed

methotrexate (“MTX”).54 Id. at 67-70.

50

Subsequently, on June 19, 2015, two years and seven and one-half months after October 31, 2012, Dr. Lin

“corrected” this history at the urging of petitioner by writing a request on June 7, 2015 that Dr. Lin change the onset

date of her joint pains to “several weeks.” Med. recs. Ex. 10, at 1. But on June 19, 2015, Dr. Lin changed the onset

of petitioner’s joint pains not to “several weeks” but to “two months since August 2012.” Med. recs. Ex. 108, at 11.

This still placed onset before the September 20, 2012 flu vaccination. On January 5, 2016, three years and two

months after petitioner saw Dr. Lin on October, 31, 2012, Dr. Lin “corrected” this initial history a second time at the

urging of petitioner to reflect an onset of “four weeks since the end of September 2012.” Med. recs. Ex. 108, at 11.

Now, the onset was after the September 20, 2012 flu vaccination.

51

Mixed connective tissue disease (“MCTD”) is “a disorder combining features of scleroderma, myositis, systemic

lupus erythematosus, and rheumatoid arthritis, and marked serologically by the presence of antibody against

extractable nuclear antigen.” Dorland’s at 539.

52

The trademark for hydroxychloroquine sulfate is Plaquenil. Dorland’s at 1456. Hydroxychloroquine sulfate is “a

4-aminoquinoline compound with antiprotozoal and anti-inflammatory properties, used for suppression and

treatment of malaria, for suppression of lupus erythematosus, and as an anti-inflammatory disease-modifying

antirheumatic drug in treatment of rheumatoid arthritis. . . .” Id. at 881.

53

Anticardiolipin antibody is “an antibody directed against cardiolipin, seen with increased frequency in systemic

lupus erythematosus; its presence correlates with increased risk for thrombotic events.” Dorland’s at 100.

54

Methotrexate (“MTX”) is “a folic acid antagonist that acts by inhibiting synthesis of DNA, RNA, thymidylate,

and protein; used as an antineoplastic in treatment of a wide variety of malignancies, including acute lymphocytic,

meningeal, and acute myelocytic leukemia; gestational choriocarcinoma; chorioadenoma destruens; hydatidiform

mole; carcinoma of the breast, lung, and head and neck; non-Hodgkin lymphomas; mycosis fungoides; and

osteosarcoma. . . . It is also used as an antipsoriatic and antiarthritic in the treatment of severe, recalcitrant,

disabling psoriasis and severe rheumatoid and psoriatic arthritis.” Dorland’s at 1151.

17

On March 4, 2013, petitioner saw Dr. Lin. On physical examination, petitioner had

swollen joints. Dr. Lin increased petitioner’s dosage of MTX and tapered her steroids. Id. at 74-

83. Dr. Lin rechecked petitioner’s ESR and CRP on March 4, 2013. They were normal. Id. at

80. Dr. Lin also rechecked petitioner’s cardiolipin IgG and IgM on March 4, 2013 and they were

both normal. Id. at 82-83.

On May 14, 2013, petitioner’s CRP was slightly elevated at 0.7 when the normal range is

at or below 0.5. Id. at 87. Her ESR was still normal. Id. Petitioner’s C4 complement was high

at 45.6 when the normal range is 10.0 to 40.0. Id. at 88. Petitioner’s C3 complement was also

high at 202 when the normal range is 83 to 180. Id. at 89.

On May 15, 2013, petitioner saw NP Cynthia A. Liu, in gynecology. Id. at 90. Petitioner

told NP Liu that she had been diagnosed with RA, lupus, and Sjögren’s. Id. at 91. She

complained of chronic pain mostly in her knees and hands, but stated “everything hurts.” Id.

She complained of frequent hot flashes and sweating. Id. NP Liu noted petitioner had been

diagnosed with GERD on March 16, 2012. Id. at 93.

On May 17, 2013, petitioner saw Dr. Lin. Petitioner complained of pain in her PIP and

MCP joints with swelling. She had skin thickness on her fingers resembling sclerodactyly.55 Dr.

Lin prescribed tumor necrosis factor (“TNF”)-inhibitor therapy for her inflammation

(etanercept).56 Id. at 98-101.

On May 30, 2013, petitioner saw Dr. Yuhjung John Tsai, an allergist, who noted she had

an allergic reaction to flu vaccinations in 1999 and 2012. Id. at 107, 109. Dr. Tsai was at Kaiser

Permanente Medical Group at San Jose, CA. After petitioner’s flu vaccination on October 7,

2009,57 she had a large bruise and mass on her shoulder extending down the left arm with

development of frozen shoulder the following week. Id. at 107. She started having migraines

afterwards. In six months, her symptoms improved and she did not have any more migraines.

She did not receive any more flu vaccinations until the county medical director indicated in

August 2012 the importance of receiving flu vaccine. After her 2012 flu vaccination, in October,

she developed weakness and shortness of breath with no previous history of rheumatoid

conditions. She saw a rheumatologist Dr. Lin who diagnosed MCTD. Id. She told Dr. Tsai that

she had quit smoking one month earlier, or April 2013. Id. at 109. Dr. Tsai advised petitioner to

55

Sclerodactyly is “localized scleroderma of the digits, as in acrosclerosis.” Dorland’s at 1679. Acrosclerosis is “a

type of systemic scleroderma of the hands and feet, especially the digits (sclerodactyly), as well as the face and

neck, in combination with Raynaud phenomenon.” Id. at 21. Raynaud phenomenon is “intermittent bilateral

ischemia of the fingers, toes, and sometimes ears and nose, with severe pallor and often paresthesias and pain,

usually brought on by cold or emotional stimuli and relieved by heat; it is usually due to an underlying disease or

anatomical abnormality.” Id. at 1430.

56

Etanercept is “a soluble tumor necrosis factor receptor that inactivates tumor necrosis factor, used in the treatment

of rheumatoid arthritis and juvenile idiopathic arthritis. . . .” Dorland’s at 650.

57

Dr. Tsai initially wrote petitioner received flu vaccine in 2009, but corrected this to 1999 in an addendum dated

June 26, 2015. Med. recs. Ex. 108, at 27. He made this change at the request of petitioner. Med. recs. Ex. 13, at

212. Petitioner’s medical records show that she had left supraspinatus tendinitis after the flu vaccine she received

in her left arm on October 7, 1999. Med. recs. Ex. 69 at 1, 2, 4. She did not however have a reaction to the flu

vaccine she received in her left arm on October 14, 2009. Med. recs. Ex. 14, at 35.

18

avoid all flu vaccinations. Id. at 110. He noted she did not have any history to suggest

immunodeficiency. Id. Dr. Tsai wrote petitioner’s symptoms were delayed and not

characteristic of an IgE-mediated drug reaction. Id.

On July 12, 2013, petitioner saw MA Carmen Santana with swelling in her knuckles. Id.

at 112.

On August 7, 2014, petitioner’s ESR and CRP were normal. Id. at 119. Her C4

complement and C3 complement were normal. Id. at 120-21.

On August 19, 2013, petitioner saw Dr. Lin. Since she started etanercept, her joint

symptoms were better. She complained of hair loss. On physical examination, petitioner had

tender finger joints and knees, swelling in one PIP joint, synovitis in the left third PIP joint, and

skin thickening of her fingers. Dr. Lin told petitioner to stop taking MTX due to hair loss, start

Leflunomide58 (anti-rheumatic drug), and use Voltaren59 cream (anti-inflammatory). Id. at 125-

28. Dr. Lin noted petitioner did not have Raynaud’s phenomenon.60 Id. at 125.

On October 31, 2013, petitioner’s ESR and CRP were normal. Id. at 130-31. Her C4

complement and C3 complement were also normal. Id. at 132,

On November 25, 2013, petitioner saw Dr. Anna Graziella Barbara because of snoring.

Id. at 141. Petitioner said she was often tired during the day and had to take a nap. Id. Dr.

Barbara suggested petitioner take a sleep study to rule out obstructive sleep apnea. Id. at 143.

On January 6, 2014, petitioner saw Dr. Lin. Her joint tenderness continued but not the

swelling since she started etanercept. She had ulnar deviation which was noted before since

October 31, 2012. Dr. Lin had petitioner taper her steroids, and considered switching DMARD

(disease-modifying antirheumatic drug) treatment to abatacept61 or tocilizumab.62 Id. at 141-55.

Dr. Lin was not seeing any synovitis.63 Id. at 149. Petitioner wanted Dr. Lin to sign a statement

58

Leflunomide is “an immunomodulator that inhibits pyrimidine synthesis, used as a disease-modifying

antirheumatic drug in treatment of rheumatoid arthritis. . . .” Dorland’s at 1017.

59

Voltaren is “trademark for preparations of diclofenac sodium.” Dorland’s at 2070. Diclofenac is “a nonsteroidal

anti-inflammatory drug derived from phenylacetic acid.” Id. at 513. Diclofenac sodium is “the sodium salt of

diclofenac . . . in the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis and also for a

variety of nonrheumatic inflammatory conditions.” Id.

60

Raynaud phenomenon is “intermittent bilateral ischemia of the fingers, toes, and sometimes ears and nose, with

severe pallor and often paresthesias and pain, usually brought on by cold or emotional stimuli and relieved by heat;

it is usually due to an underlying disease or anatomical abnormality. When it is idiopathic or primary it is called

Raynaud disease.” Dorland’s at 1430; see also 542.

61

Abatacept is “a synthetic fusion protein produced by recombinant technology, comprising the extracellular

domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to a portion of human

immunoglobulin G1 (IgG1), which acts as an inhibitor of T-cell activation; used in the treatment of moderate to

severe rheumatoid arthritis unresponsive to other medications, administered intravenously.” Dorland’s at 1.

62

Tocilizumab is trademark for Actemra. https://www.actemra.com/ra/consider-actemra/actemra-works-

differently.html (last visited October 19, 2018). It blocks the action of a protein called interleukin-6 (IL-6). Id.

63

Synovitis is “inflammation of a synovium; it is usually painful, particularly on motion, and is characterized by a

19

for petitioner to extend her disability which Dr. Lin did. Id. Petitioner was on modified work

from February 1, 2014 to December 31, 2014. Id. at 150. On January 6, 2014, petitioner’s ESR

and CSP were normal. Id. at 151-52. Her C4 complement and C3 complement were normal. Id.

at 153.

On March 27, 2014, petitioner’s ESR and CRP were normal. Id. at 158. Her C4

complement and C3 complement were also normal. Id. at 160.

On March 28, 2014, petitioner saw Dr. Lin to extend her disability. Id. at 162-63.

Petitioner’s joints were tender but not swollen. Dr. Lin noted again her ulnar deviation and

sclerodactyly. Petitioner did not have Raynaud’s phenomenon. Dr. Lin told petitioner to stop

taking etanercept and switch to abatacept because she was concerned petitioner had a lupus

component to MCTD. Id. at 163-66.

On April 8, 2014, petitioner had x-rays to rule out interstitial disease. Id. at 176. The

results were normal. Id.

On June 12, 2014, Dr. Lin switched petitioner to leflunomide. Id. at 180-82. On June 12,

2014, petitioner’s ESR and CRP were normal. Id. at 180.

On September 25, 2014, petitioner’s ESR and CRP were normal. Id. at 184. Her C4

complement and C3 complement were also normal. Id. at 186.

On November 19, 2014, petitioner saw Dr. Lin who started her on tocilizumab. Id. at

190-94. In the range of systems, Dr. Lin noted petitioner did not have sclerodactyly or

Raynaud’s phenomenon. Id. at 192. Yet in her assessment and plan, Dr. Lin wrote petitioner

had arthritis and Raynaud’s phenomenon currently. Id. at 194.

On December 8, 2014, petitioner saw Dr. Golara Honari, a dermatologist, for

telangiectasia64 and subtle erythema on her cheeks and nose, sparing the bridge of her nose, with

keratotic65 papules on the sides of her face. Dr. Honari diagnosed petitioner with rosacea66 and

keratosis pilaris67 rubra faceii. Med. recs. Ex. 13, at 409-11.

On June 7, 2015, petitioner wrote to Kaiser Permanente San Jose Medical Center

requesting a correction of her records. Petitioner did not file this request, but did file the

response from Kareem Olateju, Compliance Consultant, Corporate Compliance Department,

Kaiser Permanente San Jose Medical Center, dated June 29, 2015. Med. recs. Ex. 10, at 1. This

fluctuating swelling due to effusion within a synovial sac.” Dorland’s at 1856.

64

Telangiectasia is “permanent dilation of preexisting small blood vessels (Capillaries, arterioles, venules) to form

focal, discolored lesions, usually in the skin or mucous membranes.” Dorland’s at 1878.

65

Keratosis is “any horny growth. . . .” Dorland’s at 982.

66

Rosacea is “a chronic skin disease, usually involving the middle third of the face, characterized by persistent

erythema and often by telangiectasia with acute episodes of edema, papules, and pustules. . . .” Dorland’s at 1654.

67

Keratosis pilaris is “a common, benign condition in which hyperkeratosis occurs around hair follicles, usually on

the extensor surfaces of the thighs and arms, but sometimes elsewhere. . . .” Dorland’s at 982.

20

was after petitioner filed her petition pro se on March 13, 2015, but before she retained counsel

on August 11, 2015. The letter from Kareem Olateju in response to petitioner states as follows:

AMENDMENT REQUEST:

That Dr. Yuhjung J. Tsai should amend your medical record to

state that the Mixed Connective Tissue Disease you developed was

a result of the flu shot you received and also to amend the date of a

flu shot that you received from 10/7/2009 to 10/7/1999. You also

requested from Dr. Jan J. Lin to correct her statement in your

medical record regarding the duration of a condition you

experienced to “several weeks.”

RESPONSE: Dr. Tsai reviewed your request including your

medical record and denied your request regarding the cause of

the Mixed Connective Tissue Disease but agreed to change the

date you had a flu shot as requested. Dr. Lin also reviewed your

request including your medical record and agreed with your

request to change the duration of your condition to “several

weeks.” [emphasis added.]

On June 10, 2015, petitioner saw Dr. Xu, complaining of foot numbness for two months.

Dr. Xu diagnosed peripheral neuropathy. Id. at 587-91.

On June 19, 2015, Dr. Lin “corrected” her records as to onset of petitioner’s developing

symmetric joint pains of bilateral hands, knees, and toes, associated with prolonged morning

stiffness for two months since August 2012. Med. recs. Ex. 108, at 11. (In the original record

of Dr. Lin dated October 31, 2012, five weeks after flu vaccination, she wrote the onset of

petitioner’s symmetric joint pains of bilateral hands, knees, and toes, associated with prolonged

morning stiffness was many months. Med. recs. Ex. 8, at 48.)

On January 5, 2016, Dr. Lin again “corrected” her records as to onset of petitioner’s

developing symmetric joint pains of bilateral hands, knees, and toes, associated with prolonged

morning stiffness for four weeks since the end of September 2012. Med. recs. Ex. 108, at 11.

Also on January 5, 2016, petitioner saw Dr. Lin for a medical visit. Med. recs. Ex. 10, at

1. Petitioner still had a lot of pain in the PIPs associated with tightness of her fingers and a lot of

stiffness in her fingers and knees. Id. Petitioner did not have Raynaud’s phenomenon. Id. Dr.

Lin diagnosed petitioner with MCTD, and decided to raise her Actemra dose. Id. at 5. (These

records are also filed as Exhibit 86, at 9-14.)

In a letter dated January 19, 2016 to Kaiser Permanente, petitioner’s subject was

“Corrections to Errors in My Medical Records.” Med. recs. Ex. 112, at 1. She writes:

21

As a result of research that I have done to support my vaccine

compensation program claim (National Vaccine Injury

Compensation Program Claim No. 15-260V) I have become aware

of several errors in my medical records. It is important that that

[sic] these errors are corrected, not only for the purpose of the

claim but also to set the record straight regarding my past and

current health status.

1. On page 48 of my medical records (Exhibit 3 of the vaccine

claim) it is stated: Sandra E. Horvath is a 57 Y female with

family h/o Hashimoto’s, sister has Sjogren’s, taking mTX [sic],

developed symmetric joint pains of b hands, knees and toes,

associated with prolonged morning stiffness for many months.

The words “many months” are not correct [.] [T]hey do not

accurately describe the onset of my symptoms, and they are

misleading with regard to my medical condition at that time.

The symptoms pertaining to joint pain in my hands and knees

along with fatigue came to my attention in the later September,

2012 timeframe. This is why I made the appointment with my

primary care physician, Dr. Jing Qing Xu on October 3, 2012.

2. On page 51 of my medical records it states:

Note: she has Sjogren’s and could [sic] lupus, RA; but on page

41 the lab test for “Sjogren’s –A AB Ser” is noted to be a

negative value. Because of that the statement on page 51 that I

have Sjogren’s [sic] incorrect [.]

3. On page 107 of my medical records it states that I received a

flu shot on August 7, 2012 and my symptoms began in October

of 2012. This statement is not correct [.] I did receive a flu

shot on September 20, 2012 and I have produced the consent

form stating that to my doctors on several occasions. The

symptoms began in late September as stated in #1 above.

Please make these corrections as soon as possible, and please

ensure that they are [sic] accurately reflect what is written above.

On July 28, 2016, petitioner saw Dr. Lin. Med. recs. Ex. 86, at 173. Dr. Lin diagnosed

petitioner with MCTD and said that her right hand was very suspicious for early presentation of

scleroderma.68 Id. at 177. She also had sicca. Id.

Scleroderma is “chronic hardening and thickening of the skin, a finding in various different diseases. . . .”

68

Dorland’s at 1679.

22

On August 3, 2016, petitioner saw Dr. Richard A. Lau, a rheumatologist, for a second

opinion. Id. at 196. Dr. Lau was at Kaiser Permanente Medical Group at Santa Clara, CA. Id.

Petitioner reported that her symptoms began in 2012 possibly after a flu vaccination with

arthralgia/myalgia diffusely throughout her body. Id. at 197. Dr. Lau’s impression was

“possible overlap syndrome, even MCTD as her RNP was positive (though no titer)” or could be

“possible” undifferentiated connective tissue disease (“UCTD”) as petitioner did not quite meet

criteria for any specific CTD such as SSc or SLE with the exception of RA. Id. at 198. He wrote

that petitioner had several concrete signs and symptoms suggestive of rheumatologic illness

including arthralgia/myalgia (with synovitis on examination), Raynaud’s phenomenon,

heartburn, and scattered telangiectasia. She also had some other signs and symptoms that were

more speculative such as tightening of the skin of her fingers with edematous changes which

could be early signs of sclerodactyly and the recurrent oral ulcerations when she stopped taking

MTX. Id.

On July 13, 2017, petitioner saw Dr. Lin. Med. recs. Ex. 91, at 1. Petitioner had been

taking Mobic69 for joint pains. Id. at 2. She writes under “allergies” that petitioner is allergic to

flu vaccine. Id. at 3. She continues to diagnose her with MCTD and notes that petitioner had an

abnormal nailfold capillary exam, a finding consistent in patients with Raynaud’s phenomenon

or scleroderma. Petitioner did not have significant synovitis. Id. at 6.

On August 3, 2017, petitioner saw Dr. Neelakshi Patel for a second opinion at Dr. Lin’s

request. (Actually, this was petitioner’s third rheumatology evaluation since she saw Dr. Lau at

Kaiser for a second rheumatology opinion). Med. recs. Ex. 102, at 2. The exhibit cover page

and the medical record do not identify Dr. Patel as working at a hospital. The undersigned

looked Dr. Patel up on the internet and found she is in private practice in San Jose and Los

Gatos, CA.70

Petitioner gave Dr. Patel a history that she was in her usual state of health when she

received a vaccine in 2012. Id. Two weeks later, she could not walk for two weeks. She started

to have pain and stiffness in symmetrical joints of her hands, knees, and toes. Sometimes, her

fingers were swollen. She found it hard to close her hand into a tight fist and had significant

morning stiffness. She is on IV Actemra monthly. At present, she feels that one week prior to

infusion, her symptoms return. Physicians at UCSF reviewed her file but did not see her. They

thought she does not have MCTD. She wondered about her diagnosis and presented to Dr. Patel.

Petitioner has dry eyes and mouth and occasional oral ulcers. She has ongoing fatigue which is

worse the week before infusion. She was off work from 2002-2005 because of a back injury. Id.

On physical examination, petitioner had unremarkable bilateral upper and lower extremities with

69

Mobic is “trademark for a preparation of meloxicam.” Dorland’s at 1171. Meloxicam is “a nonsteroidal anti-

inflammatory drug used in the treatment of osteoarthritis. . . .” Id. at 1126.

70

Dr. Patel received her medical degree from Netaji Subhas Chandra Bose Medical College, Jabalpur, India, had an

internship in internal medicine at the University of Massachusetts, had a fellowship in rheumatology at the

University of California, Irvine, CA, and had a residency in internal medicine at Kaiser Permanente Medical Group.

She is board-certified in rheumatology. She is affiliated with O’Connor Hospital, El Camino Hospital, and Good

Samaritan Hospital, all in San Jose, CA. US NEWS & WORLD REPORT, https://health.usnews.com/doctors/neelakshi-

patel-854330 (last visited September 24, 2018).

23

full range of motion and no deformities, synovitis, or pain with range of motion except for tender

and mildly prominent PIP joints. Id. at 4. All of petitioner’s fingers had mild, diffuse puffiness

and slightly thickened skin, but still had elasticity. Petitioner had mild erythema on her checks

and the bridge of her nose. She had a positive ANA of 1:320 in a homogeneous pattern and a

positive RNP. Dr. Patel reviewed petitioner’s capillaroscopy71 photos which showed dilated

capillary loops and tortuous loops. Dr. Patel noted that unfortunately she did not have access to

all of petitioner’s records. Id. Dr. Patel diagnosed petitioner with CTD, stating she certainly has

Raynaud’s phenomenon, mild early sclerodactyly, heart burn, malar erythema, and a positive

ANA. Dr. Patel did not see active synovitis, but she also noted that petitioner was taking the

drugs meloxicam, hydroxychloroquine, and Actemra, which likely were controlling her

symptoms. Id. In addition, she might have a component of seronegative RA, such as

inflammatory arthropathy. Id. at 4-5. Dr. Patel wrote that the only way to determine if

petitioner has RA was for her to stop taking Actemra and see if she has an inflammatory flare.

Id. at 5.

On November 15, 2017, petitioner returned to Dr. Lin. Med. recs. Ex. 113, at 5.

Petitioner came to Dr. Lin to have nailfold capillary pictures taken. Id. at 6. She saw the

rheumatologists Dr. Lau and Dr. Patel who concurred with the connective tissue disease

diagnosis. But she needed the capillary pictures to show the UCSF rheumatologist who had

never seen or examined her, but denied she has a connective tissue disease condition. Id. Dr.

Lin diagnosed petitioner with MCTD and scheduled petitioner for a pulmonary function test and

labs in three months. Id. at 9. If her arthritis symptoms became worse, she would consider doing

hand x-rays to rule out erosions. Petitioner was to continue on Plaquenil and Actemra.

Petitioner’s friend took photos of her nailfolds and petitioner was going to mail them to Dr. Lin

to put in her file. Id.

Other Material

On May 30 2013, petitioner’s Dr. Tsai filled out a VAERS Report, stating petitioner

received flu vaccine on August 17, 2012 (this is an incorrect date; the correct date is September

20, 2012), developed weakness several weeks later, and was diagnosed with MCTD several

months later. Ex. 68, at 1.

Affidavits

On August 28, 2015, petitioner filed her first affidavit. Ex. 7. She said onset of pain and

stiffness in her knees, hands, and lower back occurred within two weeks of her September 20,

2012 flu vaccination. Id. at ¶¶ 3 and 4. A few weeks later, she had extreme exhaustion. Id. at ¶¶

5, 6. She retired on July 1, 2014 because of her symptoms. Id. at ¶ 22.

On August 28, 2015, petitioner filed her husband’s affidavit, which was consistent with

the information in his wife’s affidavit. Ex. 8.

71

Capillaroscopy is “diagnostic examination of the capillaries with the microscope.” Dorland’s at 283.

24

On July 21, 2017, petitioner filed her supplemental affidavit, discussing her course of

disease and her nailfold capillary microscopy. Ex. 92.

On July 21, 2017, petitioner filed her husband’s supplemental affidavit. Ex. 93.

On January 26, 2018, petitioner filed an affidavit concerning nailfold capillaroscopy

images she provided to Dr. Lin. Ex. 114.

Medical Experts’ CVs

Dr. S. Sohail Ahmed

Petitioner filed an updated CV for Dr. Ahmed on August 1, 2017. Ex. 95. Dr. Ahmed

was an MD Anderson Cancer Center Research Fellow in immunology, researching the role of

NK cells in murine melanoma in 1992. Id. at 4. He attended The University of Texas Medical

School, Houston, TX, in 1993, receiving an M.D. in 1998. Id. at 5. During his time in medical

school, he had an Alpha Omega Alpha research scholarship in 1996 to do HLA genotyping in

rheumatoid arthritis. Id. at 4. That same year, he was a Sarnoff Cardiovascular Fellow to study

the role of cellular actin and myosin in ventricular hypertrophy induced by aortic banding. Id.

Dr. Ahmed did an internal medicine residency at The University of Texas Medical

School, from 1998-2000. Id. at 5. He was a Sarnoff Cardiovascular Scholar to study vascular

disease development in scleroderma in 2000. Id. at 4. He was a Sarnoff Cardiovascular Scholar

at The University of Texas Medical School, from 2000-2002. Id. at 5. During that time, he was

a Wyeth–Ayers Rheumatology Fellow in 2001. Id. at 4. He also won a clinical investigator

fellowship award from the Merck/American College of Rheumatology in 2002 and a Fellow

Award from the Merck/American College of Rheumatology in 2002. Id. He was a clinical

investigator at The University of Texas Medical School from 1998-2004. Id. at 5. During this

time period, he was first author of a medical article relating that a certain subgroup of patients

with RA had an increase in rheumatoid nodulosis that the drug MTX they were taking for RA

had induced.72 Dr. Ahmed was a rheumatology fellow at The University of Texas Medical

School from 2002-2003. Id. at 4. In 2003, he was a top finalist in the Amgen Rheumatology

Young Investigator proceeding. Id.

From 2003-2004, Dr. Ahmed was an Assistant Professor of Medicine in the Division of

Rheumatology at The University of Texas Medical School. Id. From 2004-2006, he was an

attending physician at the Veterans Administration Hospital in West Roxbury, MA, and at

Boston University Medical Center. Id. at 3. From July 2004 to September 2006, he was

Assistant Professor of Medicine at the Department of Medicine section of rheumatology at

Boston University School of Medicine, becoming Clinical Assistant Professor of Medicine there

from September 2006 – May 2007. Id. From 2006-2007, he received a grant from the

72

S. Sohail Ahmed et al., The HLA-DRB1*0401 Allele and the Development of Methotrexate-Induced Accelerated

Rheumatoid Nodulosis: A Follow-Up Study of 79 Caucasian Patients with Rheumatoid Arthritis, 80 MEDICINE

4:271-78 (2001). Listed on Dr. Ahmed’s updated CV. Ex. 95 at 6.

25

Scleroderma Foundation to be principal investigator of vascular disease and fibrosis in patients

with systemic sclerosis. Id. at 4. From August 2007 to June 2008, Dr. Ahmed was a clinical

associate in the Division of Rheumatology, Allergy, and Immunology at Harvard Medical

School/Massachusetts General Hospital. Id. at 3.

From September 2006 to March 2008, Dr. Ahmed was a translational medicine expert at

Novartis Pharma, Cambridge, MA. Id. He led the clinical development of novel compounds

from Discovery (e.g., next generation follow-up to Gilenya) and mature compounds (e.g.,

Glivec) targeted for clinical profiling related to autoimmunity and inflammation. Dr. Ahmed

managed a matrix-based team involving representatives from drug metabolism and

pharmacokinetics, drug chemistry, research, toxicology, marketing, and clinical development to

support design and implementation of proof-of-concept (“PoC”) studies. He developed an

approach incorporating modeling and simulations for the design of studies targeting

immunosuppression and fibrotic pathways. He leveraged parallel collaborations with the

Genomics Institute of the Novartis Research Foundation for the identification of human

therapeutics (e.g., biologics) and their application to various autoimmune diseases. He was a

clinical expert for in-licensing opportunities. Id.

From March 2008 to January 2011, Dr. Ahmed was head of the Clinical Science Unit,

Translational Medicine, at Novartis Vaccines, Siena, Italy. Id. He directed an adjuvant safety

initiative to enable an approach that was rational for preclinical studies using novel adjuvants

such as toll-like receptor agonists to lessen safety risks in subsequent clinical trials. Id. Dr.

Ahmed managed a team that was responsible for designing and implementing an exploratory

trial of cell-mediated immunity from flu vaccination. He provided cross-functional support to

the clinical development personnel in response to regulatory authorities on safety topics of

autoimmune diseases associated with vaccination. He also led the design of clinical studies to

reach PoC rapidly for Group A streptococcus and respiratory syncytial virus vaccines. Id.

From January 2011 to March 2015, Dr. Ahmed was Global Head of Clinical Sciences, at

Novartis Vaccines, Siena, Italy. Id. at 2. He was Executive Manager. He was also chairman of

a steering committee to develop antibody repertoire signatures that would predict natural, rapid

recovery to guide future vaccine antigen discovery efforts or the design of clinical trials with

patient groups most likely to respond to vaccine candidates in clinical development. He also led

cross-functional teams working on staphylococcus aureus, influenza, or candida infections to

ensure “seamless” application of this next-generation approach to vaccine development. Id. Dr.

Ahmed managed the recruitment of applicants for World Health Organization-TDR Clinical and

Development Fellowships to develop human resources promoting high-quality clinical research

and development and enhancing capacity on diagnostics, drugs, and vaccines for infectious

diseases that disproportionately affect poor and marginalized populations. Id. at 2-3. He led a

cross-functional team to prioritize populations to be targeted with vaccines containing novel

adjuvants such as TLR-agonists and pushed efforts to mitigate potential safety risks with a novel

vaccine delivery platform of lipid nanoparticle self-amplifying RNA, e.g., anti-RNA antibodies

and autoimmune disease risk. Id. at 3. Dr. Ahmed guided project leaders in principles of

medicine and human infectious diseases to ensure preclinical studies aligned with subsequent

26

human target populations in vaccine clinical trials concerning clostridium difficile, nontypeable

haemophilus influenza, and Escherichia coli. Id. He led the design of clinical trials and

implemented exploratory studies to generate quick no/no go decisions that upper management

made concerning subsequent product development with staphylococcus aureus and candida

albicans. He managed a diverse matrix-based team involving clinical development, toxicology,

technical development, vaccine chemistry, research/clinical serology, and regulation. Id.

From May to December 2015, he was global head of clinical sciences at GSK

(GlaxoSmithKline) Vaccines, which acquired Novartis Vaccines in May 2015. Id. at 2. He was

Executive Manager. He had the same responsibilities he had at Novartis Vaccines plus he

managed an internal approach capitalizing on information technologies, e.g., health map which

Harvard Medical School developed, in order to provide rapid surveillance for Neisseria

meningitides disease activity and transmission in patients. Id. He led a two-tear global

collaboration with 21 scientists and physicians from Novartis Vaccines, Novartis Pharma AG,

Novartis Institutes of Biomedical Research, Atreca Inc., VisMederi Sri, Stanford University,

Harvard Medical School, Dalhousie University, University of Siena, and the National Institute of

Health and Welfare in Finland to: (1) reinforce the safety of emulsion adjuvants, e.g., MF59 and

AS03; and (2) dissect the molecular pathway responsible for narcolepsy associated with the

AS03-adjuvanted A (H1N1) pdm09 influenza vaccine. Id. Dr. Ahmed supervised a post-

graduate course entitled “From Bench to Bedside: Principles of Vaccine Research &

Development,” covering principles of pre-clinical design and assessment of antigens, adjuvants,

and formulation testing through the different phases of clinical evaluation, and elements of

management and licensure. Id. He managed an internal cross-matrix team and external

collaboration with a U.S. academic medical center to: (1) identify a correlate of protection for

staphylococcus aureus by applying proteomic analysis to clinical sera from healthy subjects that

are colonized compared to patients with infection; and (2) identify differences in antibody

profiles from patients with various types of staphylococcus aureus infections, e.g., soft-tissue,

joint, pulmonary, or blood infections, to enable selection of a patient subgroup most likely to

support vaccine efficacy in clinical development trials. Id.

From April 2016 to the present, Dr. Ahmed has been at Translational Medicine, Roche

Pharma AG, Basel, Switzerland, involved in immunology, inflammation, and infectious diseases,

and leading cross-functional global teams to bring effective therapies for autoimmune diseases

from the discovery phase to phase III clinical studies. Id.

Dr. Ahmed received an MBA at IE Business School, Madrid, Spain, in 2017. Id. at 5.

He is licensed to practice medicine in Italy and the US. Id. at 1. He is board certified in internal

medicine with a subspecialty in rheumatology. Id.

Dr. Ahmed belongs to the American Medical Association, the Stanley J. Sarnoff

Cardiovascular Research Foundation, the American College of Physicians, the American College

of Rheumatology, the Infectious Diseases Society of America, and the Beta Gamma Sigma

Honor Society for Business. Id. at 4.

27

He has patents in sphingosine 1 phosphate receptor modulators and their use to treat

muscle inflammation (WO2010010127A1), diagnostic and therapeutic methods for rheumatic

heart disease based upon group A streptococcus markers (WO2011048561A1), and avoiding the

risk of narcolepsy with influenza vaccines (WO2014180999A1). Id. at 5.

Dr. Ahmed’s CV lists 11 articles, only two of which deal with rheumatic diseases and

neither of those discusses clinical diagnosis. Id. at 5-6. His CV lists 18 reviews, letters,

chapters, and editorials, only two of which deal with rheumatic diseases and neither of those

discusses clinical diagnosis. Id. at 6-7.

During the last 12 years, Dr. Ahmed has been doing research and working for vaccine

manufacturers. His clinical practice (as a clinical associate) ended in June 2008, 10 years ago.

Dr. Mehrdad Matloubian

Respondent filed the CV of Dr. Matloubian on June 23, 2016. Ex. B. Dr. Matloubian

received his M.D. in 1996 from the University of California, Los Angeles. He also has a Ph.D.

in virology. Id. at 1. He did an internship and residency in medicine at the University of

California, San Francisco (“UCSF”),73 from 1996-1998, and was a fellow in rheumatology at the

same institution from 1998-2001, followed by a post-doctoral fellowship at the same institution

from 1999-2004. Id. He has a medical license in California and is board certified in internal

medicine with a subspecialty in rheumatology. Id. at 2. He has been at UCSF since 2001,

holding positions as assistant adjunct professor, assistant professor in residence, associate

professor in resident, and currently associate adjunct professor. Id. In 2001, he was awarded a

Pfizer Postdoctoral Fellowship in Rheumatology/Immunology. In the same year, he received the

American College of Rheumatology Distinguished Fellows Award. In 2003, he was awarded the

Ephraim P. Engleman Award for Research in Rheumatology. Id. He states in his CV that, since

July 2014, he has had a full-day clinic once a week and continues to attend one month on the

inpatient rheumatology consult service. Id.

Dr. Matloubian is a member of the American College of Rheumatology, the Northern

California chapter of the Arthritis Foundation, the American Association of Immunologists, and

the American Society for Clinical Investigation. Id. at 2-3. He has written 33 articles, all of

them on the immune response.

Medical Expert Reports filed before the hearing

On February 6, 2016, petitioner filed the expert report of Dr. Ahmed. Ex. 67, at 2.

Dr. Ahmed states in his expert report “the development of an autoantibody-mediated

disease is the result of a complex interaction between genetic and environmental factors.” Ex.

73

UCSF is ranked in 2018-2019 as the seventh best hospital for adult rheumatology in the United States. Best

Hospitals. Best Hospitals for Rheumatology, US NEWS & WORLD REPORT, https://health.usnews.com/best-

hospitals/rankings/rheumatology (last visited September 24, 2018).

28

67, at 4. The most common skin involvement in MCTD is Raynaud’s phenomenon. Id. Joint

involvement and muscle pain are common in MCTD. A major cause of death in MCTD is

pulmonary arterial hypertension (“PAH”). In answer to whether petitioner had signs and

symptoms of MCTD before her September 20, 2012 flu vaccination, Dr. Ahmed says no. Id. at

5-6. She had pre-vaccination shoulder tendinitis in 2000 with x-ray showing calcifications of the

supraspinatus muscle of the shoulder. Id. at 5. She had low back pain and right leg hypesthesia

in 2001 related to a work injury when transferring a patient from a slideboard. Petitioner had

asymmetric aching in the fingers and thumb of the right hand, a negative RF, a normal ESR,

none of which suggests RA, but are more consistent with osteoarthritis. Id. Dr. Ahmed views

the 2008 detection of ANA of 1:160 in a homogeneous pattern nonspecific which 20% of the

normal population has. He thinks that her normal CPK muscle enzymes in August 9, 2000 and

the nature of her musculoskeletal complaints make her having a myositis component of MCTD

unlikely prior to her flu vaccination in 2012. Id. Her 2000 complaint of erythema in the face

while having nausea and headaches was consistent with a vascular response, such as migraine.

In 2014, petitioner was diagnosed with rosacea. Thus, Dr. Ahmed says the erythema of

petitioner’s face was not consistent with a malar rash, and she does not have the SLE of MCTD

before flu vaccination in 2012. Id.

Dr. Ahmed says petitioner likely has high genetic susceptibility to MCTD because her

mother has Hashimoto’s74 thyroid disease and her sister has Sjögren’s syndrome (“SS”) for

which she takes methotrexate. Id. at 6. He states that since petitioner’s immediate family

members most likely carry genes that increased their susceptibility to autoimmune diseases

associated with antibodies to the thyroid (Hashimoto’s) or to glandular tissues (Sjögren’s),

petitioner’s family history of autoimmune disease was a risk factor for her to develop

autoimmune disease. Dr. Ahmed posits a sequence of events leading a genetically susceptible

host presented with an antigen/peptid stimulus which her regulatory mechanisms failed to

control, resulting in autoimmune disease, e.g., disease-specific autoantibodies such as anti-RNP.

Id.

To answer the question whether petitioner developed MCTD after receiving flu vaccine

in 2012, Dr. Ahmed comments that definitively diagnosing MCTD is often complicated since

overlapping features of SLE, SSc, and inflammatory myopathy often occur associated with high

titers of anti-RNP antibodies. He states a key feature to suspect MCTD is unexplained

Raynaud’s phenomenon. Diagnosing MCTD often takes years because of typical overlap

features. After petitioner received flu vaccine on September 20, 2012, she saw Dr. Xu on

October 3, 2012 with swelling in her hands for the first time. Blood tests showed antibodies to

RNP with an index at 1.2 (Ex. 3, at 37-41), positive ANA tier of 1:320 (Ex. 3, at 45-46), which

was greater than the prior titer of 1:160 four years earlier. From then on, petitioner’s swelling

and joint pain resembled RA (Ex. 3, at 98-101). Doctors put her on various disease-modifying

anti-rheumatic drugs, including methotrexate, hydroxychloroquine, etanercept, abatacept, and

74

Hashimoto disease is “a progressive type of autoimmune thyroiditis with lymphocytic infiltration of the gland and

circulating antithyroid antibodies; patients have goiter and gradually develop hypothyroidism. It has a familial

predisposition, usually affects women, and sometimes precedes the onset of Graves disease or is manifested after the

major symptoms subside.” Dorland’s at 535. Graves disease can manifest as hyperthyroidism. Id. at 534.

29

tocilzumab. On May 13, 2013, she had elevated CRP and elevated complement levels, evidence

for systemic inflammation, consistent with an evolving autoimmune disease (Ex. 3, at 86-89).

On May 15, 2013, petitioner was noted to have skin thickening over her fingers (sclerodactyly), a

feature of SS, which is another autoimmune disease (Ex. 3, at 98-101). Id.

Dr. Ahmed opines that the two-week interval between petitioner’s 2012 flu vaccination,

detection of disease-specific autoantibodies for MCTD, and increasing ANA titer fall within a

plausible window for linking flu vaccine to the dysregulation of petitioner’s immune response.

Id. at 7. Petitioner’s gradual progression of clinical symptoms (eight months after vaccination,

systemic inflammation detected in lab tests and thickening of skin of her fingers; 18 months

later, Raynaud’s phenomenon diagnosed) is typical for MCTD. Dr. Ahmed concludes that the

presence of autoantibodies to RNP and Raynaud’s phenomenon occurring after flu vaccination

on September 20, 2012 suggests a causal relationship. Id. In the alternative, the flu vaccination

of September 20, 2012 may have caused significant aggravation of an underlying autoimmune

process that was asymptomatic, transforming it into a clinically apparent disease. Petitioner’s

initial positive ANA detected on March 5, 2008 may have been due to her October 7, 1999 flu

vaccination priming her (Ex. 14, at 20; Ex. 16, at 1). Priming involves generating immune

memory in a vaccinee. Thus, petitioner’s initial immune response to flu vaccination on October

7, 1999 started the process of asymptomatic autoimmunity and the next flu vaccination

administered October 14, 2009 further boosted it. The flu vaccination she received on

September 20, 2012 could have also boosted the immune response, transforming the underlying

autoimmunity into an autoimmune disease, i.e., MCTD. Ex. 67, at 7.

Dr. Ahmed says that vaccines can cause autoimmune diseases even if epidemiologic

studies do not confirm that because of the small number of cases, unlike the considerable number

of cases of GBS (500) among 45 million people who received swine flu vaccine in 1976. Id. at

8. He says “rare adverse events still occur in genetically susceptible subjects….” Id. Dr.

Ahmed states that molecular mimicry has been demonstrated specifically for MCTD in reaction

to various viruses: HIV, Epstein-Barr virus, and human influenza B virus dealing with systemic

sclerosis. Id. at 9.

On June 23, 2016, respondent filed the expert report of Dr. Mehrdad Matloubian. Ex. A.

Dr. Matloubian doubts that petitioner has MCTD and suspects that her musculoskeletal pain is

related to her chronic pain syndrome and osteoarthritis, and therefore unrelated to her flu

vaccinations. Id. at 5-6. He says MCTD is considered an overlap syndrome because it has

features of other better-defined autoimmune diseases, such as SLE, SS, and polymyositis. Id. at

6. The symptoms may occur over time, thus making diagnosis at the outset of the disease

challenging. He states a major characteristic of patients whom doctors eventually diagnose with

MCTD is the presence of Raynaud’s phenomenon in association with high-titer speckled ANA

with fine specificity for U1 RNP. The remaining criteria are clinical signs showing

inflammatory disease, e.g., myositis, acrosclerosis, synovitis, and swollen hands. Id.

Dr. Matloubian states that when Dr. Lin diagnosed petitioner with MCTD on October 31,

2012, she based her diagnosis on petitioner’s non-specific joint complaints without any clinical

30

sign of synovitis and primarily because petitioner had a positive anti-RNP. Dr. Matloubian

regards petitioner’s positive anti-RNP as a false positive result which does not support a

diagnosis of MCTD. On October 15, 2012, petitioner’s serologic tests showed a low to moderate

ANA titer of 1:320 with a homogeneous pattern (Ex. 3, at 45-46). This result is consistent with

petitioner’s previous ANA test done in 2008, which was positive at 1:160 with a homogeneous

pattern (Ex. 14, at 20). A homogeneous pattern as petitioner had corresponds to anti-dsDNA,

nucleosomes, and histones, usually seen in SLE, drug-induced lupus, and autoimmune thyroid

disease. Ex. A, at 6. In contrast, when someone has antibodies to U1-RNP, such as someone

with MCTD, the staining pattern is speckled, not homogeneous. Id. at 7. Dr. Matloubian’s

opinion is that petitioner’s homogeneous ANA result on two separate tests performed at two

different laboratories suggests the anti-RNP result was most likely a false positive. Id.

Dr. Matloubian has other issues with this positive anti-RNP test result. Firstly, the assay

showed a low positive anti-RNP at 1.2 with the cutoff for this assay being less than 1 and the

highest value being 8. Dr. Matloubian does not know how the tech person reached a value of 1.2

and how this relates to an ANA titer of 1:320, but in light of the moderate ANA titer and the

homogeneous pattern, petitioner’s 1.2 value does not seem to qualify for the high titer ANA

(>1:10,000) with speckled pattern that is a mandatory diagnostic criterion for MCTD. Secondly,

in addition to testing for anti-RNP, petitioner was tested for anti-Sm+RNP, and the result was

negative (Ex. 3, at 41). Since the same antigens are used to test for RNP as for Sm+RNP, Dr.

Matloubian expected both test results to be positive. Bio-Rad Laboratories, which manufactures

this assay, has a statement that if someone has a positive RNP test, but a negative SmRNP and

Sm test, this decreased the probability of connective tissue disease. Ex. 7, at 7. Bio-Rad

Laboratories’ Interpretation Guide also indicates that this result can be seen in 2.3% of normal

blood donors.75 Id.

Dr. Matloubian concludes that if petitioner had a truly positive anti-RNP associated with

MCTD, she should have had high-titer speckled ANA, positive anti-RNP (AI >8) and three

positive autoantibodies; all of the MCTD patients were positive for RNP and SM+RNP. Dr.

Matloubian ascribes petitioner’s false positive anti-RNP result to the type of bead-based

multiplex assay that Bio-Rad Laboratories used to determine autoantibodies. Id. He states many

experts have raised concerns about the sensitivity and specificity of such assays. False positives

are not uncommon and Dr. Matloubian thinks petitioner is an example of a false positive. She

initially tested low positive for anti-cardiolipin IgM and IgG antibodies, but testing several

months later resulted in normal results (Ex. 3, at 63, 82). He strongly believes based on his own

experience with patients whose lab results are contradictory that petitioner’s anti-RNP test result

was a false positive. Id.

75

On August 1, 2017, respondent filed as exhibit E the Bio-Rad Laboratories BioPlex 2200 Interpretation Guide:

SmRNP vs Sm & RNP. If someone tests negative for Sm, positive for RNP, and negative for SmRNP, the

interpretation guide states: “If low titer without other associated antibodies, decreased probability of connective

tissue disease; retest patient every 6-12 months to monitor titer. Potential predictive antibody for early stage SLE.”

The prevalence of this test result of negative Sm, positive RNP, and negative SmRNP is 2.3% in normal blood

donors, and 4.1% in rheumatology patients. Id.

31

Dr. Matloubian describes petitioner’s treating rheumatologist Dr. Lin’s charting of

petitioner’s clinical symptoms of MCTD as “not ideal.” Id. at 8. He noted that Dr. Lin did not

correct her initial incorrect diagnoses in subsequent records and her records have many internal

inconsistencies. Id. Dr. Matloubian describes as “clear” was Dr. Lin’s not observing petitioner

having hand or joint swelling or clear synovitis when petitioner first came to her on October 31,

2012. During the next three years, Dr. Lin documented only one possible swelling in a PIP joint

(Ex. 3, at 124) which apparently resolved. He states Dr. Lin never documented diffuse hand

swelling in petitioner, even though diffuse hand swelling is often seen in early MCTD. Dr. Lin

thought petitioner might have sclerodactyly. Id. Being certain of the presence of synovitis is

more difficult in patients, such as petitioner, who are overweight. Id. Petitioner’s BMI on May

17, 2013 was 30 (Ex. 3, at 99). Dr. Matloubian would have used an MRI to determine if

petitioner had synovitis, but Dr. Lin did not perform any imaging studies of petitioner, such as x-

rays of her hand and knees or an MRI of her hands to detect inflammation or other causes of

joint pain, such as osteoarthritis. Id. Dr. Matloubian thinks Dr. Lin diagnosed MCTD solely

based on the results of the RNP test without any clinical findings to support the diagnosis and

then over time looked for signs and symptoms to justify her diagnosis. Dr. Matloubian noted

that 75 percent of patients with MCTD have lung involvement including pulmonary

hypertension, but Dr. Lin did not order a high-resolution CT or echocardiogram to screen

petitioner for this possibility. In addition, Dr. Lin did not note administering a PPD76 test, which

is a requirement before beginning a patient on anti-TNF therapy such as Enbrel. Id.

Dr. Matloubian says patients with MCTD generally have Raynaud’s disease as an early

symptom. Id. But the earliest notation Dr. Lin made of petitioner having Raynaud’s

phenomenon is November 19, 2014, a year after Dr. Lin diagnosed petitioner with MCTD. Id. at

9. Petitioner does not mention in her affidavit dated August 2015 that Raynaud’s phenomenon

was part of her symptoms. Dr. Lin again diagnosed petitioner with Raynaud’s phenomenon on

January 5, 2016 and prescribed topical medication (Ex. 20, at 1-5). Dr. Matloubian states that it

would be quite unusual for Raynaud’s phenomenon to be a late manifestation of MCTD. Dr.

Matloubian thinks that petitioner’s moderately positive ANA with a homogeneous pattern is

more consistent with autoimmune thyroid disease than MCTD. Id. That petitioner’s sister has

Sjögren’s disease, which is autoimmune, increases the likelihood that petitioner would have a

positive ANA. Id.

Dr. Matloubian thinks petitioner’s true diagnosis is chronic pain syndrome and

osteoarthritis, both of which predate her flu vaccination in September 2012. Id. at 10. As for Dr.

Ahmed’s opinion, Dr. Matloubian takes issue with Dr. Ahmed’s reliance on the theory of

molecular mimicry because the presence of linear sequence homology does not necessarily

translate to immunogenicity. Id. at 11. Proteins consist of linear sequences of amino acids, but

fold into complex three-dimensional structures. Dr. Ahmed’s diagram in Exhibit 25 is too

simplistic and does not convey that a similar linear sequence of amino acids in one protein may

be hidden within its three-dimensional structure and not accessible to antibodies. Id. Thus

sequence homology is insufficient evidence for molecular mimicry. Id. at 12. Concerning the

76

PPD is “purified protein derivative (tuberculin). . . .” Dorland’s at 1506. Tuberculin is “used in skin tests for

tuberculosis” and is also “a commonly used antigen in laboratory immunology.” Id. at 1979.

32

theory that if a vaccine can cause a disease, so can the infection that the vaccine was created to

prevent cause the same disease, Dr. Matloubian did medical article research, but could not find

any medical articles linking flu virus infection with MCTD. Id. at 12-13. He concludes that

since the flu virus shares genetic similarity with components of flu vaccine but is not associated

with MCTD, it is highly unlikely that a mechanism such as molecular mimicry causes MCTD

due to flu vaccine. Id. at 13.

Dr. Matloubian is unimpressed with the two-fold change in ANA titer petitioner had from

1:160 in 2008 to 1:320 in 2012 because the change has unclear clinical significance. Id. He

takes issue with Dr. Ahmed’s opinion that petitioner’s 1999 and 2009 flu vaccinations primed

her ANA, which the 2012 flu vaccination then boosted so that petitioner developed autoimmune

disease. Id. at 14. Dr. Matloubian questions why, if the 1999 flu vaccination primed petitioner,

the 2009 flu vaccination did not boost her to have clinical autoimmune disease, instead of just

being another priming vaccination. To Dr. Matloubian, it seems as if Dr. Ahmed were

interpreting events to fit his thesis and not considering other interpretations. Id. Dr. Matloubian

does accept the prime and boost theory as applied to an acute infection or a vaccination when

someone’s immune system is exposed briefly to an antigen, but it does not make sense in the

context of an autoimmune response for which self-antigen persists. He gives an example of a

memory response proceeding to a reaction against poison ivy or poison oak. When someone is

exposed to poison ivy, he may have no symptoms but is immunized and generates memory T-

cells to the plant’s antigens. When the person has a subsequent exposure, he develops a severe

and rapid response within a couple of days due to expansion of poison ivy specific memory T-

cells and localization to exposed areas. This response also subsides because the antigen is not

persistent. Thus, the poison ivy specific memory T-cells are dormant and do not cause any

symptoms. Id.

Dr. Matloubian says a similar process occurs after flu immunization, i.e., generation of

memory T-cells to the vaccine component. These memory T-cells are inactive unless they

encounter their specific antigen through exposure to flu virus or re-immunization with the same

seasonal flu vaccine. If Dr. Ahmed’s opinion that prior flu vaccinations generate memory T-

cells that are cross-reactive for self-antigens is correct, Dr. Matloubian says he would not expect

these cells to be dormant and inactive waiting for another flu vaccination since their putative

self-antigens are always around and constantly stimulating them. In addition, they would not

need a boost from another flu vaccination since their antigen is a self-antigen and always present.

To Dr. Matloubian, Dr. Ahmed’s explanation does not make biologic sense. Id.

Dr. Matloubian further discounts Dr. Ahmed’s opinion that petitioner has a genetic

predisposition and thus was susceptible to developing an autoimmune disease because immediate

family members have autoimmune diseases. He states that multiple studies in medical literature

show that patients with autoimmune diseases receive vaccinations, including against flu, without

exacerbation of their disease or developing a new one. Id.

Dr. Matloubian concludes his report by stating petitioner’s tests do not support a

diagnosis of MCTD because MCTD necessitates a high-titer ANA with a speckled pattern. Id. at

33

15. Petitioner on two occasions had two different laboratories conclude she had a relatively low-

titer ANA with a homogeneous pattern, inconsistent with a diagnosis of MCTD. Moreover,

petitioner’s marginally positive anti-RNP was most likely a false positive. Dr. Matloubian

opines petitioner suffers from chronic pain syndrome and osteoarthritis, both of which pre-

existed her September 2012 flu vaccination. Id.

On June 28, 2016, petitioner filed Dr. Ahmed’s response to Dr. Matloubian. Ex. 70. Dr.

Ahmed states that a low-titer positive RNP suggests a decreased probability of connective tissue

disorder, but does not exclude the diagnosis of MCTD. Id. at 2. Guidelines for diagnosing

MCTD capture most, but not all, MCTD patients. Id. Dr. Ahmed states that natural flu infection

but not flu vaccine have been observed to exacerbate RA and SLE. Id. at 4. He explains this

discrepancy as due to degree, duration, and dispersion of inflammation in the context of a

systemic infection which is greater than the controlled immune stimulation involved in

vaccination. Id. Dr. Ahmed states, “In my opinion, it is possible that influenza vaccination

triggered MCTD” in petitioner. Id. at 5.

On July 11, 2016, respondent filed Dr. Matloubian’s response to Dr. Ahmed. Ex. C. He

reiterates that he thinks Dr. Lin’s assessment of petitioner suffers from confirmation bias, i.e.,

her subsequent records presume her initial diagnosis of MCTD was correct without considering

other possible causes of petitioner’s symptoms. Id. at 2. He is suspicious of Dr. Lin’s physical

examinations of petitioner. Id. He states that Dr. Ahmed’s interpretation of petitioner’s

numbness in the bottom of her feet as indicative of Raynaud’s phenomenon is absolutely

incorrect. Id. at 3. Dr. Matloubian denies that petitioner was ever diagnosed with scleroderma

and did not have documented laboratory features of scleroderma which most commonly affects

the skin and lungs. Id. He reiterates that petitioner’s ANA was low specificity and can be seen

in autoimmune thyroid disease, with which petitioner was diagnosed. Id. at 6. He notes that the

ANA titer does not correlate with disease activity. Id. Dr. Matloubian also notes that the Bio-

Rad laboratory insert states that 2.3 percent of blood donors have borderline positive anti-RNP

and negative everything else. Id.

Dr. Matloubian asked his rheumatology colleagues at UCSF, including the Chief of the

UCSF Rheumatology Clinic and the director of the UCSF Scleroderma Center, how they would

interpret petitioner’s test results and they unanimously said that the anti-RNP was a false positive

and they would repeat the test with a different type of assay. Id. at 7. They also said petitioner

did not have MCTD and they had great doubt that she had any rheumatologic disease. He also

asked a rheumatology colleague who has practiced at Kaiser in the bay area about petitioner’s

serologies and he replied that the subserologies were done by automated testing and the so-called

BioPlex testing and unfortunately automated testing can give non-specific results. Id.

Dr. Matloubian agrees with Dr. Ahmed that natural infections, such as flu virus, lead to a

much stronger immune response that immunization with inactivated flu vaccine. Id. at 11. Thus,

it would be highly unlikely for a vaccine, which induces a much weaker immune response than a

natural infection, to lead to autoimmune disease when the natural infection with the flu virus

itself is not associated with that autoimmune disease. Id. Dr. Matloubian concludes with the

34

statement:

As a practicing rheumatologist at a major academic referral center,

neither I nor any of my colleagues would have diagnosed the

petitioner as having MCTD or any other rheumatologic

autoimmune disease based on the provided serological testing for

autoantibodies. Her anti-RNP test result, the sole basis of the

diagnosis of MCTD made by Dr. Lin, was most likely a false

positive since it was discordant with the remainder of her test

results. It is my strong opinion that the petitioner did not develop

MCTD or any other rheumatic autoimmune disease as the result of

receiving the influenza vaccine.

Id. at 12.

On August 19, 2016, petitioner filed Dr. Ahmed’s response to Dr. Matloubian. Ex. 87.

Dr. Ahmed states that patients with autoimmune disease do not always fulfill the standard

criteria. Id. at 6. Most of the standard criteria were designed for the purpose of following and

classifying patients in clinical studies. Moreover, the association of anti-RNP antibodies with

MCTD does not occur in up to 5 percent of patients with MCTD. Therefore, it is not always

present in MCTD. If petitioner did not have anti-RNP antibodies, that would not exclude her

from the diagnosis of MCTD in light of her clinical signs after flu vaccination. Id. Dr. Ahmed

explains petitioner’s ANA homogeneous pattern as due either to the 5 percent of MCTD patients

who do not have RNP antibodies, or the laboratory detecting the ANA pattern used a different

technology and thus reflected a different pattern at initial dilutions. Id. at 8. Dr. Ahmed states

that antibodies can fluctuate during a stage of a disease and a low positive does not mean a false

positive. He says the manufacturer Bio-Rad states that a low-titer positive RNP suggests a

decreased probability of connective disorder. This does not mean a low-titer positive RNP

excludes the diagnosis of MCTD since five percent of patients with MCTD do not have anti-

RNP antibodies. Id.

Dr. Ahmed states that molecular mimicry is not speculative and is proven for

streptococcus and rheumatic fever. Id. at 9. The theory is also accepted to explain GBS

following the 1976 swine flu vaccine campaign. Id.

On May 2, 2017, respondent filed the second supplemental report of Dr. Matloubian

responding to the additional medical records (Ex. 86) and Dr. Ahmed’s supplemental report (Ex.

87). Ex. D. He states that he highly doubts the diagnosis of MCTD and recommended petitioner

seek a second opinion from a doctor with an academic rheumatology practice, such as Stanford

or UCSF. Id. at 3. However, petitioner obtained a second opinion from Dr. Lau, who is another

rheumatologist at Kaiser Permanente, just as Dr. Lin is. Id. Dr. Lau “speculated” petitioner

could have MCTD or UCTD. Id.

Dr. Matloubian notes that petitioner had one positive anti-RNP result while another RNP

antigen test (anti-RNP/Smith) was negative. This is highly unusual. Id. at 3. That makes two

35

discrepancies in her autoantibody testing, which makes these tests results inconsistent with a

diagnosis of MCTD. Id. at 3-4. The consultant rheumatologist Dr. Lau appeared to be unaware

that petitioner had a history of rosacea when he diagnosed her with CTD. Id. at 4. What is more,

Dr. Lau attributed petitioner’s skin problem as telangiectasia due to connective tissue diseases.

Id. Petitioner’s GERD predates her flu vaccination on September 20, 2012. Id. Dr. Matloubian

disagrees that the pictures of petitioner’s fingers reflect active Raynaud’s phenomenon. Id. at 5.

Petitioner’s main complaints are musculoskeletal pain, but she does not have elevated muscle

enzymes, which rules out inflammatory myopathy (usually associated with MCTD and other

connective tissue diseases). Two of petitioner’s rheumatologists, Dr. Lau and Dr. Lin, performed

physical examinations of petitioner within one week and came to different conclusions as to what

they saw. Determining a diagnosis of joint inflammation in an overweight patient such as

petitioner makes the doctors’ conflicting diagnoses suspect. Id. This is why Dr. Matloubian

relies on objective studies as MRIs to detect joint inflammation. Dr. Lau appeared unaware that

petitioner’s oral ulcers when she was not taking MTX were due to herpes simplex virus and

treated with acyclovir. Id. Dr. Matloubian states that some of the therapies petitioner received,

e.g., Enbrel, Orencia, and Actemra, could have led to her developing further autoantibodies. Id.

at 6. He states if he were petitioner’s treating rheumatologist, he would repeat autoimmune tests

using an ELISA77 assay, discontinue her immunosuppressive medications, do MRI imaging of

her hands while she was off medications to evaluate her for joint inflammation, and treat her

with gabapentin or pregabalin for her chronic pain syndrome. Id.

Medical Articles

Petitioner’s Medical Articles

Petitioner filed as Exhibit 22 Dr. Ahmed’s reference 7 in his first expert report (Ex. 67), a

medical article by Hidetoshi Kaneoka et al., Molecular Genetic Analysis of HLA-DR and HLA-

DQ Genes Among Anti-U1-70-kd Autoantibody Positive Connective Tissue Disease Patients, 35

ARTHRITIS & RHEUMATISM 1:83-94 (1992). The authors state that patients with systemic

rheumatic disease such as SLE and MCTD frequently have autoantibodies against U small

nuclear ribonucleoproteins (“[U]snRNP”). Id. at 83. They discuss different research finding an

association of autoantibodies reactive with U1 RNP (U1-70-kd78) and different types of HLA,

i.e., HLA-DR4 and HLA-DR2.79 Id. at 83, 90. They state:

77

ELISA is “[enzyme-linked immunosorbent assay] any enzyme immunoassay utilizing an enzyme-labeled

immunoreactant (antigen or antibody) and an immunosorbent (antigen or antibody bound to a solid support). A

variety of methods (e.g., competitive binding between the labeled reactant and unlabeled unknown, or a sandwich

technique in which the unknown binds both the immunosorbent and labeled antibody) may be used to measure the

unknown concentration.” Dorland’s at 605.

78

Kd stands for “kilodalton.” A kilodalton is “a unit of mass, being one thousand (10 3) daltons.” Dorland’s at 986.

A dalton is “an arbitrary unit of mass, being 1/12 the mass of the nuclide of carbon-12, equivalent to 1.657 x 10-24 g.

Called also atomic mass unit.” Id. at 470.

79

HLA are “human leukocyte antigens.” Dorland’s at 864. HLA complex is “histocompatibility antigens governed

by genes of the HLA complex (the human major histocompatibility complex), a region on the short arm of

chromosome 6 containing several genetic loci, each having multiple alleles. Loci are designated by letters; the

classical loci are HLA-A, -B, -C, -E, -F, -G, -DP, -DQ, and -DR (there are at least three subloci in the D region).

Alleles at each locus are designated by numbers. HLA-A1, provisional designations being indicated by “w” (for

36

Both genetic and nongenetic factors may contribute to the

production of anti-U1-70-kd autoantibodies. While HLA-DR

genes are associated with the presence of anti-U1-70-kd

autoantibodies, it is clear that the majority of individuals

possessing these genes do not have anti-U1-70-kd autoantibodies,

not do they develop CTD. This could be explained by interactive

effects between and among nongenetic factors and multiple genes

that contribute to autoantibody production.

Id. at 91. The authors posit, “The finding of the association of specific HLA genes with the

presence of autoantibodies reactive with the U1-70-kd polypeptide could be compatible with an

immune response gene-regulated and antigen-driven immune response [citations omitted].” Id.

No doctor ever tested petitioner for HLAs of any type.

Petitioner filed as Exhibit 26 Dr. Ahmed’s reference 1 in his first expert report (Ex. 67), a

medical article by Gordon C. Sharp et al., Mixed Connective Tissue Disease—An Apparently

Distinct Rheumatic Disease Syndrome Associated with a Specific Antibody to an Extractable

Nuclear Antigen, 52 AM J MED 2:148-59 (1972). The authors state that they observed in a clinic

over eight years a spectrum of patients with rheumatic disease whose serum contained a high

titer of ANA which persisted through periods of active disease and clinical remission. Id. at 148-

49. The authors comment that common to all patients with MCTD are high titers of speckled

pattern on fluorescent ANA testing. Id. at 156.

Petitioner filed as Exhibit 27 Dr. Ahmed’s reference 2 in his first expert report (Ex. 67), a

chapter by Robert Bennett, Scleroderma, inflammatory myopathies, and overlap syndromes,

1381-99, in KELLEY’S TEXTBOOK OF RHEUMATOLOGY (8th ed. 2008), but what she actually filed

was Robert Bennett, Overlap Syndromes, 1431-51, chapter 86 in KELLEY’S TEXTBOOK OF

RHEUMATOLOGY (Gary S. Firestein et al., 2012). On page 1440, Bennett states, “The first clue to

diagnosing MCTD is usually a positive ANA with a high-titer speckled pattern. The titer is often

greater than 1:1000 and sometimes greater than 1:10,000. … [P]atients destined to follow a

course most consistent with MCTD have sera with predominant U1-RNP reactivity.” On page

1441, Bennett states, “Early in the course of the disease most patients complain of easy

fatigability, poorly defined myalgias, arthralgias, and Raynaud’s phenomenon . . . .” Petitioner

did not have a high-titer positive ANA and high-titer serum antibodies to RNP. She did not have

Raynaud’s phenomenon until two years after her initial diagnosis.

Petitioner filed as Exhibit 28 Dr. Ahmed’s reference 3 in his first expert report (Ex. 67),

an article by Melissa R. Arbuckle et al., Development of Autoantibodies before the Clinical

“workshop”), e.g., HLA-DRw10. The A, B, C, and DR antigens are defined and typed by serologic reactions. The

D antigens are defined and typed by one-way mixed lymphocyte culture (MLC) using panels of HLA-D-

homozygous typing cells. The SB (for “secondary B cell”) antigens are defined and typed by primed lymphocyte

typing.” Id. at 105.

37

Onset of Systemic Lupus Erythematosus, 349 NEJM 16:1526-33 (2003). Arbuckle explains that

SLE is virtually always accompanied by the production of autoantibodies. Id. at 1527. Since

autoantibodies contribute directly to the pathologic changes of SLE, Arbuckle states their

development must coincide with or precede the clinical symptoms of SLE. Arbuckle evaluated

serum samples of 130 persons in the US Armed Forces who received a diagnosis of SLE. Id. In

101 patients, there was a nine-year interval between the detection of ANA in their sera and their

first clinical sign of SLE. Id. at 1529. The proportion of patients with SLE who had anti-Sm or

anti-RNP increased dramatically the year before their SLE diagnosis. Id. at 1530. These

findings reflect the close temporal relationship between development of these autoantibodies and

clinical disease. Id. Arbuckle concludes that some autoantibodies (ANA, anti-Ro, anti-La, and

antiphospholipid antibodies) usually preceded the onset of SLE by many years. Id. at 1531.

Anti-Sm and Anti-RNP antibodies typically appeared only months before diagnosis during the

time when characteristic clinical manifestations appeared. Id.

ANA are relatively common in normal persons who never have clinical symptoms of

rheumatic disease. However, anti-RNP antibodies are very rare in normal persons. Id. Arbuckle

states that the data of sera of a substantial proportion of patients (69 percent) were censored

because autoantibodies were present in the first available serum sample, which was obtained a

mean of four years before diagnosis. Id. at 1532. But she says if she could have seen serum

samples obtained before the development of autoantibodies for all patients, her estimates of the

mean time from autoantibody development to clinical diagnosis would have been longer.

“Consequently, this study provides a lower-boundary estimate of the time before the diagnosis at

which particular autoantibodies develop.” Id.

Arbuckle concludes based on the serological and clinical findings along with prior studies

that there are at least three phases in the development of SLE autoantibodies: (1) the normal

phase in which the person is asymptomatic with no SLE autoantibodies (only 32 patients or 25

percent of the 130 patients who developed SLE were in this first, normal phase); (2) the benign

autoimmunity phase, in which a laboratory finding of ANA, anti-Ro. anti-La, or antiphospholipid

antibodies were present, but without immediate clinical manifestations of SLE; and (3) the

pathogenic autoimmunity phase, in which the more ominous autoantibodies—anti-dsDNA, anti-

Sm, and anti-NRP antibodies—were present as was the onset of signs and symptoms leading to a

clinical presentation and diagnosis of SLE. Id. Arbuckle states data showing increased

concentrations of autoantibodies before diagnosis and progressive accrual of autoantibody

specificities at the epitope level also support this concept of a crescendo of autoimmunity

culminating in clinical disease, a process usually underway for many years before diagnosis. Id.

Petitioner filed as Exhibit 29 Dr. Ahmed’s reference 4 in his first expert report (Ex. 67),

an article by Robert M. Bennett & Dennis J. O’Connell, Mixed Connective Tissue Disease: A

Clinicopathologic Study of 20 Cases, 10 SEMIN ARTHRITIS RHEUM 1:25-51 (1980). The authors

give the origin of the diagnostic entity of MCTD:

In 1972, Sharp and his coworkers described an overlap syndrome

of SLE, generalized scleroderma, and polymyositis, which they

38

considered a “distinct rheumatic disease syndrome,” giving it the

name Mixed Connective Tissue Disease (MCTD). The unifying

feature of this concept was the presence of antibodies to a saline

extractable nuclear antigen (ENA) that was RNAase sensitive.

Subsequent work by Mattioli and Reichlin has resolved ENA into

two distinct moieties: soluble ribonucleoprotein (RNP) and a

glycoprotein termed “Sm’ antigen. RNAase-sensitive ENA is

synonymous with RNP; RNP antibodies are a sine qua non for the

diagnosis of MCTD . . . [footnotes omitted].

Id. at 25. All the patients included in the authors’ study had a high-titer speckled pattern

antinuclear factor. Id. at 42. The RNP antibody titer did not correlate with disease activity. Id.

Petitioner filed as Exhibit 30 Dr. Ahmed’s reference 5 in his first expert report (Ex. 67), a

review by Sevdalina N. Lambova & Stefka J. Kuzmanova, Raynaud’s Phenomenon in Common

Rheumatic Diseases, 48 FOLIA MEDICA (PLOVDIV) 22-28 (3 & 4 2006). The authors state that

Raynaud’s phenomenon occurs about 85 percent in MCTD and often as one of the initial

symptoms. Id. at 26. Some authors (Alarcon-Segovia and Villareal, Kasukawa, et al. and Sharp)

define Raynaud’s phenomenon as one of the criteria of MCTD. Id. They state anti-U1-RNP

antibodies appear to be a specific immune marker for MCTD. Id.

Petitioner filed as Exhibit 31 Dr. Ahmed’s reference 6 in his first expert report (Ex. 67),

an article by Siri Tennebø Flam et al., The HLA profiles of mixed connective tissue disease

differ distinctly from the profiles of clinically related connective tissue diseases, 54

RHEUMATOLOGY 528-35 (2015). The authors state that MCTD is identifiable by high-titer serum

antibodies to U1-70 kDa RNP and a complex phenotype that encompasses Raynaud’s

phenomenon, puffy hands, arthritis, pleuritis, pericarditis, myositis, esophageal dysmotility

and/or lung fibrosis. Id. at 528. They state the etiology of MCTD is unclear but may involve

chronic immune activation after exposure to environmental risk factors in those with a

predisposing genetic background. Id. at 529. Similar to other CTDs, genetic factors within the

HLA complex appear important. Id. The authors discovered that the HLA associations observed

in MCTD differ from the HLA associations seen in SLE and SSc. Id. Across different

populations, MCTD appeared to be associated with HLA-DR4 allelic variants, whereas SLE and

PM/DM were primarily associated with HLA-DR3 and SSc with DR5. Id. The authors’ HLA

analysis confirmed that MCTD is an immune-mediated disease distinct from SLE, SSc, and

PM/DM. Id. at 532.

Petitioner mistakenly filed as a second Exhibit 31 Dr. Ahmed’s reference 7 (which

petitioner mistakenly marked as reference 6) and then filed the same article as Exhibit 32 Dr.

Ahmed’s reference 7 (but still marked as reference 6) in his first expert report (Ex. 67), an article

by Hidetoshi Kaneoka et al., Molecular Genetic Analysis of HLA-DR and HLA-DQ Genes

Among Anti-U1-70-kd Autoantibody Positive Connective Tissue Disease Patients, 35 ARTHRITIS

RHEUM 1:83-94 (1992). The authors state that autoantibodies against U small nuclear

ribonucleoproteins (“[U]snRNP”) are frequently present in the sera of patients with systemic

39

rheumatic diseases, e.g., lupus and MCTD, and serve as useful markers for diagnosis. Id. at 83.

MCTD is associated with HLA-Dq1 as well as HLA-DQw3. Id. The authors find interesting the

association of anti-U1-70-kd autoantibody positive CTD with more than one HLA allele. Id. at

90. The authors posit that finding an association of specific HLA genes with the presence of

autoantibodies reactive with the U1-70-kd polypeptide could be compatible with a gene-

regulated and antigen-driven immune response. Id. at 91. The authors recognize that both

genetic and nongenetic factors may contribute to the production of anti-U1-70-kd autoantibodies,

and that while HLA-DR genes are associated with the presence of anti-U1-70-kd autoantibodies,

it is clear that the majority of individuals possessing these genes do not have anti-U1-70-kd

autoantibodies or develop CTD. This could be explained by interactive effects between and

among nongenetic factors and multiple genes that contribute to autoantibody production. Id.

Petitioner filed as Exhibit 33 Dr. Ahmed’s reference 8 in his first expert report (Ex. 67), a

short analytical review by Robert W. Hoffman & Marcos E. Maldonado, Immune pathogenesis

of Mixed Connective Tissue Disease: A short analytical review, 128 CLIN IMMUNOL 1:8-17

(2008). The authors state MCTD is a systemic autoimmune disease which the presence of

autoantibodies and T-cells reactive with U1-RNP polypeptides of the spliceosome complex

including their associated uridine-rich (U) small nuclear RNAs. Id. at 8. Sharp et al. in 1972

described MCTD patients as a novel group based on the presence of high levels of antibodies

against an extractable nuclear antigen (ENA) that was RNase- and trypsin-sensitive. Id. Sharp

et al. showed that ENA contained both the ribonuclease (RNase)- and trypsin-sensitive RNP

antigen associated with MCTD. Id. at 9.

The authors state there are four published classification criteria for MCTD. Id. The

authors state the primary clinical features of MCTD are Raynaud’s phenomenon, swollen fingers

or diffusely swollen hands, arthralgia, with or without associated arthritis, esophageal reflux or

esophageal dysmotility, acrosclerosis (i.e., sclerodactyly), mild myositis, and pulmonary

involvement of a variety of forms. Id. Characteristic immunologic findings in MCTD are a

high-titer fluorescent antinuclear antibody (FANA) with a speckled pattern and the presence of

antibodies to RNP at moderate to high level in the serum. Id. Patients with MCTD have an

increased frequency of HLA-DR4 compared to healthy controls. Id. The initial emergence of

anti-RNP antibodies has a strong association with clinical disease. Id. at 10. The authors state

that independent observations over the past decade converge with the view that both the innate

and adaptive immune systems play central roles in the development of many systemic

autoimmune diseases including MCTD. Id. at 11. Citing Sharp and his colleagues, the authors

state that anti-RNP antibodies are required for the diagnosis of MCTD and to meet any of the

four classification criteria developed for MCTD. Id. at 12. They state that anti-RNP antibody in

MCTD can constitute up to one-third of total serum immunoglobulin in some patients. Id.

Moreover, the authors state a hallmark of MCTD is hypergammaglobulinema. Id. They

write the anti-RNP and anti-U1-RNA antibodies display immunoglobulin class switching to

immunoglobulin G (IgG). Id. Petitioner was never diagnosed with hypergammaglobulinema

and testing of her IgG levels always showed a normal result.

40

Citing the Arbuckle80 study of banked sera of military personnel who developed lupus-

like disease, the authors of this article recount Arbuckle’s discovery that military personnel

developed onset of clinical disease within one year after testing of their sera showed they had

anti-RNP antibodies without clinical disease. Id. In addition the authors in this article state that

the presence of IgG anti-U1-RNA antibodies is a well-documented feature of MCTD. Id.

Petitioner filed as Exhibit 34 Dr. Ahmed’s reference 9 to his first expert report (Ex. 67),

an article by Susan Cappelli et al., “To Be or Not To Be,” Ten Years After: Evidence for Mixed

Connective Tissue Disease as a Distinct Entity, 41 SEMIN ARTHRITIS RHEUM 4:589-98 (2012).

The authors state the initial clinical presentation of MCTD usually includes Raynaud’s

phenomenon, swollen puffy hands, and polyarthritis or polyarthralgias. Id. at 590. High-titer

anti-U1 snRNP antibodies are a serologic marker for MCTD and an association of HLA-DR4

haplotype has been observed with both anti-U1 snRNP and with MCTD per se. Id. The authors

studied 161 patients diagnosed with MCTD. Id. At the first visit of these 161 patients to a

doctor for diagnosis, 93.2 percent had Raynaud’s phenomenon, 96.9 percent had ANA, and 100

percent had anti-RNP. Id. at 592.

Petitioner filed as Exhibit 35 Dr. Ahmed’s reference 11 to his first expert report (Ex. 67),

an article by Sumit Sen et al., Cutaneous Manifestations of Mixed Connective Tissue Disease:

Study from a Tertiary Care Hospital in Eastern India, 59 INDIAN J DERMATOL 1:35-40 (2014).

The authors state MCTD is associated with the presence of antibody against a specific uridine-

rich U1RNP. Id. at 36. They classified 23 patients with MCTD when they were serologically

positive for U1RNP at a titer of 1:1600 or higher, with the presence of at least three clinical

features, e.g., edema of the hands, synovitis, myositis, Raynaud’s phenomenon, and

acrosclerosis. Id. Most of those in the study group tested positive for ANA and the pattern was

solely speckled. Id. at 39.

Petitioner filed as Exhibit 45 Dr. Ahmed’s reference 20 to his first expert report (Ex. 67),

an editorial by David S. Pisetsky, Antinuclear antibodies in healthy people: the tip of

autoimmunity’s iceberg? 13 ARTHRITIS RES THER 2:109-10 (2011). The author states that 20

percent or more of otherwise healthy people can express an ANA. Id. at 109.

Petitioner filed as Exhibit 57 Dr. Ahmed’s reference 32 to his first expert report (Ex. 67),

an article by himself and others, Assessing the Safety of Adjuvanted Vaccines, 3 SCI TRANSL

MED 93:93rv2:1-10 (2011). Ahmed, citing a study, notes that flu infection but not flu vaccine

exacerbated preexisting autoimmune disease. Id. at 2. He states that vaccine antigens are

screened for molecular mimicry to exclude autoantigens in vaccine intended for humans. Id.

The adjuvants used in vaccines for humans differ from strong adjuvants, such as complete

Freund’s adjuvant, used in animal studies which deliberately break immunological tolerance in

the animals to study animal models of autoimmune disease. Id. Ahmed states:

Human autoimmune diseases are diverse and complex, and the

80

Melissa R. Arbuckle et al., Development of autoantibodies before the clinical onset of systemic lupus

erythematosus, 349 NEJM 1499-1500 (2003). Ex. 28.

41

nature of the trigger cannot be simplified to the point that one

“test” can be reliably expected to predict disease induction.

Evaluating the effects of a vaccine or adjuvant on one or two

disease models within this category would provide no information

about the effects on other diseases within the category. Difficulties

and limitations with these tests include the differences between

animal disease models and real human disease as well as

fundamental genetic and physiological differences between

humans and commonly used laboratory animals. … In addition,

factors that initiate disease in animal models might not necessarily

be relevant to human disease development. … Both the incomplete

correlation with human disease and the divergent mechanisms of

disease initiation limit the relevance of even the “best” animal

models to specific human diseases.

Id. at 4.

Dr. Ahmed states that a major hurdle facing development of predictive biomarkers for

vaccine-related autoimmune disease is the absence of predictive markers for spontaneous human

autoimmune disease. Id. Dr. Ahmed analyzes three parts of this hurdle. Id. at 5. Firstly,

scientists do not know how identified biomarkers would behave in the context of immunization.

Id. Secondly, biomarker data are inconsistent and unreliable when the source of them is doctors

and their vaccinated patients. Thirdly, scientists would need to collect and store blood samples

from tens of thousands of subjects to attain adequate statistical power to evaluate biomarkers of

rare adverse events that occur after a delayed period of time post-vaccination such as

autoimmune disease or autoimmune-related symptoms. Id.

Dr. Ahmed says:

With the introduction of any vaccine there is the risk for

coincidental association with naturally occurring autoimmune

disease. That is, in any population, there is a background rate of

these events that occur despite vaccination and a concomitant risk

of such event occurring at the same time as the vaccine, by chance

alone. These ‘temporal’ associations can confound the

interpretation of vaccine safety

Id.

Dr. Ahmed notes that “the possibility that autoimmune diseases may begin months or

years before clinical diagnosis poses logistical challenges, emphasizing the importance of

discovering biomarkers predictive for autoimmune disease.” Id. at 6. Dr. Ahmed lists a number

of factors that must be considered when evaluating whether or not a vaccine adverse event

occurred: environment, diet, age-related changes in the immune system, and conditions

42

associated with triggering autoimmune disease in susceptible subjects, such as pregnancy or

exposure to natural infections. Id. at 8. Dr. Ahmed thinks following vaccinated subjects to

detect autoimmune adverse events should extend out to six months. Id. He notes that older

epidemiologic studies followed 18,000 recipients of flu vaccine for 16 to 18 years without

detecting an increase in allergic and autoimmune diseases. Id.

Petitioner filed as Exhibit 79 Dr. Ahmed’s reference 9 of his supplemental expert report

(Ex. 70), a medical article by Hans H. Guldner et al., Human Anti-P68 Autoantibodies

Recognize a Common Epitope of U1 RNA Containing Small Nuclear Ribonucleoprotein and

Influenza B Virus, 171 J EXPERIMENTAL MED 3:819-29 (1990). The authors used small nuclear

ribonucleoprotein particles (“U1snRNP”) as a model system. Anti-U1snRNP autoantibodies are

characteristic for certain inflammatory rheumatic diseases, and a 68-kD protein (p68) of the

U1snRNP particle is a major antigenic target. Id. at 819. Thirty-five percent of 103 anti-p68

autoimmune sera recognized a particular autoreactive region in amino acid position 234-253,

which the authors term domain A. Id. at 820. They demonstrate that a subset of human anti-

p68/domain A autoantibodies react with a p68 epitope present on the matrix protein M1 of

human influenza B viruses, and that autoimmune sera recognized this shared epitope. Id. The

authors took these sera from patients with MCTD and SLE. Id. The influenza strains were

B/Beijing/1/8781 and A/Singapore/6/86 (H1N1). Id.

The authors conclude that a subset of human anti-p68 autoantibodies recognize an

epitope shared by the p68 autoantigen and the influenza B virus M1 matrix protein. Id. at 824.

They posit that autoimmune sera of antibodies reactive with a shared epitope may represent

molecular mimicry and implicate influenza B viruses as triggers for the development of

autoantibodies to p68. Id. at 825. The authors identified a sequence motif of five amino acids as

an autoepitope that a subset of anti-p68 autoantibodies from (U1) RNP-positive patients’ sera

recognized. Id.

They note that influenza viruses may contribute to autoimmune disease because they

interact with lymphocytes, which may lead to partial breakdown of self-tolerance, and they can

cause polyclonal B cell activation, considered important for autoantibody formation. In addition,

flu viruses impair the function of phagocytes, which may lead to delayed clearance of self-

antigens, and p68 as an RNA-binding protein may interact with flu virus RNA and be secreted in

virus-encapsulated form, rendering extracellular p68 as a possible target for B cells. Lastly, a

high percentage of flu virus-infected patients develop autoantibodies. Id. at 825-26. In addition

to possibly initiating autoimmunity by molecular mimicry, influenza B might promote such an

antigen-driven process by releasing snRNP as a result of virus-induced cell lysis. Id. at 826. The

authors state that “not all individuals infected with influenza B would be expected to develop

anti-p68 autoantibodies.” Id. Other predisposing factors such as genetic predisposition, immune

deficiency, and hormonal, environmental, and other influences would be necessary. Id.

81

B/Beijing/1/87 is of the Victoria lineage. Phylogenetic tree for the HA gene and trend of strains in different

countries, RESEARCH GATE, https://www.researchgate.net/figure/Phylogenetic-tree-for-the-HA-gene-and-trend-of-

strains-in-different-countries-A_fig2_295084193 (last visited October 22, 2018).

43

The 2012-2013 influenza vaccine that petitioner received on September 20, 2012

contained A/California/7/2009-like virus (pH1N1), A/Victoria/361/2011-like virus (H3N2), and

B/Wisconsin/1/2010-like virus (Yamagata lineage). Update: Influenza Activity – United States,

2011-12 Season and Composition of the 2012-2013 Influenza Vaccine, 61 MORBIDITY AND

MORTALITY WEEKLY REPORT (MMWR) 22:414-20, Centers for Disease Control and Prevention

(June 8, 2012).82 It is unclear to the undersigned if Guldner’s research in 1990 using

B/Beijing/1/87 (Victoria lineage) influenza virus on sera as he and his co-authors described in

Exhibit 79 is relevant to petitioner who received B/Wisconsin/1/2010 flu vaccine in 2012, 23

years after B/Beijing/1/87/flu virus was circulating, although the authors state they found the

ERKRR motif also within the M1 matrix protein of B/Lee/40 and B/Singapore/222/79 flu

viruses. Ex. 79, at 822.

Significantly, Guldner and his co-authors did not find the cross-reaction of human anti-

ERKRR autoantibodies with influenza B M1 protein in anti-p68 sera from patients with various

rheumatic diseases and high titers of autoantibodies to other antigens (e.g., Sm, Ro, La

centromere, topoisomerase I, PM-Scl, histones, dsDNA, fibrillarin, and Jo-1) or in >50 healthy

individuals whom they tested. Id. at 824.

Petitioner would not presumably fit in either of the non-responding groups because she

does not have high titers of autoantibodies to these multiple antigens or even high-titer ANA or

high-titer anti-RNP, but she claims she has a CTD and therefore cannot be considered healthy.

Moreover, petitioner did not have an autoimmune reaction to her October 7, 1999 flu

vaccination, which raises the question of how receipt of B virus vaccine would have promoted

the development of human anti-ERKRR autoantibodies with influenza B M1 protein if she had

anti-p68 sera at all. Her reaction to the 1999 flu vaccine was left supraspinatus tendinitis. She

probably had SIRVA because she had left arm pain and difficulty raising her left arm. SIRVA is

the result of improper vaccination rather than a reaction to vaccine components.

Petitioner had no reaction whatsoever to her October 14, 2009 flu vaccination, which

again exposed her to B virus vaccine. Yet, Dr. Ahmed testified that her flu vaccinations in both

1999 and 2009 created a booster or priming effect so that when she received on September 20,

2012 B/Wisconsin/1/2010-like virus of Yamagata lineage, the vaccine caused her an

autoimmune rheumatic disease. It is a non sequitur to link a 1999 vaccination which

mechanically-induced pain with a 2009 vaccination to which petitioner had no reaction at all to a

2012 vaccination after which rheumatic disease was finally diagnosed and claim, as Dr. Ahmed

does, that the rheumatic illness was due to the repeated exposure of petitioner to the flu B strain

virus in a killed virus vaccine. Petitioner’s history of SIRVA (1999), no reaction (2009), and

putative rheumatic illness (2012) over a span of 13 years does not support an opinion that

boosting, priming, or rechallenge is present in this case.

Petitioner filed as Exhibit 72 (but marked as Exhibit 1) Dr. Ahmed’s reference 2 of his

supplemental expert report (Ex. 70), an article by Minoru Satoh et al., Clinical interpretation of

antinuclear antibody tests in systemic rheumatic diseases, 19 MOD RHEUMATOL 3:219-28 (2009).

82

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6122a4.htm (last visited October 17, 2018).

44

The authors note that while information of ANA testing includes staining pattern (speckled,

homogeneous, or peripheral), it is relatively subjective and varies depending on the laboratory or

individual reading the results. Id. at 220. They state that the classic feature of MCTD is

associated with very high titers of anti-U1RNP antibodies. Id. at 221. They note that higher

titers of ANA do not always mean that the patient’s disease is more severe or active. However,

specificity of autoantibodies is a factor correlating strongly with titers of ANA. Autoantibodies

such as anti-U1RNP and centromere may show titers of 1:10,240 or even higher. Individuals

with high titers of these antibodies may be classified as having undifferentiated connective tissue

disease (UCTD) or Raynaud’s disease, and may not require any medical treatment. Id.

Petitioner filed as Exhibit 75 Dr. Ahmed’s reference 5 of his supplemental expert report

(Ex. 70), an article by Jonathan Graf, Antinuclear Antibodies, in PRIMER ON THE RHEUMATIC

DISEASES (12th ed. 2001), consisting of two pages. On the first page, Dr. Graf writes under

“Speckled pattern (ENA or acid extractable nuclear antigens),” under MCTD, the anti U1-RNP

is nearly 100% sensitive.

Petitioner filed as Exhibit 89 attached to Dr. Ahmed’s responsive report (Ex. 87), a one-

page ARUP Consult entitled Mixed Connective Tissue Disease – MCTD.83 Under serological

criteria for diagnosis, the report lists anti-RNP ≥1:1,600 plus three or more of these clinical

signs: edema of hands; synovitis; myositis; Raynaud syndrome; and acrosclerosis. Petitioner

would not have satisfied these criteria on October 31, 2012 when she saw Dr. Lin because

petitioner’s anti-RNP was 1.2, not ≥1:1,600, and she did not have any of those clinical signs. Dr.

Lin described puffy fingers, not edema of the hands, and myalgia or muscle aching, not myositis

which is inflammation of the muscles. In addition, the ARUP Consult requires under the

category of laboratory testing an abnormal CRP (which petitioner did not have) and abnormal

connective tissue antibody testing, including an ANA showing a centromere pattern usually of

>1:1,000 (petitioner’s centromere testing was negative) and a speckled pattern (petitioner’s ANA

pattern was homogeneous, not speckled). Other ARUP tests show hypergammaglobulinemia,

but petitioner’s IgG was normal.

Respondent’s Medical Articles

Respondent filed as Tab 1, Dr. Matloubian’s reference 1 of his first expert report (Ex. A),

an article by Robert M. Bennett, Definition and diagnosis of mixed connective tissue disease,

UPTODATE.84 Bennett states:

A key feature in suspecting a diagnosis of MCTD is the presence

of unexplained Raynaud phenomenon. If systemic sclerosis can be

ruled out and the patient has a speckled-pattern antinuclear

antibody (ANA) usually in high titer, further immunological

83

ARUP CONSULT. THE PHYSICIAN’S GUIDE TO LAB TEST SELECTION AND INTERPRETATION,

https://arupconsult.com/content/mixed-connective-tissue-disease (last visited October 15, 2018).

84

UPTODATE, http://www.uptodate.com/contents/anti-u1-rnp-antibodies-in-mixed-connective-tissue-disease (last

visited September 11, 2018).

45

testing is warranted. The finding of anti-RNP antibodies provides

further important, but not conclusive, evidence for a diagnosis of

MCTD.

Id. at 1-2.

Respondent filed as Ex. A, Tab 2, Dr. Matloubian’s reference 2 of his first expert report

(Ex. A), an article by Oscar-Danilo Ortega-Hernandez & Yehuda Shoenfeld, Mixed connective

tissue disease: An overview of clinical manifestations, diagnosis and treatment, 26 BEST PRAC &

RES CLIN RHEUM 61-72 (2012). The authors state MCTD was first described in 1972 as an

illness with mixed features of SLE, “SSc”, polymyositis/dermatomyositis (“PM/DM”), and

“RA” along with the presence of high-titer anti-U1 small nuclear (“sn”) anti-RNP antibodies. Id.

at 61. The most common clinical manifestations of MCTD are Raynaud’s phenomenon,

arthralgias, swollen hands, fingers with a sausage-like appearance, and muscle weakness. Id. at

62. These symptoms appear in 90 percent of patients and usually develop insidiously. Id. The

authors state that anti-U1-RNP antibodies are the hall

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