# In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 16-538V Filed: October 4, 2021

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

JOSEPH MORAN,

Petitioner,

v.

SECRETARY OF HEALTH AND HUMAN SERVICES,

Respondent.

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Special Master Katherine E. Oler

Ruling on the Record; Entitlement; Rheumatoid Arthritis; Influenza Vaccine.

Andrew D. Downing , Van Cott & Talamante, PLLC, Phoenix, AZ, for Petitioner

Althea W. Davis , U.S. Department of Justice, Washington, DC, for Respondent

DECISION ON ENTITLEMENT 1

On May 2, 2016, Joseph Moran (“Petitioner”) fi led a petition for co mpensation under the National Vaccine Injury Compensation Program 2 alleging that he suffered rheumatoid arthritis (“RA”) as a result of the influenza (“flu”) vaccination he received on October 17, 2013. Pet., ECF

No. 1 at 1. For the re asons set forth below, I find that Petitioner has not preponderantly

demonstrated the flu vaccine can cause RA or that it did so in this case.

1 Because this Decision contains a reasoned explanation for the action in this case, I intend to post this Decision on the United States Court of Federal Claims’ website, in accordance with the E-Government Act of 2002, Pub. L. No. 107-347, § 205, 116 Stat. 2899, 2913 (codified as amended at 44 U.S.C. § 3501 note (2012)). This means the Decision will be availa ble to anyone with access to the internet . As provided by 42 U.S.C. § 300aa-12(d)(4)(B), however, the parties may object to the Decision’s inclusion of certain kinds of confidential information. Specifically, under Vaccine Rule 18(b), each party has fourteen days within which to request redaction “of any information fu rnished by that party: (1) that is a trade secret or commercial or financial in substance and is privileged or confidential; or (2) that includes medical files or similar files, the disclosure of which would constitute a clearly unwarranted invasion of privacy.” Vaccine Rule 18(b). Otherwise, the Decision in its present form will be available. Id.

2 The Vaccine Program comprises Part 2 of the Nati onal Childhood Vaccine Injury Act of 1986, Pub. L. No. 99-660, 100 Stat. 3758, codified as amended at 42 U.S.C. §§ 300aa-10 through 34 (2012) (“Vaccine Act” or “the Act”). Individual section references hereaf ter will be to § 300aa of the Act (but will omit that statutory prefix).2 I. Procedural History

Petitioner filed a statement of completion on May 26, 2016. ECF No. 9. On July 25, 2016, Respondent filed a Rule 4(c) Report recommending against compensation. ECF No. 11.

Petitioner filed an expert report authored by Dr. Thomas Zizic on October 27, 2016. Ex. 18, ECF No. 16, and supporting medi cal literature on December 5, 2016, ECF Nos. 19-21. On March 20, 2017, Respondent filed an expert report by Dr. Mehr dad Matloubian. Ex. A, ECF No. 26, and supporting medical litera ture on May 17, 2017. ECF Nos. 27- 30. Petitioner then filed Dr. Zizic’s rebuttal expert report on July 3, 2017. Ex. 49, ECF No. 31. On July 25, 2018, Respondent responded by filing Dr. Matloubian’s sec ond expert report. Ex. C, ECF No. 43.

On September 14, 2018, Petitioner f iled a status report indicating his preference for a ruling

on the record. ECF No. 45. On No vember 28, 2018, Petitioner filed his brief (ECF No. 47) and Respondent filed his response on April 2, 2019 (ECF No. 53). Petitioner filed a reply on April 9,

2019. ECF No. 54.

On May 23, 2019, I requested supplemental expe rt reports from each party responding to additional outstanding questions. ECF No. 56. Pe titioner filed Dr. Zizi c’s report on July 1, 2019, Ex. 53, ECF No. 58, and Respondent filed Dr. Ma tloubian’s report on July 22, 2019. Ex. D, ECF

No. 59.

On August 7, 2019, I asked the parties to file a joint status report indicating that all evidence

had been submitted and that no additional records needed to be filed. Non-PDF Scheduling Order of 8/7/2019. On August 27, 2019, the parties confirme d that the record is complete. ECF No. 60.

I held a status conference on February 10, 2020 where I informed the parties that I had more questions regarding Althen prong one that I did not believe could be answered by additional filings. Scheduling Order dated Feb. 10, 2020. ECF No. 61. I told the parties that I wanted to have an entitlement hearing so that I could hear the testimony of th e experts and ask questions as

necessary. Id.

I conducted an entitlement hearing via WebEx on August 18, 2020 and on October 26, 2020. The parties filed a joint status report on D ecember 17, 2020 indicating that the record was complete. ECF No. 79. This matter is now ripe for a decision.

II. Medical History

Petitioner was born on May 1, 1958. Ex. 3 at 2. Petitioner received a flu vaccination on October 17, 2013. Ex. 2.

On December 4, 2013, Petitioner visited Trista n Guevara, DO at Silver Pine Medical Group. Ex. 7 at 16. The “History of Present Illne ss” (“HPI”) section of the medical records from

this visit states that Petitione r “present[ed] with cold symptoms[...]nasal congestion[,] and postnasal drainage...” Id. Petitioner stated that “[o]ns et was sudden 2 month(s) ago.” Id . His3 symptoms included swollen lymph nodes, fatigue, and weakness. Id . The “Problem List/Past Medical” listed “[j]oint [p]roblems, “[j]oint aches,” and “[b]ackache.” Id . Petitioner was noted to be a “[f]ormer smoker” who “[q]uit [in] 1996.” Id . He was diagnosed with acute sinusitis and prescribed amoxicillin, Flonase and Claritin-D. Id . at 17.

Petitioner returned to Silver Pine Medi cal Group on December 26, 2013. Ex. 7 at 14. He reported “cold symptoms,” “nasal congestion,” and “runny nose.” Id . The “Problem List/Past Medical” again listed “[j]oi nt [p]roblems, “[j]oint aches,” and “[b]ackache.” Id . The nasal mucosa examination was described as “[b]oggy, [c]ongested and [p]ale” and the nasal septum was noted

to be “deviated to left.” Id . at 15. The assessment was acute sinusitis and note d that he had “failed

amoxicillin.” Id . He was prescribed Cefdinir and referred for his deviated septum. Id

.

On January 16, 2014, Petitioner vi sited Shores Podiatry Asso ciates. Ex. 6 at 1. The “[s]ubjective” portion of this records reads:

Patient presents to office complaining of painful bilateral plantar foot. Patient reports increased activity leading to the onset of pain. Patient st ates he was having pain in the heel of his feet and when he was [at] a hoc key game he was walking on the ball of his feet. This caused pain in th e ball and ankle of hi s feet. The heel is feeling fine now. He is pointing to the ri ght 4/5 [intermetatars al] and left dorsal

midfoot...

Ex. 6 at 1. The assessment included “neuro ma, arthritis, tinea, [and] onychomycosis.” Id . Petitioner received a dexamethasone phosphate and ma rcaine injection in his right foot. Id

.

On February 11, 2014, Petitioner saw ENT Dr. Robert Fishman, who de termined that “a lot of his symptoms [were] due to the dryness in the air and his allergies.” Ex. 8 at 6. Dr. Fishman found no evidence of persistent sinusitis. Id

.

On March 5, 2014, Petitioner returned to Dr. Guev ara at Silver Pine Me dical. Ex. 7 at 10. The HPI states “[t]he patient feels well with no complaints, has good ener gy level and is sleeping

well.” Id . The “Problem List/Past Medical” again liste d “[j]oint [p]roblems, “[j]oint aches,” and “[b]ackache.” Id . The assessment included Plantar Fasciitis. Id . at 12.

Petitioner returned to the podiatrist on March 10, 2014. Ex. 6 at 3. The “[s]ubjective” section of this record states that “[p]atient pres ents with multiple complaints. Patient [complains of] pain in both feet & ankles. Patient has noted this problem fo r several months. Patient notes recurrent pain & swelling in th e 4 space righ t foot. Patient did note some improvement with injection given previously.” Id . The physical examination revealed “a forefoot cavus deformity

bilateral.” Id . There was “pain & swelling in the 4[th] space [of the] right foot.” Id . It was noted that “[t]here is diffuse foot & ankle pain bilateral.” Id . The plan noted that “patient does have pain in both shoulders. Recommend blood work to rule out systemic arthritis.” Id . It was recommended that Petitioner have an MRI “due to patient’s recurrent pain & swelling.” Id . at 3. An MRI was done at Henry Ford Macomb Hospital on March 30, 2014. Id . at 5.

On March 28, 2014, Petitioner’s bloodwork rev ealed an abnormally high rheumatoid4 factor. Ex. 3 at 112. His C-reactiv e protein (“CRP”) and erythrocyt e sedimentation rate (“ESR”) were normal, he had a negative anti-nuclear an tibody (“ANA”) screen, and hi s vitamin D was low. Ex. 3 at 14, 16, 18-20.

Petitioner returned to Shores Podiatry Asso ciates on April 14, 2014 to review the results of the MRI. Ex. 6 at 4. The “subjective” portion of the record from the visit states, “Patient notes some continued pain in the ri ght foot. Patient’s blood work shows significant markers for

rheumatoid arthritis.” Ex. 6 at 4. The record also notes “Review MRI results. Advise patient that

the MRI shows a soft tissue ma ss which may represent a rheuma toid nodule versus neuroma. Recommend surgical exci sion. Patient wishes to defer at th is point due to need for further

evaluation & initiation of treatment for the rheumatoid arthritis.” Id . The radiology record from Henry Ford Macomb Hospital notes “3.2 cm soft ti ssue lesion that has a fourth metatarsals most

consistent with a neuroma.” Id . at 5.

On April 29, 2014, Dr. Timothy Brennan, a rheu matologist at the S hores Rheumatology, PC, examined Petitioner and opined on his condition. Ex. 3 at 101. Dr. Brennan wrote,

In October of 2013, he recalls a day where hi s left heel was painful following which he developed significant pain and discomfort in both sets of metatarsal phalangeal joints. Over time, this progressed to invol ve both wrists, his me tacarpal phalangeal joints, both elbows, and the left knee. He identifies mornings as his worst time but can’t quantify the leng th of his stiffness...

Id . Under “[f]amily history,” Petiti oner indicated that “[h]e is una ware of anyone with connective tissue diseases or inflammatory arthritis.” Id . Dr. Brennan noted that Petitioner was “judged as being a good historian.” Id . at 102. The “[j]oint examination was significant for te nderness of both elbows,” and “[h]e was tender at the right fourth PIP joint.” Id . at 102. The examination also revealed “bony hypertrophy at both first metacarpal phalangeal jo ints” and it was noted that Petitioner was “significantly tende r over all 5 of the right and le ft first metatarsal phalangeal joints.” Id . Dr. Brennan concluded that Petitioner had “chronic si gns and symptoms of an inflammatory, peripheral, symmetrical polyarthrit is and a high titer positive rheumatoid factor consistent with rheumatoid arthritis,” and that “[t] here is a soft tissue mass in the right foot between

the fourth and fifth metatars al phalangeal joints consiste nt with a neuroma on imaging.” Id . Dr.

Brennan “initiated treatment with 5 mg of prednisone per day.” Id

.

Petitioner followed up with Dr. Brenna n on May 13, 2014. Ex. 3 at 104. Petitioner requested a second opinion at th e University of Michigan. Id . The record notes that Petitioner “does not recognize any significant improvement since starting prednisone. He does complain specifically that his left elbow, left knee, and both ankles have become symptomatic.” Id . Dr.

Brennan wrote that Petitione r “is convinced that his rheumatoid disease was precipitated by receiving an influenza vaccine. It was his first and only vaccination. He has been reading online and states that prior to this he was ‘perfectly healthy.’ He info rms me that he is ‘talking to a lawyer.’” Id . The examination revealed “tenderness but no overt inflammatory synovitis, rashes,

or nodules.” Id . Dr. Brennan noted that “[Petitioner’s] anti-CCP antibody return strongly positive at greater than 200 units per mil liliter” and his impression was “Rheumatoid factor and anti-CCP positive rheumatoid arthritis.” Id . at 105. Petitioner and his doctor “had a very lengthy discussion5 about the disease, its etiology, prognosis, and therap eutic alternatives” and “[b]y the end of [their] discussion, he elected to begin treatment with methotrexate.” Id . A return visit was scheduled for

four weeks. Id

.

On June 11, 2014, Petitioner returned to Shor es Rheumatology. Ex. 7 at 65. Dr. Brennan noted that “[b]ecause he was feeli ng somewhat better, he has elected not to start methotrexate yet.”

Id . The record further indicates that “[Petitioner’ s] symptoms tend to be extremely variable. He has bad days where he feels fati gued and has diffuse joint pain a nd stiffness involving his ankles, feet, hands, and wrists. At other times he feels quite well. His morning stiffness tends to vary greatly.” Id . Dr. Brennan noted that during the exa mination he “could not detect any active inflammatory synovitis although [P etitioner] does have multiple areas of joint tenderness.” Id . The doctor’s impression was rheumatoid disease and he planned to “resubmit the request for a second opinion at the Universi ty of Michigan.” Id . at 66.

Petitioner met with Dr. Viju Moses, MBBS at the Universi ty of Michigan Rheumatology Clinic on September 2, 2014. Ex. 3 at 6. During that visit, Dr. Mo ses noted Petitioner’s history:

His symptoms started in Oct[ober] 2014, a few days after a flu shot. He first noted pain in the top of both feet. It was worse in the morning, and he had morning

stiffness of 3-4 hours...Since Mar[ch] 2014 he started gett ing pain in his hands, w rists [sic], L[eft] shoulder, R[ight] knee and L[eft] bu ttock>R[ight] buttock. Unsure about morning stiffness fo r these joints...Fluctuating fatigue, sometimes severe.

Id . Additionally, “[a]t baseline [Petitioner] is involved in various sports and exercises, and

continues to do so with difficulty. For example[,] hand sy mptoms impair playing basketball.” Id

. Petitioner reported to Dr. Moses that “more re cently his hand pains have been bothering him again.” Id . Bloodwork from that visit re vealed a high Rheumatoid fact or value of 476, noting the normal range as being 0-15 IU/mL, and a high cyclic citr ullinated peptide an tibody value of >250, noting the normal range as being 0-19 U/mL. Id . at 10. Dr. Moses conclude d that these findings

were “consistent with Rheumatoid arthritis.” Id . at 12.

On October 31, 2014, a reading of Petitioner’s September 2, 2014 MRI revealed “[f]ocal soft tissue enhancement along the dorsal web sp ace between the fourth and fifth MTP joints, without definite bony erosions,” with “possible associated fifth MTP synovial enhancement and perforation.” Ex. 3 at 48. The record s indicated that “[t]his could be compatible with focal synovitis given the patient’s apparent hist ory of rheumatoid arthritis, how ever, definite c onnection to the

intra-articular soft tissue cannot be determined on current study.” Id

.

Petitioner went to Renaissance Pl astic Surgery for excision of a nodule at the base of his glabella on December 11, 2014. Ex. 5 at 1. The me dical history included “rheumatoid arthritis occurring after a flu shot.” Id

.

On December 30, 2014, Petitioner reported to Dr. Moses that “[h]is joint symptoms were well controlled till 2-3 weeks ago, after which he has been having increased joint pains, with no swelling but possible increased mo rning stiffness for 1-2 hours. ” Ex. 3 at 55. Dr. Moses noted

Petitioner “has features of flare of RA with worsening of symptoms and morning stiffness.” Id

.6 The plan was to increase his dose of methotrexate to 20mg per week. Id

.

Petitioner returned to Dr. Mose s on May 5, 2015. Ex. 3 at 67. The record notes that “[h]e currently has pain in the L[eft]>R[ight] shoulders . Has noted locking of the L[eft] 2nd digit a few times. R[ight] knee becomes painful with exercise. The balls of his feet are sometimes painful. There is no morning stiffness, but the L[eft] shoulder pain is better after exercise.” Id . The musculoskeletal exam revealed “[ m]ild tenderness in PIPs of hands with some s ynovial thickening. Mild tenderness in MCPs. Normal ROM. No pa lpable nodule adj[acent] to the L[eft] 2nd metacarpal. L[eft] elbow flex ion deformity, milder on R[ight ].” Dr. Moses decided to add Plaquenil and sulfasalazine “to prev ent progression of joint damage.” Id . at 69.

On May 11, 2015, Petitioner saw Dr. Guevara at S ilver Pine Medical fo r “cold symptoms.” Ex. 7 at 7. Joint problems, joint aches, and backache were noted under problem list. Id . On May 20, 2015, Petitioner returned to Silver Pine Medical for a physical. Id . at 3. The record notes that he “feels well with no complaints.” Id

.

On July 17, 2015, Petitioner spoke with a medi cal assistant over the phone about his lab results and reported that “the balls of his feet are really painful. He said his toes are not swollen or painful, just the balls of his feet. He also said that the knuckle of his ri ng finger on his left hand is also very painful. He also has pain that come s and goes in his shoulder.” Ex. 3 at 81. Similarly, on August 10, 2015, Petitioner called Dr. Moses’ office “with complaints of pain in his feet in the past month. Pain/swelling in balls of feet. Pain in hands Left > Right.” Id . at 83.

On October 9, 2015, Petitioner called Dr. Mose s’ office again compla ining that he had “painful and swollen feet that he can hardly walk. He st ate[s] that the methotrexate is not working and he do[es] not want to take Prednisone.” Ex. 22 at 1. Later that day, Petitioner spoke with a resident in Dr. Moses’ office, the record from which states, “[ h]e is complaining of sever[e] bilateral feet pain and he is unable to walk comfortably. Two days ago he noted bilateral hand swelling and fingers locking o[n] him while drivi ng. He stated that steroids not working for him and he has been on steroids for [t]he last year as well as methotrexate and sulfasalazine.” Id . at 2.

Petitioner had a follow-up with Dr. Mose s on March 22, 2016 noting “pain in multiple joints, including the MTPs, knees, shoulders, and PI P joints of hands. He notes morning worsening especially in the feet.” Ex. 22 at 20. Dr. Moses no ted Petitioner was “not willing to do any further vaccinations since he was concerned about the possi bility of RA associated with a[n] influenza

vaccine.” Ex. 21 at 12.

On July 1, 2016, Janet Kennedy, RN spoke with Petitioner over the phone and reported:

Patient started Humira approximately 2 months ago. After first injection he experienced lower back muscle stabbing pain that ended in 1-2 days. Following the first injection he repor ts that he has joint pain [in] shoulders L[eft]>R[ight], hips,

hands and feet. He states that with each injec tion that the pain is getting worse and is not subsiding. He is having difficulty walking.[] Patient is also experiencing muscle spasms in lower back and calves that occurs 1-2 days after injection.7 Ex. 22 at 31.

Petitioner spoke with Dr. Moses’ office 3 over the telephone on September 6, 2016 and reported that “he has had pain in his hips for the past month and the pain is getting worse. Patient states it is really bad in his left hip and it is hard to cross his le ft leg.” Ex. 22 at 36. A record of a telephone call later that day reads “f or the past 1.5 months, he has been having significant pain in both of his hips, which is most severe in his left hip and accompanied by a loss of mobility. Patient

states that the loss of mobility prevents him fr om running, and prevents hi m from doing daily tasks such as washing his feet in the shower. Patient states that he fi nds these symptoms very worrying

. . .” Id

.

A follow-up telephone call with Laurie Coppock, RN notes that she “[s]poke with pt and he is experiencing significant limitations to his ADL s. His left hip is the most severe. He can not lift to cross his legs and the pain is a 8-9/10 when walking. Pts left elbow has had a[n] increase in pain but it is his hip that he is very concerned wi th. Pt states that he ‘feels like he has blown out his hip[.]’ It just will not work anymore.” E x. 22 at 36. On September 7, 2016, records of a call with Dr. Jessie Alperin note that Pe titioner “has severe pain in the le ft hip. He is not able to cross his leg. He has severe pain with walking. He does also note pain in the right hip, but not severe.”

Id . at 37.

III. Affidavits, Expert Reports, and Testimony

A. Petitioner’s Affidavit

Within a day or two of the shot, Petitioner stated that he began experiencing swelling around his neck and jawline which continued about a week. Ex. 1 at ¶ 4. He also began to experience pain in the tops of both of his feet. Id . The foot pain, along with fatigue, malaise, and a general stiffness of his entire body, worsened in the early morn ing and lasted for a few hours. Id

. In an effort to reduce the pain, Petitioner stated that he used over-the-c ounter medication with

some benefit. Id . Petitioner thought that he was either gett ing a cold or the flu. Id . at ¶ 5. He was having continued foot pain and stiffness. Id . He was also experien cing nasal congestion and postnasal discharge. Id

.

B. The Parties’ Experts

1. Petitioner’s Expert – Dr. Thomas Zizic

In support of his claim, Petiti oner offered the medical expert opinion of Dr. Thomas Zizic.

Dr. Zizic has been an Assistant and then an As sociate Professor of Medicine at Johns Hopkins University School of Medicine in Baltimore, Ma ryland since 1973. Ex. 19 at 2 (hereinafter “Zizic CV”). He was also the Associate Director of the Rheumatic Disease Unit for Johns Hopkins at the Good Samaritan Hospital from approximately 1975 to 1985. Id. at 4.

Dr. Zizic is a founding fellow of the American College of Rheumatology. Zizic CV at 3.

3 Records indicate Dr. Moses left the University of Mi chigan some time prior to September 6, 2016. Ex. 22

at 36.8 He received his medical degree from Johns Hopkins University School of Medicine in 1965 and completed an internship and residency in internal medicine at Johns Hopki ns University Hospital

Center from 1965 to 1967. Id. at 1-2. From 1967 through 1969, Dr. Zizi c served as a flight surgeon at the School of Aerospace Medi cine at Brooks Air Force Base in San Antonio, Texas and from 1969 to 1971, he served as Post-Doctoral Fe llow in Rheumatology at Johns Hopkins. Id. at 2.

In 1971, Dr. Zizic became an Inst ructor of Medicine and has remained on the faculty at Johns Hopkins University School of Medicine. Zizic CV at 2. For the first seventeen years, he was full-time faculty, after which he began serving pa rt time upon entering in to private practice in rheumatology. Id. at 6-7.

Dr. Zizic is former President of the Maryla nd Society of Rheumatic Disease and was on

the National Committees of the Arthritis Founda tion and the Lupus Foundation. Zizic CV at 3-4.

He is also co-Founder of the National Osteon ecrosis Foundation and curr ently on the Board of

Directors of the National Center for Osteonecrosis Research and Education. Id. at 5-6.

Dr. Zizic’s research has incl uded osteoarthritis, osteoporosis , osteonecrosis, the study of connective tissue diseases including damage to cartilage and tendons a nd such disorders as systemic lupus erythematosus, polymyalgia rheuma tica, rheumatoid arthritis, polymyositis and a variety of other diseases that have an immuno logic basis. Zizic CV at 19-25. Dr. Zizic has published approximately 100 articles and abstracts as well as several dozen chapters in medical

textbooks. Id. at 7-18.

Dr. Zizic authored a total of three reports in this case and testified during the entitlement hearing. Dr. Zizic opined that Petitioner’s flu vaccine caused his RA.

2. Respondent’s Expert – Dr. Mehrdad Matloubian

Respondent offered the medi cal expert opinion of Dr. Mehrdad Matloubian. Dr. Matloubian is a physician and Associ ate Professor of Medicine in th e division of rheumatology at the University of California, San Francisco. Ex. B at 1 (hereinafter “Matl oubian CV”). He has been on faculty at UCSF for approximately 20 years. Matloubian CV at 2. Dr. Matloubian is a boardcertified and practicing rheumatologist. Id.

Dr. Matloubian also has a Ph.D. in virology/ immunology and has been engaged in research in this area for more than twenty years. See generally , Matloubian CV. His areas of expertise include T and B cell responses, especially to viru ses as well as factors that regulate lymphocyte circulation and trafficking. Id. at 2-3. Throughout most of his re search career, he has focused on innate and adaptive immune responses, including thos e of T and B cells, to acute and chronic viral

infections. Id. at 6-7. Dr. Matloubian has published p eer-reviewed articles in both areas. Id. at 8-

11.

Dr. Matloubian actively evaluates and treats patients with complex autoimmune diseases at a tertiary referral center and has a great in terest in mechanisms of autoimmunity. Matloubian

CV at 2. Tr. at 204-08. He is qualified to address both dia gnostic and immunological issues regarding these diseases.9 Dr. Matloubian authored a total of three report s in this case. He also testified during the entitlement hearing. Dr. Matloubi an opined that Petitioner’s vacci ne was not the cause of his subsequently-diagnosed rheumatoid arthritis.

C. Expert Reports

1. Dr. Zizic’s Firs t Expert Report

Dr. Zizic authored a total of th ree reports in this case. Exs. 18, 49, 53. Dr. Zizic also testified at hearing. Dr. Zizic opined that Petitioner’s flu vaccine was th e cause of his subsequentlydiagnosed non-erosive seroposi tive rheumatoid arthritis.

In Dr. Zizic’s first report filed on Oct ober 27, 2016, he began by summarizing Petitioner’s medical history and then provided his opinion and analysis. Ex. 18 at 1-16, (hereinafter “First Zizic Rep.”). Dr. Zizic started out with an overvie w of the adaptive immune system and general immunological processes.

Dr. Zizic acknowledged that the e tiology or cause of rheumatoid arthritis is still unknown. First Zizic Rep. at 18. However, there have been major advances in ou r understanding of the pathogenesis of RA. Id . He stated that currently, it is believ ed that RA develops in a “genetically susceptible individual in response to one or more environmental triggers.” Id . Dr. Zizic said that infection and immunization, “whose function is to s timulate the immune system in order to protect against a specific infection,” are considered among those envi ronmental triggers and that “musculoskeletal symptoms (arthralgia, arthritis) may occur in response to different types of

immunizations.” Id

.

Dr. Zizic pointed to studies by Harrison et al . (Ex. 36) and Symmons et al. (Ex. 37), which showed “48 of 898 (5.3%) pa tients with early infl ammatory polyarthritis referred to the Norfolk Arthritis Register reported an immu nization with tetanus toxoid or influenza in the six weeks prior to symptom onset.” First Zizic Rep. at 19. He stated that “[t]he authors concluded that in a small number of susceptible indi viduals, immunization may ac t as a trigger for RA.” Id

.

Dr. Zizic went on to explain that this occurs when the “body’s immune system produces antibodies to infectious agents or vaccines that cross-react with self-molecules,” a process called molecular mimicry. First Zizic Rep. at 19. He stated that based on fa milial studies, it is believed that the HLA molecule plays a major role in the genetic-susceptibili ty component of RA. Id . ( citing Deighton et al., The contribution of HLA to rheumatoid arthritis , 36 C LINICAL G ENETICS , 178-82 (1989) (filed as Ex. 38); Jawaheer et al., “ Homozygosity” for the HLA-DR Shared Epitope Contributes the Highest Risk for Rheumatoid Arthritis Concordant in Identical Twins , 37

A RTHRITIS & R HEUMATISM , 681-86, 1994 (filed as Ex. 39); Gregersen et al., The Shared Epitope Hypothesis , 30 A RTHRITIS & R HEUMATISM 1205-13, 1987 (filed as Ex. 40). Dr. Zizic stated that the HLA-DRB1 shared epitope found in RA patients is the result of “cross-reactivity and molecular mimicry with a pathogen.” First Zizic Rep. at 19; citing Ollier et al., Genetic epidemiology of

rheumatoid disease , 51 B RITISH M EDICAL B ULLETIN 267-85, 1995 (filed as Ex. 29).10 Dr. Zizic highlighted acute rheumatic fever as an example of molecular mimicry from infectious disease. First Zizic Rep. at 20. Strept ococcus antigens cross-react with self-antigens resulting in inflammation in the joints, skin, brain, and heart causing acute rheumatic fever. Id . As an example of molecular mimicry in vaccine-induced autoimm une disease, Dr. Zizic pointed to Lyme vaccine, a protein which cross reacts with hLFA-1 self-molecules causing arthritis. Id . The Lyme vaccine has since been removed from the market. Id

.

Dr. Zizic explained that humans have over te n billion B and T cell receptors, randomly developed and unique to each individual. First Zi zic Rep. at 20. Some people have an effective immune response to vaccinations while others have no or an inadequate response. Id. Dr. Zizic stated that because of this vast repertoire and genetic heterogeneity, it would be unlikely that even large epidemiologic studies can capture the rare incidents of vaccine-induced autoimmunity. Id.

Dr. Zizic went on to describe research that demonstrates molecular mimicry between the influenza virus and a portion of the type II co llagen (“CII”) molecule as a mechanism by which the influenza vaccine can trigger autoimmunity. Firs t Zizic Rep. at 20-21. An article by Sekine et al. highlights the importance of CII in RA pathogenesis. See Sekine et al., Type II collagen is a target antigen of clonally expanded T cells in the synovium of patients with rheumatoid arthritis

, 58 A NN R HEUM D IS 446-50 (1999) (filed as Ex. 44). It has been shown that a CII peptide (256- 271) contains epitopes that can tri gger an RA-specific T cell response. Id . at 21 ( citing Diab et al., Human collagen II peptide 256-271 preferentially binds to HLA-DR molecules associated with susceptibility to rheumatoid arthritis , 49 I MMUNOGENETICS 36-44 (1999) (filed as Ex. 45)). Dr. Zizic explained that influenza virus hemagglu tinin 308-317 peptide sh ares a similar threedimensional structure with CII 256-271 for purposes of molecular mimicry and can thus bind HLA-DR4/1 molecules with higher affinity. Id. Dr. Zizic stated that “[t] hus, it is logical that the influenza virus hemagglutinin peptide acts in a simi lar mean as the CII peptide, with respect to induction of [RA].” Id

.

Dr. Zizic concluded that, with respect to the first prong of Althen , Petitioner’s vaccination triggered activation of B and/or T lymphocy tes through “molecular mimicry, cross-priming, immune complex formation or a combination of th ese, which because of Joseph Moran’s genetic susceptibility, resulted in autoimmu nity and the development of RA.” First Zizic Rep. at 21. As to the second prong, Dr. Zizic explained that, (1) Peti tioner did not have any symptoms prior to his vaccination, (2) his RA diagnosis was contempo raneously documented, and (3) he was found to be strongly seropositive. Id . Dr. Zizic then stated that other autoimmune diseases were excluded both clinically and after various tests. Id . He stated that “it is my opinion that this is a logical sequence of cause...and [] effect.” Id. at 21-22. Finally, with resp ect to prong three, Dr. Zizic opined that “the petitioner developed RA symptoms within days after th e influenza vaccination” and that “this is precisely the timeline that one would expect.” Id . It is Dr. Zizic’s opinion, “that the facts of this case support the view that Mr . Joseph Moran, more likely than not, developed new

onset of RA as a result of the influenza vaccination.” Id

.

2. Dr. Matloubian’s First Expert Report

In his first report filed on March 20, 2017, Dr. Matloubian high lighted a number of factors in support of his position that Pe titioner’s vaccine did not cause his condition. Ex. A (hereinafter11 “First Matloubian Rep.”). Petitione r was diagnosed with a neuroma in his foot several months after

his influenza vaccination and subsequent bloodwork revealed abnormally high rheumatoid factor and anti-CCP antibodies. Dr. Matloubian stated that developm ent of autoantibodies precedes clinical manifestation of RA by many years and th at the environmental factors that trigger fullblown disease are not yet known. First Matloubian Re p. at 6-7. He pointed to various studies into the effects of vaccines in support of his theory that no causal relationship to RA has been established, including one whic h revealed no exacerbation of symptoms following immunization of RA patients with the influenza vaccine. Id . at 8.

Dr. Matloubian attributed Petitioner’s rheuma toid arthritis to his history of smoking, calling it a “major major risk factor.” First Ma tloubian Rep. at 16. He stated that smoking “has been strongly associated with seropositive RA.” Id . Dr. Matloubian also suggested Petitioner’s use of antibiotics could have led to the developmen t of autoimmunity by affecting his gut microbiome and the balance of his immune system. Id.

Dr. Matloubian concluded that a link betw een the influenza virus and inflammatory arthritis has never been found, thus making it “implausible that an influenza vaccin e would do so.” First Matloubian Rep. at 16.

3. Dr. Zizic’s Second Expert Report

In his second report filed on July 3, 2017, Dr. Zizic respon ded to Dr. Matl oubian’s first report. Ex. 49 (hereinafter “Second Zizic Rep.”). Fi rst, he made clear that he agrees with Dr.

Matloubian that deferral to the tr eating physicians with respect to diagnosis is appropriate. Second Zizic Rep. at 1. Most notably, he highlight ed a recent study done by Firestein et al. Id .; Firestein et al., Immunopathogenesis of Rheumatoid Arthritis , 46 I MMUNITY 183-96 (2017) (hereinafter “Firestein”) (filed as Ex. 50). Dr. Zizic explained that based on this article, it is believed that “RA starts with a high-risk genetic background.” Se cond Zizic Rep. at 1. Dr. Zizic went on to quote that “[o]ne of the important lessons of this pr olonged and stepwise pre-RA process is that the sequence of events does not require autoimmunity ag ainst the native protein in the earlier stages.”

Id . ( quoting Firestein at 6).

Dr. Zizic reiterated “[i]t is still more likely that [Petitione r’s] influenza vaccination, given in a temporally-appropriate time prior to his first manifestation of symptoms of RA, was the causative agent for the development of disease.” Id

.

4. Dr. Matloubian’s Second Expert Report

In his second report filed on July 25, 2018, Dr. Matloubian responded to Dr. Zizic’s second report. Ex. C (hereinafter “Second Matloubian Rep.”). Dr. Matloubian reiterated that “the disease process starts years before” clinical manifestation of rheumatoid arth ritis in the form of joint pain or swelling. Second Matloubian Rep. at 1. Dr. Ma tloubian stated that “i mmunological processes that led to the petitioner’s development of RA were going on for years before he presented with joint pain and was diagnosed with RA.” Id . at 2.

Dr. Matloubian cited an ongoing c linical trial exploring whethe r treatment of asymptomatic12 people with positive anti-CCP antibody can prevent th e future development of clinical RA. Second Matloubian Rep. at 2. The rationale behind the study, he stated, is that “individuals with elevation of anti-CCP greater than 2 times the normal valu e have approximately a 50 % chance of developing RA within 3 years.” Id

.

In addressing Dr. Zizic’s theory of molecula r mimicry, Dr. Matloubian cited to Firestein: “‘more than 90% of patients with RA e xpress one of the variants of HLA-DR4.” Id . at 2. Dr. Matloubian argued that if Dr. Zizi c’s molecular mimicry theory were true, then one would expect to see a greater incidence of in fluenza vaccine or inf ection-related exacerbation of symptoms in this genetically susceptible gr oup. He stated that “based on me dical literature and multiple studies...1) influenza infection does not lead to deve lopment of an autoimmune arthritis similar to RA; 2) influenza vaccination is not associated with development of RA even in those who have HLA-DR4, also known as HLA-DRB1; and 3) patients with RA do not have worsening of their

disease after an influenza vaccination.” Id . at 3. Dr. Matloubian indicat ed that this is strong evidence against an association between influenza antigens and the subsequent development of RA via molecular mimicry. Id

.

5. Dr. Zizic’s Third Expert Report

In his third and fina l report filed on July 1, 2019, Dr. Zizic responded to specific questions I posed of each party’s expert. Ex. 53 (hereinafter “Third Zizic Rep.”).

In response to my first question, Dr. Zi zic opined that elevat ed levels of serum inflammatory markers, such as the erythrocyt e sedimentation rate (“ESR”) and CRP, are not necessary criteria in the diagnosis of RA. Third Zizic Rep. at 1. He highlighted a study of 9,135 active RA patients by Kay et al. that revealed approximately “58% had ne ither elevated ESR nor

CRP.” Id . at 1-2. He also pointed out that elevated acute phase response accounts for 1 point among the criteria for RA, “only a small component cont ributing to the clas sification criteria.” Id . at 2. Dr. Zizic added that “[i]f they were a requisite co mponent of the criteria the majority of patients with [RA] would no longer qualify for the diagnosis” as suggested by the Kay study. Id . at 3.

I then asked Dr. Zizic what symptom(s) he considered to be Petitioner’s clinical manifestation of onset. In response, Dr. Zizic stated that “[w]ithin days of the flu vaccination on October 17, 2013, Mr. Moran apparently developed pa in on the top of his feet, fatigue, malaise and generalized morning stiffness lasting 2 hours.” Third Zizic Rep. at 4. He went on to say, “[t]he most frequent joints involved in rheumatoid arthriti s are the small joints of the hands or the feet.”

Id . In Dr. Zizic’s opinion Petitioner’s onset of RA was this joint pain and stiffness days following

vaccination. Id

.

Finally, in response to my third question rega rding medical feasibilit y of the timing of onset, Dr. Zizic responded that “[t]he...progression from onset in a localized area such as small joints of the feet to involvement of multiple join ts with a [sic] ‘inflammatory peripheral symmetric polyarthritis, high titer rh eumatoid factor, consistent with rheumatoid arthritis’ over approximately six months is a very typical course in the deve lopment and progression of rheumatoid arthritis.” Third Zizic Rep. at 4.13 6. Dr. Matloubian’s Thir d Expert Report

Dr. Matloubian’s third and fina l report was filed on July 22, 2019, responding to specific questions I posed of each party’s expert. E x. D (hereinafter “Third Matloubian Rep.”).

In response to my first question, Dr. Ma tloubian expressed sk epticism regarding Petitioner’s diagnosis due to unremarkable physical exam s in April and May 2014. Third Matloubian Rep. at 1. Ultimately, however, he deferred to Petit ioner’s treating physicians with respect to his diagnosis of non-erosive seropositive RA. Id . at 2.

With respect to my second que stion regarding symptom onset, Dr. Matloubian stated that the medical records are unclear and they do not “p rovide any documentation [that] either physician observed joint swelling or instances of it be ing reported by the petitioner himself.” Third Matloubian Rep. at 2. Dr. Matloubian stated that Petitioner’s treaters at the University of Michigan noted “pain in other joints, including ha nds and wrists and buttocks since 3/2014.” Id . As such, Dr. Matloubian put onset “sometime in ‘3/2014.’” Id

.

Finally, I asked Dr. Matloubian for his opinion regard ing the significance of the fact that Petitioner quit smoking more than 15 years prior to onset/diagnosis. He stated that th at fact would

have no effect on his assessment. Third Matloubian Rep. at 3. Dr. Matloubian cited to an article by Malmström et al., The immunopathogenesis of seropositi ve rheumatoid arthritis: from
triggering to targeting , Nature Reviews ǀ Immunology, 1-16 (2016) (her einafter “Malmström”) (filed as Ex. A-5) to support his argument that sm oking is a high-risk factor in the development of

RA. Id . He explained that since RA is thought to go through multiple pre-c linical phases years prior to clinical pres entation, Petitioner’s smoking would ha ve led to a breakdown in tolerance resulting in autoimmunity. Id . Dr. Matloubian concluded “once this breakdown of tolerance has been triggered by smoking in a genetically susceptib le person, it can continue to progress to full blown clinical RA even if that person quits smoking.” Id

.

D. Expert Testimony

1. Dr. Zizic’s Testimony

Dr. Zizic testified during the entitlement hearing. I recognized him as an expert in the fields of immunology and rheumatology. Tr. at 14.

During his testimony, Dr. Zizic discussed severa l pieces of medical literature filed in support of Petitioner’s case. According to Dr. Zizic, the Norfolk Arthritis Re gistry was created in the United Kingdom in order to “lo ok at early polyarthritis to see wh at it evolved into.” Tr. at 23. ( see Symmons & Harrison, Early inflammatory polyarthritis: results from the Norfolk Arthritis Register with a review of the literature , B RITISH S OCIETY FOR R HEUMATOLOGY , 2000 (filed as Ex. 37) (hereinafter “Symmons”)). In discussing this article, Dr. Zizic highlighted the authors’ note, stating “there is evidence that tetanus and influenza immunizations may trigger RA in susceptible hosts.” Tr. at 29, citing Symmons at 5.14 Dr. Zizic testified that “In the NOAR case-co ntrol study there was an association between immunization in the 6 weeks preceding symptom onset and the development of rheumatoid arthritis. (Odds ratio, 2.4; 95 per cent confidence interval)” -- and they did overlap one, so it’s not totally statistically significant, just suggested". Tr. at 29-30.

Dr. Zizic also discus sed the Ray article. See Ray et al., Risk of rheumatoid arthritis following vaccination with tetanu s, influenza and hepatitis B va ccines among persons 15–59 years of age

, 29 V ACCINE 6592-97 (2011), (filed as Ex. A Tab 19) (h ereinafter “Ray”). Dr. Zizic testified that Ray demonstrated a 36 percent increased like lihood of developing rheumatoid arthritis within the 180 days after influenza vaccination as compar ed to unvaccinated individuals. Tr. at 44. Dr. Zizic also took issue with the authors’ findings , because the cohort analysis found a “possible

association” between RA and th e influenza vaccine in the previous 180 and 365 days; however, in the case-control analysis, “ cases were no more likely than cont rols to have received any of the

three vaccines .” Ray at 6592; Tr. at 36. Dr. Zizic testifie d that the authors in Ray improperly diluted the study with controls, which changed the results. He stated:

You can’t, because you don’t like the re sults of your initial study, go back and include patients that you excluded from the study initially for very good reasons. And, now, you’re going to put them back in and you put three times as many patients in as controls -- as compared to vaccinations? So if there’s a background rate, which there is, for rheumatoid arthri tis, you put three times as many controls with the background rate that’s the same as the vaccinated rate, and now the difference you’ve found is no longer statistica lly significant, which is exactly what happened here in a post-hoc analysis, wh ich is totally scientifically wrong.

Tr. at 38.

Dr. Zizic testified about simila r concerns about the validity of the Bengtsson study. He stated,

This is not a valid study because all of your cases, virtually, that occur after vaccination are going to occur within the first year. And so let's say you have a 25 percent increase in the firs t year. If you add four more years to both groups, now you've spread that 25 percent out over five years and it's 5 percen t. And so that you have so many more -- you've diluted that so that it's not significant anymore when you add four more years of observation.

Tr. at 389-90.

Dr. Zizic also discussed the Wang article. See Wang et al., Vaccinations and risk of systematic lupus erythematosus and rheumatoid arthritis: A systemic re view and meta-analysis

, 16 A UTOIMMUNITY R EVIEWS 756-65 (2017) (filed as Ex. 58) (her einafter “Wang”). According to Dr. Zizic, this article “definitively shows influe nza vaccination ... can caus e rheumatoid arthritis in some patients.” Tr. at 46. Specifically, Dr. Zizi c testified that the meta -analysis showed that “there was a 36 percent increased chance of developing rheumatoid arthritis if you got vaccination

versus no vaccination.” Tr. at 48.15 After discussing the literature that supports Petitioner’s position that flu vaccine can cause RA, Dr. Zizic testified in more detail about the specifics of his molecular mimicry theory.

Dr. Zizic began by defining some terms. He st ated that Type II collagen “is the collagen that is specific for carti lage and it is much more durable and resistant to load bearing”. Tr. at 55. He testified that type II collagen is one of the major autoantigens in RA. Id. at 56. “[W]e find antibodies to type II collagen not only circulating in the blood, but in the synovial fluid, bathing the lining of the joints in rheumatoid arthritis, and those immune complexes cause activation of the complement inflammatory system and cause damage to the joints and release the cytokines.”

Id.

Dr Zizic defined influenza vi rus hemagglutinin as “a porti on of the viral protein in influenza viruses, part of the viral antigen.” Tr. at 61. Influenza virus hemaggl utinin is also present

in the influenza vaccine.

Dr. Zizic opined that molecular mimicry is a reasonable theory by which vaccination with the influenza vaccine can cause RA. He opined that the literature demonstrates that both type II collagen and the wild type influe nza virus hemagglutinin can be recognized and activated by the same type II collagen specific T cell clones from pa tients with rheumatoid arthritis. Tr. at 169-70. When asked whether any of the medical literature specifically indicates that the same T cell can be activated by both the collagen peptide and th e influenza HA peptide, Dr. Zizic testified as

follows:

Well, as we talked a bout earlier, I think when you’re looking at the Sun article, the type II collagen and the he magglutinin peptide both ac tivated T cells and you could inhibit them by the altered hemagglutinin pe ptide. If you want to read that, we can go back to that article. That’s the one -- not every article is going to get what you want, but that one says it best, I think.

Tr. at 125-26.

He further testified as follows:

both of them activate the T cell because they’re cross-reacting here. And that

activated T cell from that clone of T cells for rheumatoid arthritis patients and peripheral blood lymphocytes, that activation can be i nduced by either one. What more do you want for molecular mimicry?

Tr. at 127.

Dr. Zizic discussed the onset of symptoms of RA in Petitioner’s case. He opined that Petitioner’s first symptom of RA was the pain an d swelling in his feet. Tr. at 72, 81. He described plantar foot pain as pain in the area under the sole and the arch of the foot. Id. at 99. He opined that pain in this region was consistent with RA because “not only do the joints get involved, sometimes the tendon sheaths get in flamed. And so you can have gene ralized pain in that plantar16 fascia area where the tendons are attaching to the small bones of the toes, the MTP joints, which

is the ball of the foot.” Tr. at 173-74.

In support of this position, Dr. Zizic disc ussed Petitioner’s January 16, 2015 medical appointment. He testified that Dr. DeYoung deter mined, “there was moderate pain and tenderness -- a moderate pain to palpation, wh ich is tenderness. She called it ar thritis and then injected with

Dexamethasone.” Tr. at 103; Ex 6 at 1.

Dr. Zizic testified that an onset of symptoms two days following vacci nation is a medically appropriate interval. His opinion wa s premised on a recall response. He stated, “one may have had exposure to that same antigen in previous influe nza injection vaccination th at weren’t sufficient to

cause effector T cells to form bu t were sufficient to activate me mory T cells, which on re-exposure would cause a more rapid -- a stronger response than the first exposure.” Tr. at 81. Dr. Zizic further opined that a prior flu infection could have caused the brisk response as well. Id. Dr. Zizic also

testified that if I were to find that onset of Pe titioner’s RA took place in March (five months after vaccination), that this interval is also consistent with his theory of mo lecular mimicry. He based this opinion on the Ra y study. Tr. at 406-07.

Dr Zizic also testified about the presence of anti-CCP antibodies prior to diagnosis. He opined that antibodies may be pres ent, but it is unknown what per centage of patients develop these antibodies before they develop clinical RA. Tr . at 114. He discussed th e Nielen study, stating, “they actually went back in the pool of indi viduals searching for an tibodies in existence prediagnosis and only half of that entire group had antibodies - therefore, the other half developed them later or acutely.” Tr. at 178; see also Nielen et al., Specific Autoantibodies Precede the Symptoms of Rheumatoid Arthritis , 50 A RTHRITIS & R HEUMATISM 2, 380-86, 2004 (filed as Ex. A-8) (hereinafter “Nielen”). He discussed the re sults from other studies, wh ich similarly indicated percentages demonstrating the presence of anti- CCP antibodies prior to diagnosis as below 50%.

Tr. at 179.

2. Dr. Matloubian’s Testimony

Dr. Matloubian also testified at the entitlement hearing. I recognized him as an expert in

the fields of rheuma tology and immunology. Tr. at 209-10. Dr. Matloubia n provided his opinion

that the flu vaccine did not cause Petitioner’s RA. Tr. at 237. This opinion is based on several

factors. Dr. Matloubian testified that RA is a relatively common disease which typically starts between the ages of 50 and 75. Id. In addition, Petitioner has an es tablished risk factor for RA, which was his prior history of smoking. Id. Further, given the millions of doses of flu vaccine administered every year, the flu vacc ine is not associated with RA in the studies that have been

conducted. Id. at 237-38. Finally, Dr. Matloubian no ted that The Amer ican College of Rheumatology recommends flu vaccine for people with RA. Id. at 238.

a. Studies on Flu Vaccine and RA

Dr. Matloubian testified about various studie s concerning the flu vaccine and RA. He discussed Singh et al., 2015 American College of Rheumatology Guideline for the Treatment of

Rheumatoid Arthritis , A RTHRITIS & R HEUMATOLOGY , 1-25, 2015, (filed as Ex A Tab 25)17 (hereinafter “Singh”). Dr. Matloubian testified that this article co ncludes that the flu vaccine is recommended for people with RA. Tr. at 291-92.

Dr. Matloubian also discussed Westra et al., Vaccination of patients with autoimmune inflammatory rheumatic diseases , 11 R HEUMATOLOGY 135-45, 2011 (filed as Ex A Tab 24) (hereinafter “Westra”). Dr. Matl oubian described Westra as “a comprehensive review on safety of different types of vaccines in people with autoimm une rheumatic diseases” Tr. at 292. He testified the article concluded that RA pa tients; “don't have increased dis ease activity or flare of their

disease” after flu vaccine. Tr. at 293; Westra at 140.

Dr. Matloubian also disc ussed the Bengtsson study. See Bengtsson et al., Common vaccinations among adults do not increase the risk of developing rheumatoid arthritis: results from the Swedish EIRA study , 69 A NN R HEUM D IS 1831-33, 2010 (filed as Ex. A-20) (hereinafter “Bengtsson”). Bengtsson is a case-control study, which Dr. Matloubian de fined as a study with two populations, one with a disease and one without. The study determines whether “the population who had disease ha[d] more exposure to a risk factor than the population that did not have disease.” Tr. at 297. According to Dr. Ma tloubian, the study found that “vaccinations neither increased the risk of RA overall, so odds ratio was one, no risk, a nd it wasn't significant, nor the risk of two major subgroups of RA, antibody citrullinated peptide positive, or ACPA positive, and ACPA negative disease.” Id. at 298.

Dr. Matloubian also testified a bout the Ray article, and specif ically addressed the issues with the study raised by Dr. Zizic. He began by discussing the difference between cohort and case control studies generally.

So in a cohort study, what you do is you don't look at the dis ease, you don't start with people who have the disease, you star t with exposure. So you pick a group that are exposed to potential risk factor and a group that is no t exposed to that potential risk factor, you follow them over time, and you ask, wait, did the exposed group have higher incidence of the disease vers us the nonexposed group, and if they did, that says that being exposed is a risk f actor or, you know, provides a relative risk. An example of this would be smoking. So you can start with a group of smokers and a group of nonsmokers, and then you fo llow them over time and then you see if one of them developed rheumatoid arthritis more than the other group.

Tr. at 304. With respect to the study itself, 4 Dr. Matloubian opined that the principles employed by the authors was not improper, as alleged by Dr. Zizic. He not ed that in Ray, they only had between 300 and 400 subjects, so th ey added more data to their analysis. Tr . at 306. Dr. Matloubian opined that “in case-control studies, it's absolutely okay to have up to three or f our controls per cases. What this allows you to do is to increase the statistical pow er of the study a nd the precision of the study. So there is nothing wrong and it's not frowned upon to use three to four times controls

for case-control studies.” Id. at 307. Dr. Matloubian further noted th at a case control analysis looks at an odds ratio, which is a proportion. As a resu lt, it does not matter “how many controls you add,

4 Dr. Matloubian also noted that the time intervals in the Ray study were based on the date RA symptoms began and not (as Dr. Zizic claimed) on the date of diagnosis. Tr. at 305.18 because you're not looking at absolute numbers of people who developed RA, you're looking at the proportion of patients who developed RA.” Tr. at 412-13. In other words, adding additional subjects into the sample size doesn’t dilute the numbers.

The Ray study concluded that th e relative risk of getting RA after flu vaccination was .72.

Tr. at 309. Dr. Matloubian te stified this means “there 's no risk to getting RA based on this within the first 90 days after influenza immunization. And basically 95 percen t confidence interval across

1.” Id.

Dr. Matloubian also discussed the medical lite rature filed by Petiti oner in support of his

claim. He discussed the Harrison article which was part of NOAR (Norfolk Arthritis Register).

See , Harrison et al., Patients Who Develop Inflammatory Polyar thritis (IP) after Immunization are Clinically Indisti nguishable from Other Patients with IP , 36 B RITISH J OURNAL OF

R HEUMATOLOGY , 366-69, 1997 (filed as Ex. 36) (hereinaft er “Harrison”). Dr. Matloubian noted that the sample size of this study was particularly small and furthe r that not all of the patients studied had seropositive RA. Tr. at 294. “So table 4, which is on page 3, it's a little bit difficult to get the exact numbers. So they have multiple co lumns in this table, the nonimmunized, immunized

and then influenza immunized. So total number of people who got influenza vaccine is only 15.

Just 15. So their conclusion is based on 15 people.” Tr. at 294., referencing Harrison at 3. Dr.

Matloubian further noted that of these 15 people with a clinical diagnosis of RA, only three of them were rheumatoid factor positive. “A nd when they compare to the group that was nonimmunized with 32 percent of rheumatoid factor positive, there is no statistical difference

between the influenza immunized and nonimmunized group.” Tr. at 295. With respect to the finding of this study, Dr. Matloubian stated, “the di fference they see is not statistica lly significant

because the odds ratio is from 0.45 to 5.4. It crosses one.” Id. at 296.

Dr. Matloubian also discussed Symmons and th e conclusion cited by Dr. Zizic: “Similarly,

there's evidence that tetanus a nd influenza immunization may tri gger RA in susceptible hosts” ( citing Symmons at 5). Dr. Matloubian not ed that this statement cites to reference 62, which is the Harrison paper. Tr. at 300. Dr. Matloubian reiterat ed that in the Harrison paper, only 15 people received the influenza vaccine, and the results did not reach statistical significance. Id. He concluded by stating that “there was really no indicat ion there to support an association between influenza vaccination and development of RA.” Id.

Dr. Matloubian testified about the Wang article. According to Dr. Matloubian, because Wang is a meta-analysis, “the quality of [the stud y] depends on the quality of the original papers, how they manipulate the data, what they think is important, what's not important.” Tr. at 310. Because of this, Dr. Matloubian testified that th e quality of a meta-ana lysis can be variable. Id.

Specifically, Dr. Matloubian referred to table 1, which depicts the five articles that relate to influenza vaccination and RA; Bengtsson, Ra y, Ho, Persson, and Vaughn. When citing to Ray, the Wang meta-analysis only discussed the cohort part of the study, not the case control portion, so, according to Dr. Matloubian, “they're being selectiv e in what part of the data they're analyzing.” Tr. at 311. Dr. Matloubian additionally noted that Persson involves the Pandemrix vaccine, which

he described as an “unusual influenza vaccine that 's been associated with narcolepsy, and it's not

the one that's used in the U.S.” Id. In summarizing the data st udied by Wang, Dr. Matloubian19 testified that “of those, the only one that's statistically significant is the Ray one, the cohort part of it, and possibly the Persson, which is the pandemrix.” Id. at 313.

b. Molecular Mimicry Theory

Dr. Matloubian defined molecula r mimicry as a process that occurs “when the same T cell receptor recognizes two different peptides bound to the same MHC molecule.” Tr. at 269. He explained that the part of the peptide that in teracts with the MHC molecule is called “anchor residue of the peptide.” Id. at 268. The part of the peptide that is recognized by the T cell is called

the “T cell contact re sidue of a peptide” Id. at 269. He further testified that “two different peptides

can share the anchor residues and bind to the same MHC molecule, but they could be different in

their T cell contact residue and bi nd to different T cell receptors. Id.

Dr. Matloubian testified that none of Petitioner’ s medical literature demonstrated that the same T cell can recognize both influenza peptide and collagen peptide in association with HLADR4. Tr. at 275-76.

Dr. Matloubian opined that the cr iteria used to establish the applicability of a molecular mimicry theory is set forth in one of Petitio ner’s exhibits, authored by Dr. Schattner. See A. Schattner, Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines , 23 V ACCINE 3876-86, 2005 (filed as Ex. 25) (hereinafter “Schattner”). He testif ied about these criteria as follows:

[T]he specific virus infection should be linked to a specific autoimmunity. So in this case, is influenza virus infection specifically linked to development of

rheumatoid arthritis.

Second is there has to be some mechanis m or mechanisms wh ere exposure to the viral antigens during infection or vaccina tion leads to autoimmunity, and one has

to establish that mechanism. So in th is case, is there any evidence to support molecular mimicry between influenza-a ssociated antigens and RA-associated antigens.

And then there has to be some evidence th at people who have vaccinated with this vaccine developed an autoimmune disease.

Tr. at 277-78, citing Schattner at 3881.

Dr. Matloubian noted that there is no evidence th at the flu virus is associated with RA. “So if there was any molecular mimicry, and especially at the level of T cells that would lead allegedly to flu vaccine causing rheumatoid arthritis, one should be able to see that with flu infection itself”. Tr. at 238. He further opined that RA is not considered to be a post- infectious autoi mmune disease.

Id. at 253.

And, in fact, you know, people who are activ ely doing research on T cell responses in patients with rheumatoid arthritis and they are spec ifically looking at T cell20 responses to antigens associated with rheu matoid arthritis, they use flu-associated antigens and responses to t hose antigens as a control.

So if they thought that there was molecular mimicry, esp ecially at the T cell level, between flu antigens and RA-associated an tigens, why would they use flu antigens as a control? And the reason they do is because there aren't -- the scientists don't

think there is molecular mimicry between them.

Tr. at 239.

c. RA Begins Years before Clinically-Apparent Disease

Dr. Matloubian made the point that pre-clinical RA begins years before it become clinically apparent. He testified that “it's important to not e that people who do rese arch on pathogenesis of RA and are writing about its na tural history believe that rheumatoid arthritis doesn't begin overnight, that it takes years for it to become cl inically apparent.” Tr. at 256. He cited to several pieces of medical literature in support of this position. See e.g ., Deane & Holers, The Natural History of Rheumatoid Arthritis , 41 C LINICAL T HERAPEUTICS 7, 1256-69, 2019 (filed as Ex. H) (hereinafter “Deane & Holers”) (noting that RA -related autoantibodies are detectable in the circulation a mean of three to five years before the clinically detectable inflammatory arthritis).

See also , Tr. at 255.

d. Smoking and RA

Dr. Matloubian testified that smoking is an es tablished environmental risk factor for RA. Tr. at 319-20. Although Petitioner quit smoking 17 years before he developed RA, Dr. Matloubian opined that “the insult” of smoking had still taken place. Id. at 250. In support of his position, Dr.

Matloubian referred to Liu. See Liu et al., Impact and timing of sm oking cessation on reducing risk for rheumatoid arthritis among women in the Nurses’ Health Studies , 71 A RTHRITIS C ARE R ES 7, 914-24, 2019 (filed as Ex. G) (hereinafter “Liu”). He noted that Liu “re ached the conclusion

that a mono state elevated RA risk was still de tectable 30 years after quitting smoking.” Tr. at 250-

51. In response to Petitioner’s point that the study only involved women, Dr. Matloubian noted that the findings in Liu also discussed “other studies that include men and women with similar findings.” Id. at 374.

e. The Onset of Petitioner’s RA

Dr. Matloubian testified with respect to the ons et of Petitioner’s RA that “his joint pains

that are more consistent with possible rheumatoid arthritis started sometime in March of 2014.” Tr. at 237. He disputed Petitioner’s point that he re ported foot pain consiste nt with RA soon after vaccination. Specifically, Dr. Matloubia n testified that heel pain and plantar pain are not consistent with or typical of RA. Tr. at 383. Pain in balls of the feet is a typical mani festation of RA, but Dr.

Matloubian noted that Petitioner desc ribed the tops of feet as being on fire, which is not the same thing as the balls of the feet. Tr . at 322-23. Further, Dr. Matloubian made the point that the balls of Petitioner’s feet could have been hurting becau se he was walking on them due to his heel pain.

Id. at 382.21 Dr. Matloubian also noted that when Petitione r went to the podiatrist , he described pain

which turned out to be a neuroma. Further “ on the MRI, it did not show bone marrow edema or

inflammation in a lot of -- in all the MTP joints.” Tr. at 383. Dr. Matloubian opined that if Petitioner had RA, one would expect to see bone marrow edema and synovitis on MRI:

You would expect to see bone marrow edema in the -- so MTP is the joint, but the

bone across the MTP is calle d the phalanx, so you w ould see bone marrow edema in the phalanx, or in the metatarsal, and you would see synovitis, which is basically inflammation of the synovial tissue. But even that can sometimes be nonspecific because you can get synovitis from osteoarthritis and trauma.

Id. Dr. Matloubian noted the MRI did not reveal ev idence of bone marrow ed ema or inflammation.

Id.

In discussing Petitioner’s af fidavit, Dr. Matloubian acknowle dged that Petitioner reported fatigue, malaise and general stiffn ess which seemed to be worse early in the morning and lasted for a few hours. However, he noted that he was,

trying to reconcile that on the March 5th visit with Dr. Guevara when he says he's feeling fine, energetic, exercises multiple times a week. And so I'm just trying to see, you know, if this is happening a few days after his immunization, but four months later he's doing well, and is not complaining of morning stiffness and exercising well. So I'm just trying to reconcile those.

Tr. at 323. For these reasons, Dr. Matloubian opined that Petitioner more likely than not developed RA in March 2016 and not several days after vaccination.

IV. Applicable Law

A. Petitioner’s Burden

Under the Vaccine Act, a petitioner may prevail in one of two ways. First, a petitioner may demonstrate that he suffered a “Table” injury—i.e., an injury listed on the Vaccine Injury Table that occurred within the time period provided in the Table. § 11(c)(1)(C)(i). “In such a case, causation is presumed.” Capizzano v. Sec’y of Health & Hum. Servs. , 440 F.3d 1317, 1320 (Fed. Cir. 2006); see § 13(a)(1)(B). Second, where the alleged injury is not listed in the Vaccine Injury Table, a petitioner may demonstrate that he suff ered an “off-Table” injury. § 11(c)(1)(C)(ii).

For both Table and non-Table claims, Vaccine Program petitioners bear a “preponderance of the evidence” burden of proof. Section 13(1)(a). That is, a petitioner must offer evidence that

leads the “trier of fact to believe that the existenc e of a fact is more proba ble than its nonexistence before [he] may find in favor of the party who has the burden to pe rsuade the judge of the fact’s

existence.” Moberly v. Sec’y of Health & Hum. Servs. , 592 F.3d 1315, 1324 (Fed. Cir. 2010); see also Snowbank Enter. v. United States , 6 Cl. Ct. 476, 486 (1984) (mer e conjecture or speculation is insufficient under a preponderance standard). Proof of medical cert ainty is not required. Bunting22 v. Sec’y of Health & Hum. Servs., 931 F.2d 867, 873 (Fed. Cir. 1991). In particular, a petitioner must demonstrate that the vaccine was “not only [the] but-for cause of the injury but also a

substantial factor in brin ging about the injury.” Moberly , 592 F.3d at 1321 (quoting Shyface v. Sec’y of Health & Hum. Servs. , 165 F.3d 1344, 1352 (Fed. Cir. 1999)); Pafford v. Sec’y of Health

& Hum. Servs. , 451 F.3d 1352, 1355 (Fed. Cir. 2006). A peti tioner may not receive a Vaccine Program award based solely on his assertions; rather, the petition must be supported by either medical records of by the opinion of a competent physician. Section 13(a)(1).

In attempting to establish entitlement to a Vaccine Program award of compensation for a non-Table claim, a petitioner must satisfy all three of the elem ents established by the Federal

Circuit in Althen

. Althen requires that petitioner establish by preponderant evidence that the vaccinations he received caused her injury “by provi ding: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical se quence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.” Id. at 1278.

Each of the Althen prongs requires a di fferent showing. Under Althen prong one, petitioners must provide a “reputable medical theory,” demonstrating that the vaccine received can cause the type of injury alleged. Pafford , 451 F.3d at 1355-56 (c itations omitted). To satisfy this prong, a petitioner’s theory must be base d on a “sound and reliable medical or scientific explanation.” Knudsen v. Sec’y of Health & Hum. Servs ., 35 F.3d 543, 548 (Fed. Cir. 1994). Such a theory must only be “legally probable, not medica lly or scientifically certain.” Id. at 549.

Petitioners may satisfy the first Althen prong without resort to medical literature, epidemiological studies, demonstr ation of a specific mechanism, or a generally accepted medical theory. Andreu v. Sec’y of Health & Hum. Servs. , 569 F.3d 1367, 1378-79 (Fed. Cir. 2009) (citing Capizzano , 440 F.3d at 1325-26). Special Masters, despit e their expertise, are not empowered by statute to conclusively resolve what are comp lex scientific and medi cal questions, and thus

scientific evidence offered to establish Althen prong one is viewed “not through the lens of the laboratorian, but instead from th e vantage point of the Vaccin e Act’s preponderant evidence

standard.” Id. at 1380. Accordingly, special masters mu st take care not to increase the burden placed on petitioners in offering a scient ific theory linking vaccine to injury. Contreras v. Sec’y of

Health & Hum. Servs ., 121 Fed. Cl. 230, 245 (2015) (“[p]lausibi lity ... in many cases may be enough to satisfy Althen prong one” (emphasis in original)), vacated on other grounds , 844 F.3d 1363 (Fed. Cir. 2017). But this does not negate or re duce a petitioner’s ultimat e burden to establish

her overall entitlement to dama ges by preponderant evidence. W.C. v. Sec’y of Heal th & Hum.

Servs ., 704 F.3d 1352, 1356 (Fed. Cir. 2013) (citations omitted).

The second Althen prong requires proof of a logical se quence of cause and effect, usually supported by facts derived from a petitioner’s medical records. Althen , 418 F.3d at 1278; Andreu

, 569 F.3d at 1375-77; Capizzano , 440 F.3d at 1326 (“medical r ecords and medical opinion testimony are favored in vaccine ca ses, as treating physicians are lik ely to be in the best position to determine whether a ‘logical se quence of cause and e ffect show[s] that th e vaccination was the reason for the injury’”) (quoting Althen , 418 F.3d at 1280). Medical records are generally viewed as particularly trustworthy evidence, because they are created contemporaneously with the23 treatment of the patient. Cucuras v. Sec’y of Health & Hum. Servs. , 993 F.2d 1525, 1528 (Fed. Cir. 1993).

However, medical records and/or statemen ts of a treating physician’s views do not per se bind the special master to adopt the conclusions of such an individual, even if they must be considered and carefully evaluated. Section 13(b)(1) (providing that “[a]ny such diagnosis, conclusion, judgment, test result, report, or summary shall not be binding on the special master or court”); Snyder v. Sec’y of Health & Hum. Servs ., 88 Fed. Cl. 706, 746 n.67 (2009) (“there is nothing ... that mandates that the tes timony of a treating physi cian is sacrosanct -- that it must be accepted in its entirety and cannot be rebutted”). As with expert testimony offered to establish a theory of causation, the opinions or diagnoses of treating physicians are only as trustworthy as the reasonableness of their suppositions or bases. The views of treati ng physicians should also be weighed against other, contrary evidence also present in the record -- including conflicting opinions among such individuals. Hibbard v. Sec’y of Health & Hum. Servs ., 100 Fed. Cl. 742, 749 (2011) (not arbitrary or caprici ous for special master to weigh competing treating physicians’ conclusions against each other), aff’d , 698 F.3d 1355 (Fed. Cir. 2012); Caves v. Sec’y of Health &

Hum. Servs ., No. 06-522V 2011 WL 1935813 at *17 (Fe d. Cl. Spec. Mstr. Apr. 29, 2011), mot. for review den’d , 100 Fed. Cl. 344, 356 (2011), aff’d without opinion , 475 Fed. App’x 765 (Fed. Cir. 2012).

The third Althen prong requires establishing a “proxima te temporal relationship” between the vaccination and the injury alleged. Althen , 418 F.3d at 1281. That term has been equated to the phrase “medically-acceptable temporal relationship.” Id. A petitioner must offer “preponderant proof that the onset of symptoms occurred within a timeframe which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan v. Sec’y of Health & Hum. Servs ., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for what is a medically acceptable timeframe must also coinci de with the theory of how the relevant vaccine can cause an injury ( Althen prong one’s requirement). Id. at 1352; Shapiro v. Sec’y of Health &

Hum. Servs ., 101 Fed. Cl. 532, 542 (2011), recons. denied after remand on other grounds , 105 Fed. Cl. 353 (2012), aff’d without op., 503 F. App’x 952 (Fed. Cir. 2013). Koehn v. Sec’y of Health

& Hum. Servs ., No. 11-355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for

review den’d (Fed. Cl. Dec. 3, 2013), aff’d , 773 F.3d 1239 (Fed. Cir. 2014).

B. Law Governing Analysis of Fact Evidence

The process for making factual determinati ons in Vaccine Program cases begins with analyzing the medical records, wh ich are required to be filed with the petition. Section 11(c)(2). The special master is required to consider “all [] relevant med ical and scientific evidence contained in the record,” including “any diagnosis, conclusion, medical judg ment, or autopsy or coroner’s report which is contained in the record regarding the nature, cau sation, and aggravation of the petitioner’s illness, disability, injury, condition, or death,” as well as the “results of any diagnostic

or evaluative test which are contained in the reco rd and the summaries and conclusions.” Section 13(b)(1)(A). The special master is then required to weigh the evidence presented, including contemporaneous medical records and testimony. See Burns v. Sec’y of Health & Hum. Servs ., 3 F.3d 413, 417 (Fed. Cir. 1993) (it is within the speci al master’s discretion to determine whether to afford greater weight to contem poraneous medical records than to other evidence, such as oral24 testimony surrounding the events in question that was given at a la ter date, provid ed that such determination is evidenced by a rational determination).

Medical records created contemporaneously with the events they describe are generally trustworthy because they “contain information supplied to or by hea lth professionals to facilitate diagnosis and treatment of medical conditions ,” where “accuracy has an extra premium.” Kirby v. Sec’y of Health & Hum. Servs. , 997 F.3d 1378 (Fed. Cir. 2021) citing Cucuras , 993 F.2d at 1528. This presumption is based on the linked proposition that (i) sick people visit medical professionals; (ii) sick people honestly report their health problems to those professionals; a nd (iii) medical professionals record what they are told or observe when examining their patients in as accurate a manner as possible, so that they are aware of en ough relevant facts to make appropriate treatment

decisions. Sanchez v. Sec’y of Health & Hum. Servs. , No. 11-685V, 2013 WL 1880825 at *2 (Fed. Cl. Spec. Mstr. Apr. 10, 2013).

Accordingly, if the medical records are clear, consistent, and complete, then they should be afforded substantial weight. Lowrie v. Sec’y of Health & Hum. Servs. , No. 03-1585V, 2005 WL 6117475 at *20 (Fed. Cl. Spec. Mstr. Dec. 12, 2005). Indeed, contemporaneous medical records are generally found to be deserving of greater evidentiary weight th an oral testimony -- especially where such testimony conflicts with the record evidence. Cucuras , 993 F.2d at 1528; see also Murphy v. Sec’y of Health & Hum. Servs. , 23 Cl. Ct. 726, 733 (1991), aff’d per curiam , 968 F.2d 1226 (Fed. Cir. 1992), cert. den’d

, Murphy v. Sullivan , 506 U.S. 974 (1992) (citing United States v. U.S. Gypsum Co. , 333 U.S. 364, 396 (1947) (“[i]t has genera lly been held that oral testimony

which is in conflict with contem poraneous documents is entitled to little evidentiary weight.”)).

However, there are situations in which comp elling oral testimony may be more persuasive than written records, such as where records are deemed to be incomplete or inaccurate. Campbell v. Sec’y of Health & Hum. Servs. , 69 Fed. Cl. 775, 779 (2006) (“like any norm based upon common sense and experience, this rule shou ld not be treated as an absolute and must yield where the factual predicates for its applicati on are weak or lacking”); Lowrie , 2005 WL 6117475 at *19 (“[w]ritten records which are, themselves, inconsistent, shou ld be accorded less deference than those which are internally consistent”) (quoting Murphy , 23 Cl. Ct. at 733)). Ultimately, a determination regarding a witness’s credibility is needed when determining the weight that such testimony should

be afforded. Andreu , 569 F.3d at 1379; Bradley v. Sec’y of Health & Hum. Servs. , 991 F.2d 1570, 1575 (Fed. Cir. 1993).

When witness testimony is offered to overcom e the presumption of accuracy afforded to contemporaneous medical record s, such testimony must be “c onsistent, clear, cogent and compelling.” Sanchez , 2013 WL 1880825 at *3 (citing Blutstein v. Sec’y of Health & Hum. Servs.

, No. 90-2808V, 1998 WL 408611 at *5 (Fed. Cl. Spec. Mstr. June 30, 1998)). In determining the accuracy and completeness of medical records, the Court of Federal Claims has listed four possible explanations for inconsistencies between contem poraneously created medical records and later testimony: (1) a person’s failure to recount to the medical profe ssional everything that happened during the relevant time period; (2) the medical professional’s failure to document everything reported to her or him; (3) a pe rson’s faulty recollection of the events when presenting testimony; or (4) a person’s purposefu l recounting of symptoms that did not exist. LaLonde v. Sec’y of Health

& Hum. Servs. , 110 Fed. Cl. 184, 203-04 (2013), aff’d, 746 F.3d 1334 (Fed. Cir. 2014). In making25 a determination regarding whether to afford grea ter weight to contemporaneous medical records or other evidence, such as testimony at hearing, there must be evid ence that this decision was the

result of a rati onal determination. Burns , 3 F.3d at 417.

C. Analysis of Expert Testimony

Establishing a sound and reliable medical theory connecting the vaccine to the injury often requires a petitioner to present expert te stimony in support of his or her claim. Lampe v. Sec’y of

Health & Hum. Servs. , 219 F.3d 1357, 1361 (Fed. Cir. 2000). V accine Program expert testimony is usually evaluated according to the factors for analyzing scientific reliability set forth in Daubert
v. Merrell Dow Pharm., Inc. , 509 U.S. 579, 594-96 (1993). See Cedillo v. Sec’y of Health & Hum.

Servs. , 617 F.3d 1328, 1339 (Fed. Cir. 2010) ( citing Terran v. Sec’y of Health & Hum. Servs. , 195 F.3d 1302, 1316 (Fed. Cir. 1999). “The Daubert factors for analyzing the reliability of testimony are: (1) whether a theory or technique can be (and has been) tested; (2) whether the theory or technique has been subjected to peer review and publication; (3) whet her there is a known or potential rate of error and whether there are standa rds for controlling the er ror; and (4) whether the theory or technique enjoys general acceptance within a relevant scientific community.” Terran

, 195 F.3d at 1316 n.2 (citing Daubert , 509 U.S. at 592-95).

The Daubert factors play a slightly different role in Vaccine Program cases than they do when applied in other federal judicial fora. Daubert factors are employed by judges to exclude evidence that is unreliable and potentially confusi ng to a jury. In Vaccine Program cases, these factors are used in the weighing of th e reliability of scientific evidence. Davis v. Sec’y of Health

& Hum. Servs. , 94 Fed. Cl. 53, 66-67 (2010) (“uni quely in this Circuit, the Daubert factors have been employed also as an acceptable evidentiary- gauging tool with respect to persuasiveness of expert testimony already admitted”). The flexible use of the Daubert factors to evaluate persuasiveness and reliability of expert testimony has rout inely been upheld. See , e.g., Snyder , 88 Fed. Cl. at 743. In this matter, (as in numerous other Vaccine Program cases), Daubert has not been employed at the threshold, to determine what evidence should be ad mitted, but instead to determine whether expert testimony offe red is reliable a nd/or persuasive.

Respondent frequently offers one or more expert s of his own in order to rebut a petitioner’s case. Where both sides offer expe rt testimony, a special master’s decision may be “based on the credibility of the experts and the relative pe rsuasiveness of their competing theories.”

Broekelsc hen v. Sec’y of Health & Hum. Servs. , 618 F.3d 1339, 1347 (Fed. Cir. 2010) (citing Lampe , 219 F.3d at 1362). However, nothing requires the acceptance of an expert’s conclusion “connected to existing data only by the ipse dixit of the expert,” especially if “there is simply too great an analytical gap between th e data and the opi nion proffered.” Snyder

, 88 Fed. Cl. at 743 (quoting Gen. Elec. Co. v. Joiner , 522 U.S. 136, 146 (1997)). A “spe cial master is entitled to require some indicia of reliability to suppor t the assertion of the expert witness.” Moberly

, 592 F.3d at 1324. Weighing the relative persuasivene ss of competing expert testimony, based on a particular expert’s credibility, is part of the overall reliability an alysis to which special masters must subject expert testimony in Vaccine Program cases. Id. at 1325-26 (“[a]ssess ments as to the reliability of expert testimony often turn on credibility determinations”); see also Porter v. Sec’y of Health & Hum. Servs. , 663 F.3d 1242, 1250 (Fed. Cir. 2011) (“this court has unambiguously explained that special masters are expected to c onsider the credibility of expert witnesses in26 evaluating petitions for compensa tion under the Vaccine Act”).

D. Consideration of Medical Literature

Finally, although this decision disc usses some but not all of the medical literature in detail,

I have reviewed and considered all of the medica l records and literature submitted in this matter. See Moriarty v. Sec’y of Health & Hum. Servs.

, 844 F.3d 1322, 1328 (Fed. Cir. 2016) (“We generally presume that a special master consider ed the relevant record evidence even though [s]he does not explicitly reference such evidence in h[er] decision.”); Simanski v. Sec’y of Health &

Hum. Servs. , 115 Fed. Cl. 407, 436 (2014) (“[A] Special Master is ‘not required to discuss every piece of evidence or testimony in he r decision.’” (citation omitted)), aff’d , 601 F. App’x 982 (Fed. Cir. 2015).

V. Analysis

A. Rheumatoid Arthritis Generally

Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes joint inflammation, pain, and degeneratio n. Deane & Holers at 1256. Its pa thogenesis is incompletely understood. First Matloubian Rep. at 7. If left untreated, RA leads to loss of physical function and ability to perform and carry out daily tasks. Scott et al., Rheumatoid arthritis , 376 L ANCET 1094- 1108, 2010 (filed as Ex. A-13). RA is a disease that af fects peripheral joints typically in the hands, wrists, and feet. Tr. at 16; First Matloubian Re p. at 6. Those affected experience over 30 minutes of morning joint stiffness. Id. Two different type of RA include seropositive and seronegative RA.

See Malmström at 1. Seropositive RA is the more co mmon of the two, affecting two-thirds of the RA population. Id. In order to be classified as having se ropositive RA, an individual has anti-CCP

antibodies. Tr. at 214.

The incidence of rheumatoid arthritis is approximately 24 per hundred thousand per year.

See Ahmed at 6. Dr. Matloubian te stified that based on these num bers, you would expect 55,000 new cases of RA in the U.S. each year. Tr. at 316; Ahmed at 6.

The American College of Rheumatology’s (“ACR”) 2010 RA classification criteria provide an established guide for the diagnosis of RA:27 Aletaha et al., Rheumatoid Arthritis Classification Criteria , 62 A RTHRITIS & R HEUMATISM 2569 (2010) (filed as Ex. A-4). On a scal e of 0 to 10, a score of 6 or gr eater is indicative of “definite

RA.” Id. An involved joint is any joint with swelling or tenderness on examination that is indicative of active synovitis. Id. at 8. Small joints include the wrist and various joints in the hands and feet.

Id. at 9. Large joints are defined as the shoulders, elbows, hips, knees and ankles. Id.

Patients typically experience both pre-clinical and clinical phases. De ane & Holers at 1256. The pre-clinical phase, during which visible symptoms are not present, may last several years prior to onset of clinically diagnos able signs of joint disease. Id. at 1257.

B. Petitioner’s Diagnosis

On April 29, 2014, Petitioner visi ted rheumatologist Dr. Timot hy Brennan and reported to him that foot pain started in October 2013. Ex. 13 at 7. The pain then progressed to include his wrists, hands, elbows and his left knee. Petitioner reported that the pain and stiffness were worse in the morning. Id. During a May 13 follow-up visit, Dr. Brennan noted a strongly positive antiCCP antibody result and the impression was RF-positive and anti-CCP-positive RA. Ex. 7 at 67.

Petitioner obtained a second opinion from Dr. Viju Moses at the University of Michigan Rheumatology Clinic on September 2, 2014. Ex. 3 at 6. Dr. Moses reviewed Petitioner’s record and determined that the findings were consistent with RA.

Petitioner’s expert, Dr. Zizic agrees with th e treating rheumatologists that Petitioner has

RA. Dr. Matloubian also testified that he believes Petitioner’s co rrect diagnosis is seropositive rheumatoid arthritis. Tr. at 234. As a result, I find that Petitioner has provid ed sufficient evidence to show that more likely than not, he suffers from seropositive RA.28 C. Althen Prong One

In the context of the Program, “to establish causation, the standard of proof is preponderance of evidence, not scientific certainty.” Langland v. Sec’y of Health & Hum. Serv.

, 109 Fed. Cl. 421, 441 (Fed Cir. 2013 ). Petitioner’s burden under Althen ’s first prong is to provide a medical theory causally connectin g the vaccination and the injury. Id. This theory must be sound

and reliable. Boatmon v. Sec’y of Health & Hum. Servs. , 941 F.3d 1351, 1359 (Fed. Cir. 2019).

For the reasons discussed in de tail below, I find that Petiti oner has not provided a sound and reliable medical theory causally connecting flu va ccination to RA.

Petitioner filed the Schattner article which deline ates three criteria that must be met in order

to establish a role for viral vaccines in the development of autoimmunity. These criteria are:

First, virus infections should be linked to autoimmunity. Second, a mechanism or mechanisms whereby exposur e to viral antigens (be it during infection or vaccination) leads to autoimmunity must be established. Third, evidence must be obtained that patients who have been vaccinated against viruses developed an autoimmune disease, bearing in mind that association alone does not necessarily indicate causality.

Schattner at 3881. Both experts ge nerally endorsed these criteria during the enti tlement hearing (except as noted below with respect to Dr. Zizic). See Tr. at 151, 277-78. I have used them as a framework in evaluating Petitioner’s Althen prong one theory. 5

1. There is not an Established Conn ection between Flu Virus and RA

Dr. Matloubian opined that th ere is no establishe d connection between the flu virus and RA. First Matloubian Rep. at 16. He testified that

this allegation that flu vaccine could cause rheumatoid arthritis is illogical because, you know, flu virus infection itself has not been associated with rheumatoid arthritis. And the antigens that are in the flu vaccine are also in the wild-type flu virus. So if there was any molecular mimicr y, and especially at the level of T cells that would lead allegedly to flu vaccine causing rheumatoid arthritis, one should be able to see that with flu infection itself[.]

Tr. at 238-39. Dr. Zizic also agreed with the pos ition that there is no evidence of an association

between flu virus and RA. He testified as follows at the entitlement hearing:

Q: Is there data that de novo wild flu infection causes RA?

5 While I have used the criteria outlin ed by Schattner as a way to organize the Althen prong one analysis, I understand that petitioners are not required to demonstrate a specifi c biologic mechanism which caused their disease, nor are they required to present medical literature or epidemiological studies in support of their theory. See Kottenstette , ---Fed. Appx.---, 2021 WL 2434329 (Fed. Cir. June 15, 2021) (reaffirming the principle that “proof of causation does not ‘require identification and proof of specific biological mechanisms[.]’” citing Knudsen , 35 F.3d at 549; Andreu, 569 F.3d at 1378-79.29 A: No, not that I’m aware of.

Tr. at 152. Accordingly, both expert s agree on this point. However, Dr. Zizic cont ended that Dr. Schattner’s first criterion is inapplicable to this cas e; he testified that “if you[‘ve] got evidence that the vaccine causes it, yo u don’t need evidence th at infection causes it.” Id. at 151. The reason Dr. Zizic provided in support of this opinion is that it is too difficult to measure whether a viral

infection causes a disease because viral infections are very common and “[p]eople don’t remember

those details” in terms of onset of illness. Id. Dr. Zizic did generally agr ee that if the flu vaccine causes RA, then the virus should as well. Id. at 152-53. His issue with th e first criterion appeared to be the ability to accurately measure and study the question.

I note this this position articu lated at hearing is a departur e from the position expressed in his first expert report. When citing to Schattner in that document, Dr. Zizic opined that Schattner’s

first criterion meant that some viral infections should cause some form of autoimmunity generally. He stated,

With respect to the first condition, it is cl ear that some viral an d microbial infections result in autoimmune diseases. Evidence exists for the association of streptococcus pyogenes infection with the development of rheumatic fever, Trypanosoma cruzi parasitic infection and Chagas dise ase cardiomyopathy, the spirochete Borellia burgdorfii [sic] and Lyme disease, Campylobacter jejuni infection and GuillanBarre [sic] syndrome and Ebstein-Barr [s ic] virus and multiple sclerosis.

First Zizic Rep. at 17. As noted above, Dr. Zizi c did not advance this position at hearing, and

instead testified that the first criterion was unn ecessary because the sec ond had been satisfied.

I do not find Dr. Zizic’s position on this issue to be persuasive. There are several notable examples of specific viral infections that have been linked to disease. See First Matloubian Rep. at 12 (“natural infection with the measles virus may lead to thrombocytopenia. Therefore, when thrombocytopenia (ITP) occurs after immunization with MMR, IOM considers it an adverse event due to the vaccine.”); s ee also , Terry L. Moore, MD, Pathogenesis and diagnosis of viral arthritis,

U P T O D ATE , 2016 (filed as Ex. A-17) for examples filed in this case ( noting “the most common viruses causing arthritis and arthra lgias are parvovirus, he patitis B, hepatitis C, rubella, EpsteinBarr virus, and the alphaviruses.”). Medical literature filed in the Vaccine Program is also replete with examples of studies that involve infection. Additionally, it seems counterintuitive that Dr.

Schattner would include as her firs t criterion a connection that could not be studied or established. Accordingly, I decline to credit the position that it is too diff icult to measure whether a viral

infection can cause a condition. Th e evidence preponderantly demonstr ates that there is not an

established connection betw een the flu virus and RA.

2. Petitioner’s Molecular M imicry Theory is not S ound and Reliable in this

Particular Case

In this case, Dr. Zizic has opined that the fl u vaccine can cause RA through the process of molecular mimicry. Pursuant to this theory, the structure of a fore ign invader mimics the structure30 of cells in the body. This similarity causes the i mmune system to produce antibodies that attack

the host.

Before discussing the specifics of Dr. Zizic’s th eory, it is important to define some terms. The purpose of the T cell is to eradicate infections and to activate other cells (such as macrophages and B lymphocytes). Abbas et al., C ELLULAR AND M OLECULAR I MMUNOLOGY , Elsevir, 9 th ed. 2018, at 117 (filed as Ex. E) (herei nafter “Abbas”). Each T cell ha s a unique T cell receptor; when a T cell sees a peptide an d it is a peptide the T cell recognizes, it become s activated. (figure 4, A5). The immune response is trigge red due to the T cell’s ability to recognize a specific peptide. Id.

Antigen presenting cells (APC) are the cells that “capture an tigens and display them to T lymphocytes.” Abbas at 117. MHC molecules are f ound on the surface of antigen presenting cells and display “host cell-associate d antigens for recognition by CD4 + and CD8 + T cells.” Id.

HLA-DR4 is “a human HLA or MHC molecule” a nd “certain alleles of it called the shared epitope have been associated with risk of ser opositive rheumatoid arthritis.” Tr. at 271. Influenza virus hemagglutinin is “a portion of the viral prot ein in influenza viruses.” Tr. at 61. It is also present in the influenza vaccine. Id. at 61-62.

Type II collagen is an important structure i nvolved in the pathogenesi s of RA. Tr. at 56. The collagen II peptide binds to HLA-DR molecule s, which are associated with susceptibility to

RA. As Dr. Matloubian stated in his report, “Many autoimmune di seases are associated with a specific HLA molecule. ... specific alleles of HLA- DR (class II molecule) are associated with the development of rheumato id arthritis.” First Matloubian Rep. at 9.

In the present case, Dr. Zizic has opined th at molecular mimicry between a portion of the flu virus molecule and a portion of type II collagen caused Petitioner to develop RA.

Dr. Zizic described a specific viral antig en (influenza virus hemagglutinin 308-317 peptide) and how it can bind to HLA-DR4. He also identified the collagen II autoantigen (CII 256- 271) which can also bind to HLA-DR4. The infl uenza virus hemagglutinin 308-317 peptide shares

a similar structure w ith CII 256-271 and both can bind to HLA-DR4 mo lecules. Sun et al., Superior Molecularly Altered Influenza Virus Hemagglu tinin Peptide 308-317 Inhibits Collagen-Induced Arthritis by Inducing CD4+ Treg Cell Expansion , 64 A RTHRITIS & R HEUMATISM 7, 2158-68, 2012 (filed as Ex. 47) (hereinafter “Sun”). Based on this , Dr. Zizic opined that “it is logical that the influenza virus hemagglutinin peptide acts in a simila r manner as the type II collagen peptide, with respect to the induction of rheumatoid arthritis.” First Zizic Rep. at 21.

Dr. Matloubian defined molecula r mimicry as a process that occurs “when the same T cell receptor recognizes two different peptides bound to the same MHC molecule.” Tr. at 269. He explained that the part of the peptide that in teracts with the MHC molecule is called “anchor residue of the peptide.” Id. at 268. The part of the peptide that is recognized by the T cell is called the “T cell contact residue of a peptide”. Id. at 269.

Dr. Matloubian referred to the followi ng figure to illustrate these points:31 Abbas at 5. He further testified that “two different peptides can share the anchor residues and bind to the same MHC molecule, but they could be different in their T cell contact residue and bind to different T cell receptors. Id.

In explaining how molecular mimicry works, Dr. Matloubian used an analogy to Legos. In his analogy, the MHC molecule is represented by a flat Lego sheet ; the peptides are different figurines; and the T cells are represented by differen t children that only like one type of figurine.

Tr. at 262-63. Dr. Matloubian note d that each figurine can fit onto the ma in Lego platform. Similarly, MHC molecules bind to many different peptides. Dr. Matloubian further opined that a peptide binding to an MHC molecule does not c onstitute molecular mimicry; instead, molecular mimicry occurs when the same T cell (child) b ecomes activated (interested) by more than one peptide (Lego figurine). Id. He testified: “And that's what the T cells are. They are really highly specific for one peptide and they get excited or activ ated when they see that peptide. MHC is just there to provide the platform for the T cells.” Tr. at 263.

Dr. Matloubian does not contest that HLA-DR4 can bind to an influenza-derived peptide as well as a collagen-derived one. First Matloubia n Rep. at 14. In his view, the question that remains unanswered by any literature Petitioner filed is “can the same T cells recognize both type II collagen peptide and influenza HA peptide bound to HLA-DR4?” Id. at 14. In other words, can T cells be activated by both peptides? This is im portant because the ability of T cells to recognize two different antigens is the de finition of molecular mimicry. Without this T cell involvement, there is no mimicry. Tr. at 271.

In order to further elucidate this issue, Dr . Matloubian presented a model of the bonds that exist between an antigen presenting cell and a T cell.32 First Matloubian Rep. at 15. The first bond is be tween the antigen presenting cell and the antigen (either flu or collagen). The second bond is between the antigen and the T cell.

During the hearing, Dr. Zizic agreed that molecular mimicry occurs at the level of the T cell but testified that the articles filed by Petitio ner demonstrate that eith er type II collagen or influenza virus hemagglutinin are able to activat e and bind with the same T cells. Tr. at 70.

Dr. Zizic cited to a specific portion of the Sun article to support his position that the same T cells recognize both type II collagen peptide and influenza HA peptide. Sun wrote,

In our previous studies, we designed an altered hemagglutinin antigen 308-317 peptide with amino acid substitutions at sites of T cell receptor contact (YAKQATLALA). In vitro, the alte red HA 308-217 peptide inhibited T cell activation induced by wild he magglutinin antigen 308-317 peptide and wild type II collagen 263-272 peptide in the collagen II specific T cell clones and peripheral lymphocytes in patients with rheumatoid arthritis.

Sun at 2159. Dr. Zizic testified that “obviously , those T cell clones and peripheral lymphocytes from patients with rheumatoid arthritis activat ed T cells. Both of them did.” Tr. at 126.

Dr. Matloubian testified that Dr. Zizic’s interp retation of this portion of the Sun article was incorrect. He explained that the authors of Sun a ltered the T cell contact re sidue of the influenza peptide. Tr. at 284. Then when they inducted with a peptide that binds to HLA-DR4, it was not recognized by the T cell receptor of the influenza specific T cells because the T cell contact residue

had been altered. Id. “[T]hey're hoping, because this peptide has higher affinity than the collagen peptide, that it will stay in there and block the collagen peptide from binding to the same HLADR4, and as a way, they will stop the response of the T cell to that collagen peptide.” Tr. at 284.33 In fact, the Sun authors conclude d that this process suppressed the severity of CIA (collagen induced arthritis), and as a resu lt, the altered peptide ligand coul d be a “promisi ng candidate” in

RA treatment. Sun at 2158.

Dr. Matloubian testified “basically what they are designing here is so mething that sits in the HLA-DR4 molecule and sits much tighter so that the collagen peptides don't bind. Nothing about molecular mimicry, nothing about cross-react ivity, nothing about the same T cell receptors seeing the same antigen.” Tr. at 286-87. Dr. Matloubian’s interpreta tion of the Sun article appears to be correct. The Sun authors are specifically addressing the contact between the HLA-DR4 molecule and peptides, not whet her the same T cells recognize bot h type II collagen peptide and influenza HA peptide. The latter would constitu te support for molecular mimicry, the former does

not.

I am similarly convinced that the Skinner arti cle does not stand for the proposition that the same T cell can recognize and become activated by both the type II collagen peptide and influenza HA peptide. See Skinner et al., Lymphocyte responses to DRl/4 restricted peptides in rheumatoid
arthritis, 53 A NN R HEUM D IS , 171-77, 1994 (filed as Ex. 48) (herei nafter “Skinner”). Similar to Sun, the authors in Skinner made an altered pept ide ligand that binds to HLA-DR4 which in turn prevented the collagen-specific T cells from responding to it. See generally , Skinner; Tr. at 288. Dr Matloubian again noted, “ There's no molecular mimicry, there' s no showing of the same T cell receptor sees both collagen or hemagglutinin.” Id. I again agree with Dr. Matloubian’s assessment. In sum, the articles ci ted by Petitioner do not demonstrate that the same T cells can recognize both type II collagen peptide and influenza HA peptid e bound to HLA-DR4. Thus, th ese articles to not support Petitioner’s mole cular mimicry theory. See also Tullio v. Sec’y of Health & Hum. Servs.

, No. 15-51V, 2019 WL 7580149, at *22 (Fed. Cl. Spec. Mstr. Dec. 19, 2019) (also concluding that Petitioner had not established a viable molecular mimicry theory in his flu-RA case), aff’d 149 Fed. Cl. 448 (2020).

a. Studies Use T Cell Reactivity to In fluenza Virus Antigens as a Control

The Malmström article is a revi ew article discussing the pathog enesis of RA. In describing the article, Dr. Matlo ubian testified that “patie nts who have seropositive RA have T cells that are specific for [certain] citrullinated peptides.” Tr . at 290. He then pointed to one sentence in Malmström which reads: “A parallel analysis in HLA-matched healthy controls showed much lower levels of T cell activation against these anti gens, whereas reactivity to an unrelated antigen (from influenza virus) was similar between healthy controls and pati ents with RA.” Malmström at 7. Dr. Matloubian noted that “when they're st udying patients with rheumatoid arthritis and comparing presence of unreactive T cells relevant to RA, between the RA patients and the healthy controls, they are using T cell reactivity to antigen s from influenza virus, an unrelated antigen, as

a control.” Tr. at 290-91.

The important point that Dr. Ma tloubian made was as follows:

So scientists, researchers who are st udying specifically T cell responses to rheumatoid arthritis using state-of-the-art technology be lieve that influenza virus antigens are unrelated to rheumatoid arthri tis antigen, and that's why they can use34 them as controls. So they don't believe there's any molecu lar mimicry between rheumatoid arthritis antigens and influenza-associated antigens.

Tr. at 291. I find this point is persuasive eviden ce which further undermin es Petitioner’s position that molecular mimicry between a portion of the flu virus molecule and a portion of type II collagen caused Petitioner to develop RA.

Based on the foregoing analysis, I find that Petitioner’s proffered prong one theory, molecular mimicry, is not a sound and reliable th eory that the flu vaccine can cause RA.

3. The Majority of Persuasive Studies do not Support a Connection between Flu

Vaccine and RA

Several large studies have been performed to assess whether the flu vaccine causes rheumatoid arthritis. Each study indicates that there is not an association between the two.

Epidemiologic evidence is relevant with respect to Althen prong one. See, e.g., D’Tiole v. Sec’y of Health & Hum. Servs., 2016 U.S. Claims LEXIS 2003 (F ed. Cl. Spec. Mstr. Nov. 28, 2016), mot. for review den’d , 132 Fed. Cl. 421 (2017); Blackburn v. Sec’y of Health & Hum. Servs.

, No. 10–410V, 2015 WL 425935, at *28–30 (Fed. Cl. Spec. Ms tr. Jan. 9, 2015). Ho wever, this type of evidence is not required in order for a petitioner to establish that a vaccine can cause an injury. A vaccine injury is a rare event that cannot be disproved because a vaccinee did not experience a response consistent with that of the general population. See Harris v. Sec’y of Health & Hum.

Servs. , No. 10–322V, 2014 WL 3159377, at *11 (Fed. Cl. Spec. Mstr. June 10, 2014) (finding that epidemiologic studies cannot absolu tely refute causal connections , because it is possible that a larger study could always de tect an increased risk), mot. for review dismissed , 2015 U.S. App. LEXIS 7921 (Fed. Cir. 2015).

Respondent presented several studies in support of his position that the flu vaccine does not cause RA. The Ray study was discussed extens ively by both experts. This study involved a medical chart review of approxi mately one million subjects in Kaiser Perman ente from 1997 through 1999 and included both a cohort analysis a nd a case-control analysis. In Ray, the cohort analysis found a possible association between the flu vaccine and RA in windows approximately six months and one year after fl u vaccination. The researchers in Ray then increased the power of the study and conducted a larger case -control analysis. Ultimately, th is study concluded that there was no risk of getting RA af ter flu vaccination. Ray at 6596.

Although Dr. Zizic critici zed the case control po rtion of his study for diluting the sample size of the cohort, Dr. Matloubian persuasively testified that a dding more cases should help to

confirm existence of findi ngs by increasing the power of the study. He stated,

... if there was a true difference, if ther e was a true difference, an association

between ... influenza vaccine and devel opment of RA, you woul d I think, if you bring more people, more people with RA who were vaccinated, and, you know, you would see that difference, but the fact th at they could not reproduce ... this finding and [the] fact that other studies that are well controlled didn't show this association,35 really puts into question actually the cohor t analysis rather than the case-control analysis.

Tr. at 355. Setting aside the case control portion of Ray’s findings, even the cohort analysis found

there is no increased risk of RA within 90 days of flu v accination. Ray at 6594. Petitioner seemingly relies on the Ray cohort findings which note a potential association between flu vaccine an RA within 180 days of vaccina tion. Any initial evidence of an a ssociation (which was later not borne out) is not persuasive in establishing that fl u vaccine can cause RA when that association is

so far removed from the date of vaccination. I find that the Ray study provides strong evidence

that there is not an associat ion between flu vaccine and RA.

I have also considered the Bengtsson cas e-control study. This study followed 1998 cases of RA and 2252 controls for five years after vaccination. Bengtsson did not find any association between the development of seropositive or seronegative RA and prior vaccine exposure. (“Vaccinations neither increased the risk of RA overall (OR 1.0, 95% CI 0.9 to 1.1) nor the risk of two major subgroups of RA (antibodies to citr ullinated peptide-positive (ACPA-positive) and ACPA-negative disease)). Bengtsson at 1831. This study also provides pers uasive evidence that

flu vaccine is not associated with RA.

Respondent additionally pr esented the Fomin study. See Fomin et al., Vaccination against influenza in rheumatoid arthritis: the eff ect of disease modifying drugs, including TNF α blockers

, 65 A NN R HEUM D IS

, 191-94, 2006 (filed as Ex. A-22) (herei nafter “Fomin”). Fomin assessed the safety of flu vaccine in patients already diagnosed with RA. The results of this study indicated that “Vaccination against influenza was not associated w ith a significant worsening of any clinical or laboratory index of diseas e activity.” Fomin at 193.

The Westra authors reported on six studies which addressed the safety of the flu vaccine in patients with autoimmune rheumatic diseases, to include RA. The authors stated that “no significant influence of vaccination on disease activity has been reported.” Westra at 140.

Petitioner cited to several medical articles in support of his position th at the flu vaccine can cause RA. One such paper is Basra et al., Rheumatoid Arthritis and Swine Influenza Vaccine: A Case Report , C ASE R EPORTS IN R HEUMATOLOGY , Vol. 2012, doi:10.115 5/2012/785028 (filed as Ex. 52) (hereinafter “Basra”). A lthough Basra is a case report involving the H1N1 vaccine, the authors noted that “Vaccinations that are suspec ted to cause RA include influenza, MMR, HBV, tetanus toxoid, typhoid, paratyphoid A and B (TAB), polio, diphtheria, and smallpox.” Basra at 1. This quotation references Schattner for support. See id. at 2. However, as Dr . Matloubian noted at hearing, Schattner concludes that “whenever you do controlled trials, you don't really find that

these vaccines cause autoimmune diseases.” Tr. at 342. Accordingly, this one sentence in Basra (a case report relating to a different vacc ine) is substantially undermined.

Petitioner also cited to the Symmons study. The au thors of this study st ated that “there is

evidence that tetanus and influenza immunization may trigger RA in susceptible hosts.” Symmons

at 5. Dr. Zizic testified that “In the NOAR case-control study th ere was an association between immunization in the 6 weeks preceding symptom onset and the development of rheumatoid arthritis. (Odds ratio, 2.4; 95 per cent confidence interval)” -- and they did overlap one, so it’s not36 totally statistically signif icant, just suggested". Tr . at 29-30. In fact, the conf idence interval is listed in the paper as “0.2, 23.2”. Symmons at 5. If a confidence interval overl aps one, it is no t statistically significant. See Tr. at 48-49; 296. Additionally, this statement cites to reference 62, which is the Harrison paper. In Harrison, only 15 people received the influenza vaccine, and the results did not reach statistical significance. Harrison at 3; Tr. at 294-95.

Petitioner also submitted the Wang article, which Dr. Zizic described as “a very key article that definitively shows influenza vaccination caus es -- can cause rheumatoid arthritis in some patients.” Tr. at 46. Wang is a meta-analysis, which means that the authors evaluated studies that have already been performed. Wang addressed five ar ticles that relate to influenza vaccination and RA; Bengtsson, Ray, Ho, Persson, and Vaughn. When citing to Ray, the Wang meta-analysis only evaluated the cohort pa rt of the study, not the case control portion. See Wang at 759. The fact that the authors in Wang chose to only include data that was contrary to the original study’s finding undercuts Wang’s persuasiveness. 6 While Bengtsson and Ray have been filed as exhibits in this case, the other studies referenced in Wang have not. Dr. Matloubian did not e that Persson involves the Pandemrix vaccine, which is not used in the Un ited States. It is difficult to draw conclusions about the other two studies referenced in Wang. In summarizing the data studied by Wang, Dr. Matloubian testified that “of those, the only one that's statistically significant is the Ray one, the cohort part of it, and possibly the Perss on, which is the [P]andemrix.” Tr. at 313.

Ultimately, in evaluating the medical literature fi led in this case, the weight of the evidence suggests that there is not an as sociation between flu vaccine a nd RA. Although I have considered Petitioner’s filings, I ha ve credited the larger studies (Ray, Bengtsson, Fomin, and Westra ) over case reports, studies that do not reach statistical signifi cance, and the Wang article.

4. Production of RA Auto-Antibodies

Also undercutting Petitioner’s prong one theory is the point that a growing body of medical literature indicates that autoantibodies precede clin ically apparent symptoms of RA by a period of years. According to Dr. Matloubian, the predominant thought within the rheumatological community is that autoantibodies exist within year s of a seropositive RA diagnosis. He testified as

follows:

And, you know, between Dr. Zizic and I, we have submitted 10 review articles on rheumatoid arthritis and pathogenesis of rh eumatoid arthritis, and they all say that

6 Also undercutting the persuasiveness of this article is the author’s reference to “ASIA” (Autoimmune syndrome induced by adjuvants) in their very firs t paragraph, calling it “a well defined auto-immune condition caused by adjuvants.” Wang at 757. The ASIA theory for adjuvant-induced autoimmunity has not been deemed medically reliable in prior Program cases. See, e.g., Monzon v. S ec’y of Health & Hum.
Servs., No. 17-1055V, 2021 U.S. Claims LEXIS 1269, at *26 n.6 (Fed. Cl. Spec. Mstr. June 2, 2021); see also Morris v. Sec'y of Health & Hum. Servs., No. 12-415V, 2016 WL 3022141, at *12 (Fed. Cl. Spec. Mstr. Apr. 1, 2016) (discussing lack of reliability of ASIA theory) ; Rowan v. Sec'y of Health & Hum. Servs., No. 10-272V, 2014 WL 7465661, at *16 (Fed. Cl. Spec. Mstr. Dec. 8, 2014 ), mot. for review den'd , 2015 WL 3562409 (Fed. Cl. May 18, 2015); D'Angiolini v. Sec'y of Health & Hum. Servs. , No. 99-578V, 2014 WL 1678145, at *60 (Fed. Cl. Spec. Mstr. Mar. 27, 2014), mot. for review den'd , 122 Fed. Cl. 86 (2015), aff'd , 645 F. App'x 1002 (Fed. Cir. 2016).37 it takes years for rheumatoid arthritis to develop. It do esn't happen overnight. It's ... not like you get an infection or a vaccine and the next day you develop

rheumatoid arthritis. This is years in the making.

Tr. at 247.

Some of the medical literature filed in this case supports this position. Deane & Holers in their 2019 article state that, “the re is now established and evol ving research that supports the conclusion that RA-related autoimmunity and infl ammation are present long before the first onset of IA during a period that can be termed pre-RA.” Deane & Hole rs at 1257. The authors further note that studies involving the history of RA “have found that RA-related autoantibodies are detectable in the circulation a mean of 3-5 year s before the first clinically detectable IA.” Id.

Petitioner correctly noted at hearing that in examining the data, only a percentage of patients studied tested positive for RA autoantibodi es in the years prior to their diagnoses. This suggests that a percentage of patients who go on to develop clinical RA may not develop autoantibodies prior to the clinical onset of their disease. Deane & Holers make this point when they state, “although existing studi es suggest that a high percenta ge of individuals who develop RF and/or ACPA-positive RA will have seropositivity of these antibodies before IA [inflammatory arthritis], not all individuals who develop IA ha ve detectable seropositivity for autoantibodies preceding their arthritis.” Deane & Holers at 1265. This statement is cons istent with the other evidence Respondent filed in this case. See Malmström (noting that “ACPAs [antibodies to citrullinated protein antigens] and RF [rheumatoid factor] are often present in the blood long before any signs of joint inflammation”); Nielen (stating the production of antibodies “occurred in only half of the patients before onset of symptoms”); van Steenbergen et al, The Preclinical Phase of Rheumatoid Arthritis, 65 A RTHRITIS & R HEUMATISM 9, 2219-32, 2013 (filed as Ex. A-12) (stating that “In the Swedish study, the presence of Ig M-RF and ACPA was reported in 19.3% and 33.7%, respectively, of the RA cases within 10 years before RA dia gnosis, compared to 6.0% and 1.8%, respectively ... Similarly, in the Dutch data set, 27.8% of the patients were IgM-RF positive and 40.5% were ACPA positive within 15 years prior to RA diagnosis”).

Petitioner’s point, that not all patients who go on to develop clinical RA ha ve pre-existing autoantibodies is correct. Accordingly, this belief held by members of the rheumatology community that autoantibodies prece de clinically apparent sympto ms of RA, standing alone, does

not eviscerate Petitioner’s Althen prong one theory. However, it is some evidence that I have considered in ultimately concluding that Petitioner has not met his burden under Althen’s first prong. Ultimately, I find it significant that “the researchers w ho publish articles on this believe that autoantibody and autoimmune disease that results in rheumatoid arthriti s starts years before somebody clinically develops disease, not within days or mont hs.” Tr. at 330-31.

In considering the totality of the evidence discussed above, I find that Petitioner has not presented preponderant evidence in the form of a s ound and reliable theory that the flu vaccine can

cause RA.

D. Althen Prong Two38 Under Althen ’s second prong, a petitioner must “prove a logical sequence of cause and effect showing that the vaccination was the reason for the injury.” Althen , 418 F.3d at 1278. The sequence of cause and effect must be "'logical' and legally probable, not medically or scientifically

certain." Id. A petitioner is not required to show "epidemiologic studies, rechallenge, the presence of pathological markers or genetic disposition, or general acceptance in the scientific or medical communities to establish a logical sequence of cause and effect." Id. (omitting internal citations). Capizzano , 440 F.3d at 1325. Instead, circumstantial evidence and reliable me dical opinions may be sufficient to satisfy the second Althen prong.

The incidence of rheumato id arthritis is approxima tely 24 per 100,000 per year. See Ahmed

at 6. Dr. Matloubian testified that based on these numbers, on e would expect to see 55,000 new cases of RA in the U.S. each year. Tr. at 316. Dr. Matloubian used these data to estimate the number of people who would develop RA after vaccination through chance alone. If approximately 140 million people receive the flu vaccine eachyear, approximately 1,600 people would be expected to develop RA within six weeks of receipt of the flu vaccine through chance alone. Id. at 315-16. These data lend some support for the oft- cited principle in the Vaccine Program that temporal association alone does not suffice to demonstrate causation. See, e.g.

, Zumwalt v. Sec’y of Health & Hum. Servs. , No. 16-994V, 2019 U.S. Claims LEXIS 465 at *59 (Fed. Cl. Spec. Mstr. Mar. 21, 2019), aff’d , 146 Fed. Cl. 525 (2019).

1. Petitioner’s Evidence

Dr. Zizic summarized Petitioner’s evidence in support of the second Althen prong. He stated,

With respect to the second requirement, th e petitioner did not have any persistent rheumatic symptoms prior to vaccination. There is nothing in the medical records to support any pre-existing autoimmune dise ase, nor any inflammatory form of arthritis, nor anything to suggest RA. The history subsequent to immunization clearly was contemporaneously documented as RA and was strongly seropositive with respect to both rheumatoid factor and CCP. Other autoimm une diseases were excluded on clinical grounds as well as immunological laboratory studies (e.g. ANA, ENA, C3, C4, ANCA, SCL 70, Jo 1). T hus it is my opinion that this is a logical sequence of cause (the influenza vaccine was the only perturbation to his immune system around the time of illness onset) and the effect (the development of RA). There is an absence of any othe r good explanation for a triggering event.

First Zizic Rep. at 21-22. In esse nce, Dr. Zizic has opined that Pe titioner did not have RA before his flu vaccine, he developed RA after his flu va ccine, and there is no expl anation for Petitioner’s condition, so the influenza vaccine did cause Petitioner’s RA. Although Dr. Zizic noted that

Petitioner’s RF and anti-CCP antibodies were “s trongly seropositive”, he did not explain whether or how this point demonstrates that Petitioner’s flu vaccine likely caused his RA. The Federal

Circuit in Capizzano noted that “[t]he second prong of the Althen ... test is not without meaning.” Capizzano , 440 F.3d at 1327. Indeed, in Althen , the Court stated: “Alth ough probative, neither a mere showing of a proximate temporal rela tionship between vaccination and injury, nor a39 simplistic elimination of other pot ential causes of the injury suffi ces, without more, to meet the burden of showing actual causation.” Althen , 418 F.3d at 1278.

2. Treating Physicians

In weighing evidence, special masters are expected to consider the views of treating

doctors. Cappizano , 440 F.3d at 1326. The views of trea ting doctors about the appropriate diagnosis are often persuasive b ecause the doctors have direct e xperience with the patient whom they are diagnosing. See McCulloch v. Sec’y of Health & Hum. Servs. , No. 09-293V, 2015 WL 3640610, at *20 (Fed. Cl. Spec. Mstr. May 22, 2015).

In this case, no treating physician persuasively attributed Petitioner’s RA to his flu vaccine. This is not surprising, as the cause of RA is unknown. See First Zizic Rep. at 18 (noting that “despite major advances in our understanding of the pathogenesis of rheumatoid arthritis, the etiology remains unknown”). I note that one of Pe titioner’s records, from December 11, 2014 states under past medical history: “Includes rheumatoid ar thritis occurring after a flu shot.” Ex. 5 at 1.

There is also a handwritten not e later in this record whic h states “RA from flu shot”. Id. at 3. I do not find that these notes provide a persuasive connection between the flu vaccine and Petitioner’s RA. In fact, they read more as a history provided by Petitioner than as a medical opinion. 7

3. Petitioner Had a History of Smoking

Petitioner was a former smoker who smoked “0.25 packs/day for 15 years.” Ex. 3 at 7. The medical records are clear that Petitioner quit sm oking approximately 17 years before the onset of

his RA. See Ex. 13 at 7 (noting, “He smoked cigarett es until June 17, 1997 and none since.”); Ex. 23 at 2, (“Has not smoked since 6/7/1997.”); E x. 51 at 2.9. (indicating Petitioner was a former smoker with a quit date of 1/1/1997 and that he smoked 0.25 packs/day for 15 years).

It is also clear that smoking is an established risk factor for RA. See Malmström at 2 (noting that smoking has a large impact on ACPA-positive patients); McInnes & Schett, The pathogenesis of rheumatoid arthritis , 365 N E NGL

. J M ED

. 23, 2205-19, 2011 (filed as E x. A-1) (stating that “Smoking and other forms of br onchial stress (e.g., exposure to silica) increase the risk of rheumatoid arthritis among persons with suscep tibility HLA–DR4 alleles”); Hunt & Emery, Defining populations at risk of rheumatoid arthritis: the first steps to prevention , R HEUMATOLOGY

,

7 Several other medical records discuss Petitioner’s RA in the context of his vaccination, but none persuasively link his vaccination to his RA; ind eed, these records do not discuss a causal relationship between the two. For example, on September 2, 2014 , a treating physician noted, “Symptoms started in Oct 201[3], a few days after a flu shot. See Ex. 3 at 6, 85, Ex. 7 at 57, Ex. 51 at 63. On May 13, 2014, it was

noted that Petitioner “is convinced that his rheuma toid disease was precipitated by receiving an influenza vaccine. It was his first and only vaccination. He has been reading online states th at prior to this he was ‘perfectly healthy’. He informs me that he is ‘talking to a lawyer.’” Ex. 7 at 67, Ex. 13 at 10, 37, Ex. 51 at 95. On September 10, 2016, Petitioner refused a flu v accine because “he was concerned about the possibility

of RA associated with an influenza vaccine.” Ex. 21 at 12. On August 9, 2017, a history taken from Petitioner noted that: “Relevant background history begi ns in Oct 2013 a few days after patient received a flu shot: he first noted pain in the top of both feet that was worse in the mornin g and associated with morning stiffness of 3-4 hours.” Ex. 51 at 32, 48.40 Vol. 10, 521-30, 2014 (filed as Ex. A-7) (observing th at smoking is a risk factor for seropositive RA).

While Petitioner concedes the fact that he has a history of smoking and that smoking generally is an established risk factor for RA, he asserts that the increased risk declines slowly back to normal within 10 y ears of smoking cessation. Be cause Petitioner quit smoking approximately 17 years before the onset of his disease, Petitioner contends that smoking is not a

factor in his situation.

Petitioner cited Firestein & McInnes, Immunopathogenesis of Rheumatoid Arthritis , 46

I MMUNITY 183-96, 2017 (filed as Ex. 50) (hereinafter “F irestein & McInnes”) in support of his position. The authors of this review article note that

Epidemiologic/genetic studies, particularly those arising from impressive Swedish registries, have highlighted the role of cigarette smoking as a prominent environmental risk factor for RA[.] ... The amount and duration of smoking are important, with the highest risk observed with greater than 20 pack-years of exposure. Risk declines slowly back to normal within 10 years of smoking cessation, suggesting that effe cts are not solely toxin dependent but may also arise by altering immunol ogic function.

Firestein & McInnes at 185. The au thors cited to one study (Kallb erg et al. 2011) as support for the point that risk declines back to normal within 10 year s of smoking cessation. Id.

Dr. Matloubian opined that the fact that Petitioner quit smoking approximately 17 years before his RA diagnosis does not impact his asse ssment that smoking was still a risk factor in

Petitioner’s case. Third Matloubia n Rep. at 3. Dr. Matloubian noted that since RA is thought to go through multiple pre-clinical phases years prior to clinical presentation, Petitioner’s smoking

would have led to a breakdown in to lerance resulting in autoimmunity. Id . Dr. Matloubian

concluded “once this breakdown of tolerance ha s been triggered by smoking in a genetically susceptible person, it can continue to progress to full blown clinical RA even if that person quits smoking.” Id.

Dr. Matloubian testified at the entitlement hearing that although Petitioner quit smoking 17 years before he developed RA, “the insult” of smoking had still taken place. Tr. at 250. In support of his position, Dr. Matloubian referred to the Liu article. The authors in Liu asked the question: “what's the impact of smoking cessation on developing RA in different serological phenotypes”? Id. They concluded that “With increasing duration of sm oking cessation, a decreased trend was observed in risk for all RA.” Liu at 1. However, the authors went on to note that “a modestly elevated RA risk was still de tectable 30 years af ter quitting smoking.” Id. Liu also discussed Kallberg, stating that “ this case-control study may have been limited by recall bias and there were few cases in the sustained smoking cessation group so there may have been limited power to detect a true difference.” Id. at 7.

Petitioner responded to this test imony by highlighting the fact that the study discussed by Liu involved 230,000 women and did not include men. Indeed, the authors in Liu noted that one41 possible limitation of their st udy was that a study population “ consisting of mos tly healthy, welleducated, white US women working in nursing professions at baseli ne, may not be representative of the general population.” Liu at 9. In response to Petitioner’s poi nt that the study only involved women, Dr. Matloubian noted that the findings in Liu also discussed “other studies that include men and women with similar findings.” Tr. at 374.

Liu did refer to other studies, although I did not note any st udies that included men. They referenced “[r]ecent results fro m the French E3N cohort study prospectively followed 71,248

women since 1990 and found that past smokers (HR 1.32, 95% CI 1.06–1.64) and current smokers (HR 1.57, 95% CI 1.13–2.19) had increased RA risk co mpared to never smoke rs.” Liu at 7. The

Liu article also refe rred to the Swedish Mammography C ohort study, which followed 34,101 women from 1997 to 2010, identifying 219 incident RA cases. Liu summ arized the results of this study, noting that “[p]ast smokers who quit smoking ≥ 15 years had increased RA risk (HR 1.99, 95% CI 1.23–3.20) compared to never smokers, s uggesting that residual elevated RA risk

remained even after sustained cessation.” Id.

In evaluating the experts’ test imony and the various pieces of medical literatur e, I conclude there is preponderant evidence to suggest that the risk of smoking decrease s in the years following smoking cessation, but that the risk does remain el evated above that of a non-smoker, even after 20+ years. The Liu study is subs tantially better powered than th e other studies discussed by the experts, involving 230,000 women who were studied over decades. I have also considered the fact that the literature filed into the record only includes studies i nvolving women. The fact that men were not studied in Liu does not, in my opinion, reduce the value of that study to something below preponderant evidence.

Because smoking is a demonstrated risk factor for RA, it is more likely that this played a role in the development of Petitioner’ s disease rather than his flu vaccine. See Stone v. Sec’y of

Health & Hum. Servs. , 676 F.3d 1373, 1379-80 (Fed. Ci r. 2012) (finding that special masters can consider other possible sources of in jury in making a determination under Althen prong two). 8

As noted previously, autoantibodies likely preced e clinically apparent symptoms of RA by a period of years. This position, espoused pe rsuasively by Dr. Matloubian, further diminishes Petitioner’s ability to demonstrate that flu vaccine did cause RA in this particular case. For all these reasons, I conclude that Petitioner has not presented pr eponderant evidence in support of

Althen’s second prong.

E. Althen Prong Three

The timing prong contains two parts. First, a pe titioner must establish the “timeframe for which it is medically acceptable to infer causation” and second, he must de monstrate that the onset of the disease occurred in this period. Shapiro, 101 Fed. Cl. at 542-43 (2011).

8 I note that while smoking has been persuasively iden tified as an environmental trigger for RA, Respondent has not contended that smoking is an alternate cau se of Petitioner’s disease. Although I have considered Petitioner’s history of smoking in my analysis, even without this evidence, I wo uld have found Petitioner’s prong two showing to have been deficient for the reasons articulated in this decision.42 1. The Onset of Petitioner’s Clinically Apparent RA

Petitioner contends that the onset of his symp toms of RA began several days after his flu vaccine. I find there is preponderant evidence to support this contention. I based this assessment

on the medical records filed in the case.

On January 16, 2014, Petitioner vi sited Shores Podiatry Asso ciates and complained of bilateral plantar foot pain. Ex. 6 at 1. Plantar foot pain refers to pain in the arch of the foot. Tr. at 223. Petitioner reported increased activity before onset of his pain. Ex. 6 at 1. The subjective portion of this record indicates that: “Patient states he was having pain in the heel of his feet and when he was at a hockey game he was walking on the ball of his feet. This caused pain in the ball and ankle of his feet. The heel is feeling fine now.” Id. Petitioner indicated his foot pain was in the

“4/5 IMS 9 and left dorsal midfoot.” Id.

Petitioner returned to the podi atrist on March 10, 2014 complaining of pain in both feet

and ankles which Petitioner indica ted had been ongoing for “several months.” Ex . 6 at 3. He also noted “recurrent pain & swelling in the 4 space right foot.” Id. Petitioner also has pain in both

shoulders. Id.

On April 29, 2014, Dr. Timothy Brennan, a rheu matologist at the S hores Rheumatology, PC, examined Petitioner and opined on his condition. Ex. 3 at 101. Dr. Brennan wrote,

In October of 2013, he recalls a day where hi s left heel was painful following which he developed significant pain and discomfort in both sets of metatarsal phalangeal joints. Over time, this progressed to invol ve both wrists, his me tacarpal phalangeal joints, both elbows, and the left knee. He identifies mornings as his worst time but can’t quantify the leng th of his stiffness...

Id

.

Petitioner met with Dr. Viju Moses, MBBS at the Universi ty of Michigan Rheumatology Clinic on September 2, 2014. Ex. 3 at 6. During that visit, Dr. Mo ses notes Petitioner’s history:

His symptoms started in Oct[ober] 2014, [sic ] a few days after a flu shot. He first noted pain in the top of bot h feet. It was worse in the morning, and he had morning

stiffness of 3-4 hours...Since Mar[ch] 2014 he started gett ing pain in his hands, w rists [sic], L[eft] shoulder, R[ight] knee and L[eft] bu ttock>R[ight] buttock. Unsure about morning stiffness fo r these joints...Fluctuating fatigue, sometimes severe.

Id . While this last record is certainly the most spec ific, it is not inconsistent with the other medical records in this case. I find that bilateral foot pain constituted the onset of Petitioner’s RA. This finding is consistent wi th Dr. Zizic’s testimony. See Tr. at 72, 81 (Dr. Zizic indicating that Petitioner’s first symptom of RA was the pain a nd swelling in his feet). I further find there is

9 The 4/5 IMS is the space between the 4 th and 5 th metatarsal. Tr. at 233.43 preponderant evidence that Petitione r’s onset of bilateral foot pain began approximately three days

after his flu vaccination.

2. There is not Preponderant Evidence that Three Days Post-Flu Vaccine is a Medically-Acceptable Timefr ame for Onset of RA

I note there is not extensive evidence in the r ecord discussing the appropriate onset interval of RA after flu vaccine. Dr Zizic opined that “t he petitioner developed RA symptoms within days

after the influenza vaccination, and developed full-blown poly arthritis that was believed to be rheumatoid arthritis by both rheumatologists. This is precisely the timeline that one would expect

from a vaccine induced autoimmune response.” First Zizic Rep. at 22. This opinion was not substantially developed in subseque nt reports or at hearing. Dr. Zizi c generally testified that onset of disease two to three days after flu vaccine wa s medically appropriate under a molecular mimicry theory due to the recall response Petitioner likely experienced after having a prior flu infection.

Tr. at 81-82.

Petitioner pointed to case reports as support for Dr. Zizic’s opinion. See Basra at 1 (noting one week after flu shot, patient developed “joint pain and aches in hands, wrists, and knees, which resolved within a few days and patient became asymptomatic.” Patient then received H1N1 vaccine and developed symptoms of RA one w eek later). Ex. 33 (a case report describing symptoms of polyarthritis that began a few da ys following systemic reaction to tetanus-toxoid vaccine); and Ex. 34 (joint manife stations after vaccination began 9 to 27 after rubella vaccine). These case reports involving vaccines othe r than the vaccine in the present case 10 do not provide preponderant evidence that three days is a medically-a ppropriate window for RA to develop after flu vaccine. In addition, and im portantly, Dr. Matloubian persuasi vely opined that RA does not develop in a matter of days af ter an inciting event but is “y ears in the making”. Tr. at 247.

I agree with Chief Special Master Corcoran’s discussion of this topic in Monzon v. Sec’y of Health & Hum. Servs

, 2021 WL 2711289 (Fed. Cl. Spec. Mstr. June 2, 2021) . He stated:

Indeed, given what is known about RA (and in particular the fact that the presence of the antibodies closely associated with it often long precede onset of RA symptoms), it is highly unlikely a vaccine could either cause these autoantibodies to develop in a medi cally-reasonable timeframe, or spark an autoimmune process dependent upon th em, such that a vaccine administered close in time to appearance of RA symptoms could be deemed causal.

Monzon at *19. Petitioner has not pres ented preponderant evidence that three days is a medically acceptable timeframe for the onset of RA after flu vaccine, and thus has not established the third

Althen prong.

10 Although Basra discussed a patient who received seas onal flu vaccine, her symptoms resolved within a few days. Examining Basra in the context of the en tire report demonstrates the authors were discussing the

H1N1 vaccine.44 VI. Conclusion

Upon careful evaluation of all th e evidence submitted in this matter, including the medical records, the testimony, as well as the experts’ opi nions and medical litera ture, I conclude that Petitioner has not shown by preponderant evidence that he is entitled to compensation under the

Vaccine Act. His petition is therefore DISMISSE D. The clerk shall enter judgment accordingly. 11

IT IS SO ORDERED.

s/ Katherine E. Oler

Katherine E. Oler Special Master

11 Pursuant to Vaccine Rule 11(a), the parties may expe dite entry of judgment by each filing (either jointly or separately) a notice renouncing their right to seek review.