THE AUTOIMMUNE CONNECTION BLOG
October 31, 2016
IWe’ve been hearing a lot lately about new “biosimilar” drugs being approved for rheumatoid arthritis (RA) and other autoimmune diseases. While these drugs promise to be a potentially less expensive alternative to older biologics like Humira, don’t confuse the term “biosimilar” with “generic.” And don't think they'll be a bargain.
Biosimilar medications are not cheaper “generic” versions of existing biologic drugs.
Here’s what you need to know:
The three new anti-rheumatic biosims approved by the FDA -- Amjevita, Inflectra,and Erelzi – copycats of adalimumab (Humira), Remicade (Infliximab), and etanercept (Enbrel) – all target the same inflammatory molecule tumor necrosis factor-alpha (TNF-α) and are approved to treat the same autoimmune and arthritic conditions as the original biologics:
• Amjevita (adalimumab-atto): a subcutaneous injection approved for moderate to severe rheumatoid arthritis (RA), Crohn’s disease and ulcerative colitis, as well as psoriatic arthritis (PsA), ankylosing spondylitis (AS), and moderate to severe plaque psoriasis.1
• Erelzi (etanercept-szzs): an intravenous injection approved for treating polyarticular juvenile idiopathic arthritis (JIA) and RA, as well as PsA, AS, and moderate to severe plaque psoriasis.2
• Inflectra (infliximab-dyyb): intravenous infusion approved for adults and children two years old and over with moderate to severe Crohn’s disease or ulcerative colitis for whom conventional therapies were not effective, for AS, PsA, chronic severe plaque psoriasis, and for treating RA in combination with methotrexate.3
Because these drugs are “similar” but not exact copies of older TNF-α inhibitors, your pharmacy can’t just swap them without consulting your doctor as they can with other brand-name prescription drugs and their generic versions.
Biosimilars vs. Interchangables vs. Generics
The FDA approves biological drugs in two categories: “biosimilar” and “interchangeable.”
To be approved as a biosimilar a drug must “highly similar” to an already FDA-approved biological drug (“reference drug”) and have “no clinically meaningful differences” in purity, potency, safety and effectiveness.4
A biosimilar must also have the same “mechanism of action,” route of administration, dosage form, and strength as the reference drug. They can only be prescribed for the same indications and conditions of use as the original drug.4
To be FDA-approved as an interchangeable biological, the drug must also “produce the same clinical result as the reference product in any given patient” and pose no greater risk in terms of safety and effectiveness if alternated or switched with the original.4 This is important, because many patients with RA, Crohn’s disease, and other autoimmune conditions are switched from one biologic to another if the first drug produces an inadequate response.
Generic drugs must have exactly the same active chemical components, dosage form, and route of administration as the brand-name, and produce the same effects. In pharma-speak, they’re “bioequivalent.”
Because biological drugs are very complex, it’s simply not possible to make exact copies of a drug like Remicade to produce a generic. According to the FDA, biologics are “large molecule” drugs, lab-produced proteins derived from living sources including humans, microorganisms, and yeast. In contrast, conventional prescription drugs are considered “small molecules” and compounds made from chemical formulas.4
Manufacturing a biologic medication is also more complicated. The process involves gene splicing and other techniques to produce a drug engineered to home in on and disable a specific protein that causes inflammation in the body, in this case TNF-α.
Amjevita, Erelzi and Inflectra are approved as biosimilars and not as “interchangeables.” They must be specifically prescribed by name and can’t be substituted for the original drug without permission from your rheumatologist.
Prescribing information for two of the new biosim drugs doesn’t indicate whether they are interchangeable or not.1,2 For Inflectra, information on switching medications cautions only that “Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.”3
The American College of Rheumatology (ACR) is calling on the FDA to specify on drug labels whether or not a biological has official interchangeable status -- and set up rules to protect patients, including guidelines for substituting medications.
“Substituting non-interchangeable biosimilars, especially without notifying the prescribing provider, poses uncertain safety risks to rheumatology patients due to the complexity of these drugs and the possibility of patients being forced to switch,” warned Angus Worthing, MD, incoming chair of the ACR’s Government Affairs Committee.5
Positive Trials Data and Price Points
All three drugs passed muster with the FDA after years of positive clinical trials among thousands of patients.
A systematic review conducted by researchers at Johns Hopkins University and Brigham and Women’s Hospital in Boston, evaluated 19 studies (including 13 clinical trials) of biosimilars to Remicade and Humira in patients with rheumatoid arthritis and inflammatory bowel disease. Phase 3 clinical trials suggest the biosims and their reference drugs produced similar clinical responses. The authors also note that four studies of patients switched from reference drugs to biosimilars suggested similar efficacy and safety outcomes.6
The analysis, published online August 2nd in the Annals of Internal Medicine, concluded that, so far, these biosim TNF blockers and their brand-name “reference drugs” do appear to be interchangeable.6
A clinical trial of an etanercept copycat, marketed in Europe asBenepali (etanercept SB4), came to the same conclusion. That 52-week study found that the drug could be safely switched in patients with moderate to severe RA. An open label extension trial lasting almost two years suggests patients could safely and effectively switch from reference etanercept to etanercept (SB4).7
While Inflectra is expected to come on the market shortly, patent disputes, especially over Humira, may delay Amjevita and Erelzi for at least five years.
Meanwhile, other questions remain to be answered.
For one thing, the three biosimilars haven’t been tested in every disease for which their reference drugs are approved. In the case of Amjevita, clinical trial results in RA and plaque psoriasis were reportedly extrapolated so the drug could be approved for all the conditions for which Humira is currently indicated.8 While experts are optimistic, there’s no way to know how these biosims will actually perform in a variety of real-world autoimmune patients outside the controlled confines of clinical trials.9
In light of that, the ACR’s Dr. Worthing called on the FDA at a public hearing October 20th, to set up a post-marketing surveillance program to watch for any adverse events related to non-interchangeable substitutions.5
Then there’s the issue of drug pricing. While industry experts expect the biosims to be priced just below the original drugs,10 it’s unclear if autoimmune patients will benefit. These days, even generic drugs can end up costing as much -- or even more -- than their brand-name equivalents.
According to a May report in the “pharmaceutical companies have been raising prices on biotech drugs about to lose patent protection to squeeze out more revenue before competition arrives… And makers of the knockoffs are setting their prices just below those marked-up ones.”10
In the case of Humira, whose patent expires December 31, WSJ.com says maker AbbVie, Inc., increased the drug’s list price eight times in the past three years -- by a total of 73% -- to $49,362 for one year’s treatment.10
So what will Amjevita cost when it’s finally launched? WSJ.com quotes an AbbVie spokesman as saying the company “prices its medicines based on the value that those medicines bring to patients and the competitive environment.”
Judging from the current pharmaceutical marketplace, that often means whatever the market will bear.
1 FDA approves Amjevita, a biosimilar to Humira. FDA News Announcement, September 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm.
2 FDA approves Erelzi, a biosimilar to Enbrel, FDA News Announcement, August 20, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm
3 FDA approves Inflectra, a biosimilar to Remicade. FDA News Announcement, April 5, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm
4 FDA, Information for Consumers (Biosimilars). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm
5 ACR Calls for Clearer FDA Guidelines and Increased Congressional Funding to Ensure Safe and Effective Adoption of Biosimilars in the U.S. American College of Rheumatology News Release, October 20, 2016.
6 Chingcuanco F, Segal JB, Kim SC, et al . Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic Review. Ann Intern Med. 2016;165(8):565-574. Published online 2 August 2016 doi:10.7326/M160428.
7 Burness CB and Duggan ST, Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases. BioDrugs. 2016; 30(4):371-378. doi:10.1007/s40259-016-0188-z.
8 Clarke T. “FDA panel backs Amgen copy of AbbVie arthritis drug Humira.” Reuters Health News, July 12, 2016. http://www.reuters.com/article/us-amgen-humira-fda-idUSKCN0ZS2NC Accessed August 20, 2016.
9 Lupkin, S, “Study Bodes Well For Biosimilars, But Highlights Need For More Research.” Kaiser Health News, August 1, 2016. http://khn.org/news/study-bodes-well-for-biosimilars-but-highlights-need-for-more/ Retrieved August 20, 2016.
10 Rockcoff JD. Knockoffs of Biotech Drugs Bring Paltry Savings. Wall Street Journal. May 5, 2016. http://www.wsj.com/articles/knockoffsofbiotechdrugsbringpaltrysavings1462458209
Retrieved August 20, 2016.
September 8, 2016
IIn the recent uproar over the soaring cost of the EpiPen, you may have missed news that could affect what you pay for autoimmune medications – pharmacy benefits managers for major insurance companies are excluding almost 240 medications from coverage.1 The lists include some frequently-used treatments for autoimmune diseases including rheumatoid arthritis and multiple sclerosis.
But wait, there’s more.
If you decide either the cost or the side effects of medications approved for inflammatory conditions like RA are just too much, Express Scripts, the nation's biggest drug benefits manager, is actually offering refunds to insurers if you quit using the drugs.2
This is part of what Express Scripts calls an “Inflammatory Conditions Care Value Program.” According to the company, this is a “comprehensive approach to control costs and improve care for people with inflammatory conditions like rheumatoid arthritis, psoriasis and Crohn's Disease.” 2
Actually, refunds to insurers are not new, although it may be news to you.
But this is the first time the refunds cover an entire category of drugs, which can only be obtained from a single mail-order company, Acredo.
As part of the plan, participating insurers will be refunded up to $6,000 if a patient discontinues any preferred anti-inflammatory medication within the first 90 days. This new reimbursement approach is “the country's first value-based refund to span multiple preferred medications that treat a group of diseases,” Express Scripts said in a press release.2
An Express Lane for Exclusions
Express Scripts revealed its preferred medications for inflammatory conditions when it issued its preliminary 84-drug exclusion list last month.3
The exclusion list includes a number of biologics such as the injectable tumor necrosis alpha (TNF-α) inhibitor Cimzia (certolizumab pegol) used to treat RA, Crohn’s disease, and psoriatic arthritis, and Taltz (ixekizumab) an interleukin-17 (IL-17) inhibitor newly-approved for moderate to severe plaque psoriasis. 3
Also on the list are:
• Anakinra (kineret) an interleukin-1 receptor antagonist (IL-1ra), excluded only for RA.
• Orencia (abatacept), a selective co-stimulation molecule, which prevents activation of destructive T-cells.
• Simponi (golimumab) a TNF-α inhibitor, 50 mg dose only
• Novolin, Apridra, and NovoLog, insulins for type 1 diabetes. sup>3
Express Scripts’ “preferred alternatives” to these drugs are: Actemra (tocilizumab), Cosentyx (secukinumab), Enbrel (etanercept), Humira (adalimumab), Otezla (apremilast), Remicade (infliximab), Simponi (golimumab) 100 mg, for ulcerative colitis only, Stelara (ustekinumab), Xeljanz (tofacitinib) and Xeljanz XR, and the insulins Humalog and Humulin.2
Under the new “Inflammatory Conditions Care Value Program,” patients must use the mail-order company, Accredo to get their medications. Acredo is billed as Express Scripts "Rheumatoid Arthritis and Inflammatory Disease Therapeutic Resource Center." The center offers some personalized care, which the company says boosts drug adherence.2
Express Scripts claims that between 21% and 36% of patients discontinue their meds within the first 90 days, but adherence is higher with this service. 2 The drugs have an average of $3,036 for a 30-day supply. If you do decide to stop taking one of them, your insurer may get a refund, but you (or your employer, if your benefits come through your job) will still be stuck with the bill.
Actemra (and other medications) may be “reassessed later this year to reflect anticipated product launches,” says Express Scripts. So they could well end up on the exclusion list, too.4
In addition, Express Scripts will now manage the inflammatory drugs formulary category around each individual condition.2 So the same medication could be approved for one autoimmune disease and excluded for another.
Caremark’s New Cuts
As of January 1, 2017 CVS Caremark is excluding 154 medications from its formulary, including three for multiple sclerosis and two for inflammatory bowel disease (IBS).5
The MS drugs are interferon-based treatments, including the widely-used Avonex (interferon beta-1a), the longer-acting Plegridy (peginterferon beta-1a) and Extavia,a copy-cat drug of Betaseron (interferon beta-1b).
Approved alternatives for the excluded MS drugs are Tecfidera, Gilenya (fingolimod), Copaxone (glatiramer), Rebif (interferon beta-a1), Betaseron, and Aubagio (teriflunomide).
The excluded drugs for IBS are Asacol HD and Delzicol (mesalamine). Approved IBS drugs are balasalazide, Apriso (mesalamine extended release caps), Entocort EC (budesonide delayed-release caps), Azulfidine (sulfasalazine) and its extended-release formula, Azulfidine EN-Tabs.
CVS’ has only two approved biologicals -- Enbrel and Humira -- used for a range of inflammatory autoimmune diseases.
It’s important for patients to note that these and other approved autoimmune medications are classified as “specialty medications” and carry restrictions from drug managers.
According to Caremark, medications in this category require “prior authorization” (that means a note from your doctor) and may only be “dispensed in limited quantities.”6 CVS' specialty drugs include the older, conventional DMARD methotrexate along with Enbrel and Humira.6
The exclusion list may well change in 2017, as new medications enter the market, older drugs on the approved list will be re-evaluated, with some medications added back and others excluded, Caremark says.6
Cost-Cutting Helps Insurers – What About Patients?
Together, Express Scripts and CVS Caremark handle pharmacy benefits for more than 200 million Americans.7
Both companies contend that their medication exclusions and care plans are a way to help contain the ever-escalating price of prescription drugs, especially those for inflammatory conditions like RA.7
“Painful inflammatory conditions like rheumatoid arthritis can cripple patients and obliterate payer budgets," said Glen Stettin, MD, Senior Vice President and Chief Innovation Officer at Express Scripts in a statement. "By finding creative ways to take better care of patients and protect our clients' budgets, Express Scripts is uniquely tackling one of the biggest health challenges facing our country today."2
By labeling and excluding select drugs as “hyperinflationary,” Caremark says it is “taking a stand against egregious drug price increases that unnecessarily add costs for clients and their members."6
That may be a bit of hyperbole. “Pharmacy benefits managers can claim to be standing up to pharma on behalf of payers, regardless of the actual dollar or patient impact,” comments the online drug industry economic newsletter Drug Channels.1
Express Scripts says its participating plan sponsors will save approximately $1.8 billion throughout the year through drug exclusions, according to Drug Channels. Caremark claims its formulary exclusions from 2012 to 2017, will save its clients $9 billion.1
But will you save money?
Generally, when drugs are cut from formularies you pay full price for your prescription unless you and your physician accept substitutions or you find a discount program. And some formularies require patients to try older, less expensive DMARDs before they’re allowed to move on to biologicals.
Less than 1% (0.12%) of patients who get their meds from Express Scripts “will be asked to use a different medication that achieves the same health outcome than one they are currently using,” the company says. “If any of these patients have rare clinical needs that require a medication that’s not on the formulary, we have provided a pathway to have that drug covered.”3
MS drug makers were quick to reassure CVS' patients there are mechanisms in place to insure they will have access to their medications.7
Just finding your drug on an exclusion list doesn’t mean you’ll automatically lose coverage. Formularies are only “recommended” and insurers are not required to follow them (of course, plans face higher costs if they do opt out).
Using an approved medication doesn’t automatically mean you’ll save money, either. That depends on your insurance plan’s co-pay. GoodRx medical editor Elizabeth Davis notes that patients may also be able to enlist their doctor’s help to appeal exclusions with their insurance provider.7
If you opt for less expensive brand-name medications or generics, your wallet may take a smaller hit. But prices have been steadily rising for generics, too.
And more drug exclusions are expected from other benefit management companies, reports GoodRx.com, an online service that helps consumers comparison shop for medication prices.7
The cuts do not apply to Medicare plans. If your Medicare coverage is managed by CVS or Express Scripts, check with Medicare.gov or your pharmacist, advises GoodRx.7
Find out all you can about drug exclusions and “care plans.” Investigate manufacturers’ discount programs or coupons. Check whether your state has a Pharmaceutical Assistance Program, which may help you get subsidies or discounts. Shop around for the best prices at GoodRx.com, Discount DrugNetwork.com, EasyDrugCard.com, and similar services.
And, of course, ask your physician whether switching medications is advisable.
1 Fein, AJ. “Seven Takeaways from the New 2017 CVS Health and Express Scripts Formulary Exclusion Lists,” Drug Channels, August 3, 2016. http://www.drugchannels.net/2016/08/seven-takeaways-from-new-2017-cvs.html
2 Express Scripts Launches Inflammatory Conditions Care Value Program(SM), Making America's Costliest Medication Class More Affordable. PR Newswire, September 8, 2016. http://www.prnewswire.com/news-releases/express-scripts-launches-inflammatory-conditions-care-value-programsm-making-americas-costliest-medication-class-more-affordable-300324538.html.
3 Express Scripts, 2017 Preferred Drug List Exclusions. https://www.express-scripts.com/art/pdf/Preferred_Drug_List_Exclusions2017.pdf
4 Express Scripts: 2017 National Preferred Formulary. Aug 1, 2016 http://lab.express-scripts.com/en/lab/insights/drug%20options/2017%20national%20preferred%20formulary.
5 CVS Formulary Drug Removals July 2016. http://www.caremark.com/portal/asset/Formulary_Exclusion_Drug_List.pdf
6 CVS Value Formulary List, Effective July 1, 2016. https://www.caremark.com/portal/asset/Value_Formulary.pdf
7 Davis, E. 40+ Drugs to be Dropped by Insurance. The GoodRx Prescriptions Savings Blog, August 17, 2016. http://www.goodrx.com/blog/40-drugs-to-be-dropped-by-insurance/
August 27, 2016
As mosquito-borne Zika virus continues to spread in southern Florida and threaten other Gulf Coast states, its connections with autoimmunity are cause for concern.
In addition to causing birth defects and severe brain damage (microcephaly) in hundreds of babies born to Zika-infected women,1 the virus is also being blamed for an increase in cases of a rare autoimmune neurological disorder called Guillain-Barré syndrome (GBS).2
Viral infections have long been suspected as a potential cause of autoimmune diseases, notably Epstein Barr virus (EBV). Infections are also a frequent trigger for Guillain-Barré, which affects peripheral and sensory nerves, causing difficulty walking and temporary paralysis. The mechanism is thought to be “molecular mimicry,” in which the structure or proteins of a virus are similar to normal cells in the body, so the immune system not only attacks the virus, but also the healthy tissue.3
So far, 18 countries report an increased incidence of GBS associated with Zika, according to the World Health Organization.4 At least seven cases of Zika-associated GBS have been reported in the U.S.5 and 30 in Puerto Rico, one of them fatal. A public health emergency has been declared in Puerto Rico, with almost 11,000 cases of locally-acquired Zika, including more than 1,000 pregnant women.6
Researchers say a second rare, autoimmune neurological disorder -- acute disseminated encephalomyelitis (ADEM) -- may also be linked to Zika. ADEM, like multiple sclerosis, results from an autoimmune attack on the protective myelin coating on nerve cells in the brain and spinal cord.7
Zika has also been associated with cases of immune thrombocytopenia purpura (ITP), an autoimmune disease which causes destruction of platelets.8 Platelets help blood to clot and if too many are destroyed there’s a risk of serious hemorrhage. One death was reported in Puerto Rico from severe thrombocytopenia in an elderly man with a confirmed Zika infection.8
Systemic treatments for chronic autoimmune disease, especially biologic drugs, suppress an over-active immune system and carry a potential risk of serious infections, including tuberculosis. Just having an autoimmune disease puts you at risk of developing another.
So far, however, autoimmune patients don’t appear to be at particular risk from Zika, stresses Tyler M. Sharp, PhD, an epidemiologist with the Centers for Disease Control and Prevention (CDC) and co-author of a recent report on ITP and Zika.
“To date, there has not been a link established between having a history of autoimmune disease and developing either Guillain-Barré syndrome or immune thrombocytopenia purpura following Zika virus infection,” emphasizes Dr. Sharp. Still, he adds, “patients with pre-existing autoimmune disease should consult their physician before traveling to an area with ongoing Zika virus transmission.”
People Can Spread Zika, Too
Zika is an arbovirus similar to Dengue and yellow fever, carried by two types of mosquitoes -- Aedes aegypti found in southern and tropical climates and the more common Aedes albopictus mosquito, found in much of the U.S. But in the current Zika outbreak, human beings become unwitting disease carriers.
It's a dangerous cycle: A Zika-carrying mosquito bites and infects a human -- another mosquito bites that person and acquires Zika virus through a blood meal -- then that mosquito buzzes off to infect someone else.9 Since the virus doesn’t always cause symptoms, people may not even know they’ve been infected and the A. aegypti mosquito often bites multiple people in a single blood meal. That’s one reason Zika can spread quickly.9
Zika can also be transmitted sexually through semen and other body fluids, even before someone has symptoms of an infection -- and long after symptoms end.10 According to the CDC, Zika can remain in semen longer than in other body fluids (including vaginal fluids, urine, and blood). So safe sex, the use of condoms and other barrier methods, is highly advised in Zika-affected areas.11
Given the risks of sexual transmission, the Food and Drug Administration (FDA) is now calling for all donated blood in the U.S. to be tested for Zika.12
The Virus-Autoimmunity Connection
Zika isn’t the first mosquito-borne virus with an autoimmune connection.
Chikungunya virus and Dengue fever, arboviruses spread by the same mosquitoes as Zika, can cause joint pain and mimic other symptoms of rheumatoid arthritis (RA). Some people infected with Chikungunya have developed an inflammatory arthritis that can persist for months to years.13 A recent epidemic of Chikungunya in the Caribbean was associated with post-infection rheumatic and musculoskeletal disorders, including RA.14
While it’s possible that people with autoimmune diseases who become infected with Zika could develop GBS, the actual risks are unknown.
Also unknown: if Zika could pose a risk in people with suspected autoimmunity who haven’t been formally diagnosed. One recent study suggests that people with primary chronic ITP may be at an increased risk for infections up to 5 years before they are actually diagnosed.15
If people with an autoimmune condition -- or otherwise healthy individuals, for that matter -- have been in an area with ongoing Zika transmission and are pregnant or develop an illness consistent with Zika virus (fever, rash, joint pain, or conjunctivitis/red eyes) within a couple weeks after traveling, they should be evaluated by a clinician to determine if they should be tested for Zika, advises the CDC’s Dr. Sharp.
If you have an autoimmune disease and live in a Zika-zone (such as Miami-Dade County in Florida) or plan travel to such areas, “employ approaches to avoid mosquito bites, such as regular use of mosquito repellent, staying in areas that are air conditioned and/or have intact window screens, and wearing long sleeves and pants,” Dr. Sharp recommended in an email.
Right now, aerial spraying, removal of standing water and use of larvicides in affected areas are the best public health defense against mosquitos. While preliminary results from an early-phase clinical trial of a potential Zika vaccine are expected by the end of 2016, it could take several years for a vaccine to be approved by the FDA and enter the marketplace.16
Note: Read more about molecular mimicry and other suspected viral triggers of autoimmunity in "The Autoimmune Connection."
1 Centers for Disease Control and Prevention (CDC), Outcomes of Pregnancies with Laboratory Evidence of Possible Zika Virus Infection in the United States, 2016. http://www.cdc.gov/zika/geo/pregnancy-outcomes.html. Retrieved August 24, 2016.
2 Cao-Lormeau VM, Blake A, Mons S, et al., Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016;387:1531–39. http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)00562-6.pdf. Retrieved August 24, 2016.
3 Anaya JM, Ramirez-Santana C, Salgado-Castaneda I, et al., Zika virus and neurologic autoimmunity: the putative role of gangliosides, BMC Medicine2016;14:49. DOI: 10.1186/s12916-016-0601-y. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0601-y. Accessed August 25, 2016.
4 WHO Situation Report, Zika Virus Microcephaly and Guillain-Barré Syndrome, August 25, 2016. http://www.who.int/emergencies/zika-virus/situation-report/25-august-2016/en/ Retrieved August 24, 2016.
5 CDC, Zika Virus Case Counts in the US. http://www.cdc.gov/zika/geo/united-states.html . Zika Virus and Guillain-Barré Syndrome. http://www.cdc.gov/zika/healtheffects/gbs-qa.html. Retrieved August 24, 2016.
6 HHS declares a public health emergency in Puerto Rico in response to Zika outbreak. Health & Human Services (HHS) Press release, August 12, 2016. https://www.hhs.gov/about/news/2016/08/12/hhs-declares-public-health-emergency-in-puerto-rico-in-response-to-zika-outbreak.html. Retrieved August 24, 2016.
7 Zika Virus May Now Be Tied to Another Brain Disease, American Academy of Neurology Press Release, April 10, 2016. Abstract Title: Neurologic Manifestations of Arboviruses in the Epidemic in Pernambuco, Brazil. Author: Brito Ferreira ML. https://www.aan.com/PressRoom/home/GetDigitalAsset/12051. Accessed August 27, 2016.
8 Sharp TM, Muñoz-Jordán J, Perez-Padilla J, et al., Zika Virus Infection Associated with Severe Thrombocytopenia. Clin Infect Dis. (2016) doi: 10.1093/cid/ciw476. First published online: July 14, 2016.
9 Peterson LR, Jamieson DJ, Powers AM, Honein MA. Review Article: Zika Virus. N Engl J Med 2016;374:1552-63. DOI: 10.1056/NEJMra1602113.
10 CDC. Zika and Sexual Transmission. http://www.cdc.gov/zika/transmission/sexual-transmission.html. Retrieved August 25, 2016.
11 Brooks JT, MD1; Friedman A, Kachur RE, et al., Update: Interim Guidance for Prevention of Sexual Transmission of Zika Virus — United States, July 2016. MMWR, July 29, 2016;65(29):745-747.
12 FDA advises testing for Zika virus in all donated blood and blood components in the US. FDA News Release, August 26, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518218.htm Retrieved August 26, 2016.
13 Miner JJ, Aw-Yeang HX, Fox JM et al., Brief Report: Chikungunya viral arthritis in the United States: A mimic of seronegative rheumatoid arthritis. Arthritis Rheumatol. 2015; 67(5): 1214–1220. doi:10.1002/art.39027.
14 Foissac M, Javelle E, Ray S, Guérin B, Simon F. Post-chikungunya rheumatoid arthritis, Saint Martin [letter]. Emerg Infect Dis. 2015 Mar. http://dx.doi.org/10.3201/eid2103.141397.
15 Ekstrand C, Linder M, Cherif H, et al. Patients with chronic ITP may have increased infection risk before diagnosis. J Thromb Haemost. 2016;14(4):807-814. doi:10.1111/jth.13267.
16 Safety and Immunogenicity of a Zika Virus DNA Vaccine, VRC-ZKADNA085-00-VP, in Healthy Adults. https://clinicaltrials.gov/ct2/show/NCT02840487 Retrieved August 24, 2016.
August 19, 2016
Going bald can be emotionally upsetting for anyone. But imagine losing all of your hair. Not just the hair on your head – but everywhere.
Attorney Laura Freeman of Phoenix, Arizona has been living with this kind of hair loss since she was 22. She’s among an estimated 6.8 million Americans who have alopecia areata, an autoimmune disease that starts out with small bald patches that can progress to loss of scalp and facial hair (alopecia totalis) and, in rare cases, total loss of body hair (alopecia universalis).1
For Laura, a 41-year-old mother of four young children, periodic patchy hair loss began after a bout with chicken pox when she was a toddler. “Sometimes I would have large bald spots all over my head that were impossible to conceal. Other times, they would be small and hardly noticeable,” she recalls. “Yet, I remember a constant sense of worry about it. I didn’t have hair like the other kids. I never would. Children made fun of me. I remember store clerks asking my mom if I had cancer.”
For several years, Laura tried minoxidil (Rogaine), which produced only peach fuzz hair growth and caused rashes. She also had cortisone injections into her scalp. The shots worked, but they were painful and caused thinning skin, so she was forced to abandon that approach as well.
In the summer of 1998, as she was preparing to go to law school, Laura lost her eyebrows and eyelashes and became totally bald. Her only option: wearing a wig.
“It was expensive and depressing and necessary,” Laura remarks. Her lack of eyelashes and eyebrows are especially noticeable, even with the wig. “After I got my wig, I remember telling friends who asked about it or who wondered if my hair was real. It’s still socially uncomfortable for me even at the age of 41.”
A Yale University study of almost 2,000 patients published online in July finds that alopecia areata causes a negative impact on quality of life, particularly in social functioning, psychological and emotional distress.2 “The results of this study lend further support to the fact that AA [alopecia areata] is not a ‘cosmetic’ problem but rather a medical disorder with important negative health consequences,” the study authors conclude.2
Clinical trials of three drugs FDA-approved for other autoimmune disorders may one day change that outlook for alopecia areata patients.
Roots of the Problem
Our hair follicles cycle between an active growth phase – anagen -- and a resting phase -- telogen. We normally lose 60 to 100 hairs every day, as hair is shed by follicles in telogen to make room for new growth (hair grows around a half inch each month). Excessive hair loss can be triggered by stress, pregnancy, illness, genetics (male pattern baldness, or androgenic alopecia) and autoimmunity.
In autoimmune alopecia areata, killer T-cells (cytotoxic T-lymphocytes), the shock troops of the immune system, target hair follicles. T-cell invasion doesn’t destroy the follicles and hair root, but the resulting inflammation causes the follicles to shrink, forcing them into a dormant state that dramatically slows production of hair.3 Because the follicles are still alive and hair roots are still supplied with stem cells, they have the potential to produce hair again. Indeed, in some people with alopecia areata, hair starts to grow again spontaneously.1
The trio of drugs being tested in clinical trials for alopecia block a family of enzymes called Janus kinases (JAKs) involved in inflammatory cell-signalling, the same pathway that triggers killer T-cells to attack hair follicles. Blocking JAK enzymes shuts off that signal, explains Angela M. Christiano, PhD, a professor in the Departments of Dermatology, Genetics and Development at Columbia University in New York. Dr. Christiano has a personal motivation for her research; she lost her own hair to alopecia areata in 1995 (it has since grown back).
JAK inhibitors not only appear to prevent T-cells from attacking the hair follicle but also seem to act locally, awakening dormant follicles, adds Dr. Christiano. In lab experiments with mouse and human hair follicles, her team found that JAK inhibitors could promote rapid, robust hair growth.4
In 2015, the Columbia researchers reported that the JAK inhibitor ruxolitinib restored almost complete hair growth in three individuals with longstanding and severe disease.5
“The hair follicle is one of a handful of body sites normally protected from the immune system. We call this ‘immune privilege,’” Dr. Christiano explains. T-cells violate the immune privilege of hair follicles in anagen, leading to loss of the growing hair shaft.6 “To treat it we not only need to control the immune response but also restore the immune privileged state of the hair follicle,” she adds. So far, researchers haven’t found a way to do that.
Judging the JAKs
The three JAK inhibitors being tested in alopecia areata are already in use for other disorders.
Tofacitinib (Xeljanz) is approved for rheumatoid arthritis. Ustekinumab (Stelara) is used to treat psoriatic arthritis. A third JAK inhibitor, oral ruxolitinib (Jakafi) is used to treat the bone marrow disorder myelofibrosis. Their FDA-approved status means much is known about the drugs’ safety. However, their effectiveness in alopecia areata has only been tested in small numbers of patients.
A preliminary study of three patients given ustekinumab injected under the skin (subcutaneously) was conducted at Mount Sinai Hospital in New York. Just-published results show that after 20 weeks, hair growth ranged from 25% to 85% in those patients.7 The patient with total hair loss (alopecia universalis) had the greatest amount or hair regrowth -- over 90%. The researchers also reported a decrease in inflammatory markers, and normalization of hair keratin and immune-related genes seen in scalp biopsies after 20 weeks of treatment.7 A larger study is now underway.
Another newly-published study, from researchers at Yale University, reported successful hair regrowth in a patient using topical ruxolitinib.8 A follow-up study with multiple patients is being planned.
Massachusetts-based Concert Pharmaceuticals announced in May that a modified analogue of ruxolitinib, dubbed CTP543, will start Phase 1 clinical evaluation later this year, with efficacy studies expected in 2017.9 CTP543 targets two JAK enzymes: JAK-1 and JAK-2.
As with other drugs that dampen the immune system, oral or injected JAK inhibitors can increase the risk for infection. Topical formulations designed expressly for the scalp may pose less of a risk, but high concentrations will likely be needed to produce an effect, cautions Dr. Christiano.
Larger and longer clinical trials will be needed to establish JAK inhibitors safe and effective for reversing alopecia areata.
The Genetic Connection
Dr. Christiano and her colleagues have identified approximately 14 genes that predispose people to alopecia areata. Among them are genes involved in the activation of JAK enzymes and the resulting inflammation that drives alopecia areata. Those genes are also associated with rheumatoid arthritis, thyroid disease, and celiac disease.
In fact, people with alopecia areata are at higher risk for other autoimmune problems, such as thyroid disease or vitiligo, which produces patches of light or pigment-free skin.
Genetic connections also mean people with alopecia areata are more likely to have family members with autoimmune diseases. Laura was diagnosed with Hashimoto’s thyroiditis in 2013; her mother has rheumatoid arthritis.
“I am constantly worried about taking on another autoimmune disease. I worry about my children developing autoimmune disease as well,” says Laura. “One of my daughters was having gastrointestinal issues this year. Both her gastroenterologist and allergist suggested that with my history of autoimmunity that she was at risk for a GI autoimmune disease -- Crohns, Colitis, or Celiac. So far, she has tested negative, thank goodness.”
According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), loss of hair meant to protect the body can also make people vulnerable to infections and allergies. For example, your eyelashes and eyebrows are meant to keep foreign particles from getting in your eyes; hair in your nose is meant to trap dust and germs as well as foreign bodies.
Dr. Christiano is now experimenting with stem cells to promote hair growth, since these cells have the capacity to morph into any type of tissue. The idea is to inject stem cells enriched with growth factors into hair follicles. She’s formed a start-up, aptly named Rapunzel, to gather venture capital funding for the research.11
So far, Dr. Christiano and colleagues have been able to grow hair in tissue culture scaffolding in the lab.11 She hopes one day the strategy may not only help patients with alopecia areata -- but also people with hereditary hair loss.
1 Alopecia Areata Foundation, Alopecia Areata. https://www.naaf.org/alopecia-areata. Accessed July 28, 2016.
2 Liu LY, King BA, and Craiglow BG. Health-related quality of life (HRQoL) among patients with alopecia areata (AA): A systematic review. J Am Acad Dermatol. DOI: http://dx.doi.org/10.1016/j.jaad.2016.04.035. Published online July 16, 2016. 0190-9622. Accessed July 28.
3 Xing L, Dai Z, Jabbari A, et al., Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nature Medicine. 2014;20:1043-1049. doi:10.1038/nm.3645.
4 Harel S, Higgins CA, Cerise JE, et al., Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Science Advances. 23 Oct 2015:Vol.1, no. 9, e1500973. DOI: 10.1126/sciadv.1500973 http://advances.sciencemag.org/content/1/9/e1500973.
5 Mohammadi D, A Ray of Hope for Alopecia Areata Patients. The Pharmaceutical Journal, May 2016, Vol 296, No 7889, online | DOI:10.1211/PJ.2016.20201092. http://www.pharmaceutical-journal.com/news-and-analysis/features/finding-new-treatments-for-alopecia-areata-patients/20201092.article Accessed August 1, 2016.
6 Villasante Fricke AC, Miteva M. Epidemiology and burden of alopecia areata: a systematic review. Clinical, Cosmetic and Investigational Dermatology. 2015; 8: 397–403. https://dx.doi.org/10.2147/CCID.S53985. Accessed July 28, 2016.
7 Guttman-Yassky E, Ungar B, Noda S, et al., Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J Allergy Clin Immunol. 2016;137(1):301-304. DOI: http://dx.doi.org/10.1016/j.jaci.2015.11.001
8 Craiglow BG, Daniel Tavares D, King BA. Topical Ruxolitinib for the Treatment of Alopecia Universalis. JAMA Dermatol. 2016;152(4):490-491. doi:10.1001/jamadermatol.2015.4445.
9 Concert Pharmaceuticals Unveils CTP543 for Treatment of Alopecia Areata. Business Wire, May 4, 2016. http://www.businesswire.com/news/home/20160504006458/en/Concert-Pharmaceuticals-Unveils-CTP-543-Treatment-Alopecia-Areata. Accessed August 9, 2016
10 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Questions and Answers About Alopecia Areata. April 2015. http://www.niams.nih.gov/health_info/alopecia_areata/ Accessed July 28, 2016.
11 Keshavan M, There’s new hope for treating hair loss – in women, too. STAT News.August 12, 2016. https://www.statnews.com/2016/08/12/hair-loss-biotech-women/ Accessed August 16, 2016.
August 2, 2016
In my first blog post on connections between cervical cancer risk and systemic lupus erythematosus, I suggested that, since high-risk strains of sexually-transmitted human papillomavirus (HPV) cause most cases of cervical cancer, young women with SLE should ask their gynecologists about the advisability of getting the HPV vaccine.
Since there have been concerns about vaccines causing autoimmunity this raises a legitimate question: Could the HPV vaccines Gardasil, Gardasil 9, or Cervarix trigger another autoimmune disease?
A number of recent studies, including a large population study from Sweden published online July 31 in the Journal of Internal Medicine, provide some reassurance.
The study examined medical records for all 70,265 girls and women ages 10 to 30 in Sweden diagnosed with at least one of 49 autoimmune diseases between 2006 and 2010, 16% of whom had received at least one dose of HPV vaccine. The researchers found no increase in new-onset autoimmune disease in the six months after immunization.1 In fact, there was a slightly reduced risk among those who got the HPV vaccine, compared to those who were not vaccinated.1
Safe -- So Far
The scientific debate over vaccines and autoimmunity has been going on for years. Some experts contend that specific adjuvants, compounds added to vaccines to enhance immune responses, can induce autoimmune disease (notably SLE), in genetically vulnerable people.2
Studies looking at the effects of two novel adjuvants in HPV vaccines found a slight, but statistically insignificant risk of autoimmunity among women immunized in randomized clinical trials compared with controls.2
Since the first HPV vaccine, Gardasil, was licensed in 2006, the Centers for Disease Control and Prevention (CDC) has tracked adverse side effects, including autoimmune diseases such as Guillain-Barré syndrome (GBS)) and multiple sclerosis.3
GBS is a rare disorder in which immune cells damage the protective myelin sheathe around nerve cells (axons), causing muscle weakness and sometimes paralysis. GBS has been linked to viral infections (most recently to Zika virus) and, in sporadic cases, immunizations.4
Speculation is that certain proteins (peptides) in viruses and bacteria may be the same, or be similar in structure to myelin, so that antibodies the immune system produces to neutralize those threats could trigger an attack on myelin.4 As we pointed out in “The Autoimmune Connection,” such reactions could be a case of molecular mimicry and may lead to different autoimmune diseases.5
Damage in GBS is limited to peripheral axons, nerve cells outside the central nervous system in the brain and spinal cord (areas affected by MS). While most people fully recover from GBS, some do experience long-term nerve damage.4
The CDC’s Vaccine Safety Datalink has monitored adverse events after HPV immunization between August 2006 and February 2012. During that period, just over 1.4 million doses of Gardasil were administered to girls and women ages 9 to 26 years old. So far, the CDC has found no cases of GBS.3
Does HPV vaccine pose any risk?
A 2013 review of data from multiple studies by the World Health Organization’s Global Advisory Committee on Vaccine Safety concludes there has been “no increase in the risk of autoimmune diseases among girls who have received HPV vaccine compared to those who have not.” Even women who were vaccinated before they knew they were pregnant suffered no more adverse outcomes compared with those who were not vaccinated, the WHO reports.6
The largest of those studies, a register-based cohort study from Sweden and Finland, included almost 1 million girls ages 10 to 17 years, around a third of whom were vaccinated against HPV. No evidence was seen of any links between HPV vaccine and autoimmune, neurological, and venous thromboembolic events (clotting in a vein).7
An observational study in the U.S. involving almost 200,000 girls and young women who had received at least 1 dose of HPV vaccine also found no increased incidence of autoimmune diseases in the vaccinated group compared those who had not been immunized.8 The incidence of MS was not significantly higher in the vaccinated group, the study showed.
A third study cited by the WHO analyzed data from 11 clinical trials involving nearly 30,000 participants 10 years and older and also found no increased risk for autoimmune diseases with Cervarix compared with controls.9
Benefits vs. Risks
This is good news, since women with autoimmune disease are especially vulnerable to vaccine-preventable infections, says Lisen Arnheim Dahlström, PhD, of the Karolinska Institute in Stockholm, senior author of the HPV vaccine study published in July.1
Patients with rheumatoid arthritis, lupus, and other autoimmune diseases have at least 2-fold greater risk of infections compared to healthy individuals, Dahlström and her co-authors note. This may not only be due to autoimmunity but also to the immunosuppressive therapies needed to control disease activity.10
For example, there have been suggestions that therapies such as methotrexate and rituximab (Rituxan) may reduce or impair responses to common vaccines, including flu shots, while tumor necrosis factor alpha (TNF-α) drugs do not.11
Some research has found “mildly impaired” immune responses to vaccines among patients on long-term immunosuppressive therapy, but a 2008 German study concluded that “postvaccination antibody titers are usually sufficient to provide protection for the majority of immunized individuals.”8 The authors of that study contend that “the accumulated data on the safety and effectiveness of vaccines warrant immunization with the majority of vaccines for patients with chronic autoimmune or rheumatic diseases.”
The CDC stresses that studies of the HPV vaccines “have followed vaccinated individuals for ten years, and show that there is no evidence of weakened protection over time.”12
The CDC recommends HPV vaccination for 11 and 12 year-old girls, and girls and women ages 13 through 26, ideally before they become sexually active,13 a guideline supported by the American College of Rheumatology.
The WHO says it “remains reassured by the safety profile of the vaccine,” but stresses the importance of continued monitoring.
As for the risk-benefit profile, the WHO concludes “allegations of harm due to vaccination based on incomplete information may lead to unnecessary harm when effective vaccines are not used.”
Issues to discuss with your doctor for sure.
1 Grönlund O, Herweijer E, K. Sundström K, and Arnheim-Dahlström L. Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study. Journ Int Med. Early View Online, July 31, 2016. DOI: 10.1111/joim.12535
2 Orbach H, Agmon-Levin N, Zandman-Goddard G. Vaccines and autoimmune diseases of the adult. J Intern Med. 2012 Feb;271(2):193-203. doi: 10.1111/j.1365-2796.2011.02467.x.
3 Centers for Disease Control and Prevention (CDC): Frequently Asked Questions about HPV Vaccine Safety. http://www.cdc.gov/vaccinesafety/vaccines/hpv/hpv-safety-faqs.html#A6b
4 National Institute for Neurological Diseases and Stroke (NINDS). Guillain Barré Syndrome Fact Sheet. http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm
5 Baron-Faust R, Buyon JP. “The Autoimmune Connection, 2nd Edition,” 2016, McGraw-Hill, NY. Pp. 8, 26, 290, 395.
6 World Health Organization (WHO), Global Advisory Committee on Vaccine Safety, 11–12 December 2013, Geneva, Switzerland. WHO Weekly Epidemiological Record.> 2014;7(89):53–60. Online 14 February 2014. http://www.who.int/wer, retrieved August 1, 2016.
7 Arnheim-Dahlström L, et al. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013 9; 347.doi: http://dx.doi.org/10.1136/bmj.f5906
8 Chao C et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med. 2012 Feb;271(2):193-203. doi: 10.1111/j.1365-2796.2011.02467.x.
9 Descamps D, et al. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin. 2009;5(5):332-40. Epub 2009 May 20.
10 Glück T and Müller-Ladner U. Vaccination in Patients with Chronic Rheumatic or Autoimmune Diseases. Clin Infect Dis. 2008; 46(9): 1459-1465.doi: 10.1086/587063
11 Hua C, Barnetche T, Combe B, Morel J. Effect of Methotrexate, Anti–Tumor Necrosis Factor α, and Rituximab on the Immune Response to Influenza and Pneumococcal Vaccines in Patients With Rheumatoid Arthritis: A Systematic Review and MetaAnalysis. Arthritis Care & Research. 2014;66:1016–1026. doi: 10.1002/acr.22246.
12 CDC, HPV Vaccine Information for Young Women. http://www.cdc.gov/std/hpv/stdfact-hpv-vaccine-young-women.htm.
13 Kim DK, Bridges CB, Harriman KH, et al., CDC Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older — United States, 2016. Morbidity and Mortality Weekly Report (MMWR). February 5, 2016 / 65(4);88–90.
14 Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2015. doi:10.1002/acr.22783.ch02.
July 25, 2016
One of the most frequent questions I’m asked at autoimmune patient forums is about diet, anti-inflammatory foods, and autoimmunity.
There’s a lot of popular pseudo-science out there claiming that the right diet can “cure” autoimmune disease. Much of the “evidence” I’m asked about is anecdotal, largely based on reports of how patients were helped – or not – by eating -- or not eating -- certain foods (notably gluten). It’s difficult to argue with success stories and equally difficult to prove real cause and effect.
However, there’s plenty of solid scientific evidence to support the idea of an anti-inflammatory diet.
Much of what we know about the relationship between diet and inflammation comes from studies about the effects of the Mediterranean diet (and its components) in reducing inflammatory markers in cardiovascular disease (CVD)1 – a well-established risk in autoimmune diseases including rheumatoid arthritis (RA), lupus, and inflammatory bowel disease.
The Mediterranean diet encompasses many anti-inflammatory foods, notably omega-3 fatty acids found in olive and other oils, cold-water fatty fish (like salmon, mackerel, and sardines), nuts, and flax seeds. Olives and olive oil also contain compounds that act similarly to non-steroidal anti-inflammatory drugs (NSAIDs).2 Additionally, the diet includes lots of fresh fruits and vegetables rich in anti-inflammatory plant chemicals.
The diet has been shown to lower inflammatory markers in blood tied to both CVD and autoimmune diseases, including C-reactive protein (CRP), interleukins,and tumor-necrosis factor alpha (TNF-α).1 Studies also show that it helps reduce pain, joint swelling, and other symptoms of RA and other autoimmune diseases – and has beneficial effects on the immune system itself (such as moderating T-cell activity).3
It’s been suggested for years that our “Western” diet high in saturated fats and red meat may not only play a role in CVD but also in autoimmune diseases.4 Indeed, in one study, RA patients assigned to a Mediterranean diet showed a reduction in inflammatory activity and an increase in physical function compared to those assigned to a “Western” diet. 5
THE BIG FOUR INFLAMMATION FIGHTERS
•Fatty Fish & Omega 3's
Of all inflammation fighting foods in the Mediterranean diet, we know the most about fatty fish and fish oil, which contain the omega polyunsaturated fats (PUFAS) eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA).
As far back as 1991, researchers suggested that the omega-3 fats in fish may help reduce disease severity in lupus.6 More recently we’ve learned that omega 3’s may help protect against RA. A prospective study of more than 32,000 older Swedish women in 2013 found that eating one or more servings of fatty fish a week was associated with a 29% lower risk of developing RA and long-term intake of high-dose fish oil decreased the risk of RA by 52%).7
A recent British review reported that eating more fish high in omega-3s modestly reduced joint swelling, pain and morning stiffness in RA, leading to less use of NSAIDs.8 A randomized, controlled trial in people with early RA found that around 40% of those given high-dose fish oil to take with their conventional disease modifying anti-rheumatic drugs DMARDs)were in remission after a year.9
However, fairly high amounts of fish oil are needed to achieve an effect (about 3 grams of EPA and DHA in a concentrated fish oil supplement). Fish oil is also an anticoagulant and doesn’t agree with everyone.10 So consult your doctor before adding it to your diet.
Other types of omega-3 fats can be are found in olives, flax seeds, pumpkin seeds and walnuts.
•Olives & Olive Oil
Certain anti-inflammatory properties in olives and olive oil may be a big reason why the Mediterranean diet helps in autoimmune diseases.
Olives and virgin olive oil have been found to contain a polyphenol compound called oleocanthal, which blocks production of the pro-inflammatory enzymes and cyclooxygenase-2 (COX-1 and COX-2) much as NSAIDs do. In fact, research shows oleocanthal has properties similar to ibuprofen.11
The fruit of the olive tree, Olea europaea, also contains oleic acid, a monounsaturated fatty acid which also helps modulate the immune system.12
Olive oil, as well as nuts, sunflower and flax seeds, and avocados are also packed with vitamin E, which helps prevent cell damage in joints and may have anti-inflammatory properties as well.
•Fresh Fruits & Vegetables
The Mediterranean-style diet includes plenty of fresh fruits, vegetables, and beans rich in fiber plus inflammation-fighting plant chemicals (phytochemicals) and antioxidants such as vitamin A, beta carotene, vitamin E, zinc and selenium.
In particular, raspberries and cherries are packed with antioxidants called anthocyanins and vegetables containing flavonoids like onions and garlic are thought to regulate expression of key inflammatory enzymes.
I meet many autoimmune patients who swear by green tea, which is a good source of antioxidant polyphenols.
Its active ingredient, epigallocatechin-3-gallate (EGCG), has been shown to improve symptoms and reduce the pathology in some animal models of autoimmune diseases.
The effects of EGCG help suppress production of autoreactive T cells and also pro-inflammatory cytokines (such as interleukin-1).13 A recent study showed that EGCG improved rheumatoid arthritis in mice, while another showed effects in lab rats. But there’s an unfortunate lack of research in humans for this healthy beverage.
GLUTEN: GUILTY AS CHARGED?
There are a number of experts who claim that any anti-inflammatory diet must exclude gluten.
There’s no question that gluten, a naturally-occurring protein in wheat, barley and rye, causes celiac disease in genetically susceptible individuals. Gluten triggers an autoimmune inflammatory reaction that damages the small finger-like projections in the small intestine (villi) which absorb many nutrients.
The only treatment for celiac disease is eliminating gluten. It can stop the symptoms of chronic diarrhea, stomach pain, bloating, and gas and help repair damage to the villi. Intestinal healing can take three to six months in children and several years in adults, according to the National Institutes of Health.14
Some people are allergic to wheat or have non-celiac gluten sensitivity and experience severe GI symptoms. While neither problem damages the small intestine, for these people going gluten-free also makes sense.
What’s not so clear is gluten’s effects elsewhere in the body (like the brain) and whether going gluten-free helps other autoimmune diseases, prevents or even “cures” them.
“There is no evidence that a gluten free diet helps autoimmune diseases such as Hashimoto's thyroiditis. Celiac disease is the one autoimmune disease that is appropriate for the gluten-free diet,” Peter H.R. Green, MD, director of the Celiac Disease Center at Columbia University told me in an email. “It is as though celiac disease has given the gluten-free a medical legitimacy that other diet trends lack.”
As a result of what he terms a “media epidemic,” “almost a third of all American and UK consumers are trying to avoid gluten,” many of them unnecessarily, he writes in a new book, “Gluten Exposed,” (2016, William Morrow, NY).15
VEGETARIAN AND VEGAN DIETS
Any elimination diet can have adverse effects, Dr. Green adds, cutting out crucial nutrients such as fiber and essential vitamins and minerals.
The Arthritis Foundation, the Sjögren’s Syndrome Foundation, and other organizations, report that studies since the 1990s have found vegetarian diets to be beneficial for some autoimmune patients. However, you need to get plenty of plant protein from legumes and beans, among other things.
A vegan diet -- which excludes meat, fish, dairy or other animal products -- may also be helpful, possibly because of the types of polyunsaturated fatty acids included in the diet, say British arthritis researchers.10
However, if you go vegan make sure you get vital nutrients you need, especially calcium, vitamin B12, vitamin D, zinc, and selenium.
1 Giugliano D, Ceriello A, and Esposito K, The Effects of Diet on Inflammation. Journal of the American College of Cardiology. 2006;48(4):677–85. doi:10.1016/j.jacc.2006.03.052.
2 Rahmani AH, Abutti AS, and Ali SM. Therapeutics role of olive fruits/oil in the prevention of diseases via modulation of anti-oxidant, anti-tumour and genetic activity. Int J Clin Exp Med. 2014. 7(4 ):799-808. PMCID: PMC4057827. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057827/ Accessed July 20, 2016.
3 Shepshelovich D and Shoenfeld Y.Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity. Lupus. 2006. 15(3):183-190. doi: 10.1191/0961203306lu2274rr s
4 Manzel A, Muller DN, Hafler DA et al., Role of “Western Diet” in Inflammatory Autoimmune Diseases. Curr Allergy Asthma Rep. 2014;14:404. DOI 10.1007/s11882-013-0404-6.
5 Sköldstam L, Hagfors L, Johansson G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:208–214.
6 Walton AJ, Snaith ML, Locniskar M, et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis. 1991; 50:463–466.
7 Di Giuseppe D, Wallin A, Bottai M, et al., Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: a prospective cohort study of women. Ann Rheum Dis. 2014 Nov;73(11):1949-53. doi: 10.1136/annrheumdis-2013-203338.
8 Miles EA, Calder PC, Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2012 Jun;107 Suppl 2:S171-84. doi: 10.1017/S0007114512001560.
9 Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis. 2015. 74:89-95 doi:10.1136/annrheumdis-2013-204145.
10 Arthritis Research UK, Diet and Supplements. http://www.arthritisresearchuk.org/arthritis-information/complementary-and-alternative-medicines/complementary-therapies/diet-and-supplements.aspx#sthash.g3ajjiyB.dpuf Accessed July 19, 2016.
11 Lucas L, Russell A, Keast R. Molecular mechanisms of inflammation. Anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal. Curr Pharm Design. 2011;17(8):754–68. DOI: 10.2174/138161211795428911. http://www.ncbi.nlm.nih.gov/pubmed/21443487 Accessed July 19, 2016.
12 Sales-Campos H, Souza PR, Peghini BC, et al., An Overview of the Modulatory Effects of Oleic Acid in Health and Disease. Mini Reviews in Medicinal Chemistry. 2013;13(2):201-210. DOI: 10.2174/13895575113130220003.
13 Wu D, Wang J, Pae M, Meydani SN. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol Aspects Med. 2012 Feb;33(1):107-18. doi: 10.1016/j.mam.2011.10.001. Epub 2011 Oct 14. http://www.ncbi.nlm.nih.gov/pubmed/22020144. Accessed July 19, 2016.
14 Treatment for Celiac disease. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/celiac-disease/Pages/treatment.aspx Accessed July 19, 2016.
15 Green PR, Jones R. “Gluten Exposed: The Science Behind the Hype and How to Navigate A Healthy, Symptom-Free Life,” (2016, William Morrow, NY).
16 The Arthritis Foundation: Eat Right for Your Type of Arthritis. http://www.arthritis.org/living-with-arthritis/arthritis-diet/anti-inflammatory/eat-to-beat-inflammation.php Accessed July 19, 2016
July 11, 2016
OK. I admit it: I’m a major Venus Williams fan. Actually, I root for Venus and Serena.
Watching Venus power through moments of fatigue, both mental and physical, on the tennis court is always inspiring for me. Not just because of her consummate skill, elegant play, and powerful serve (not to mention her campaign on behalf of equal pay for women in tennis), but also because she’s living with an autoimmune disease that takes a toll on body and spirit.
When Venus revealed in 2011 that she had Sjögren’s syndrome, many people expected her to retire from tennis. The fatigue and joint pain that accompanies Sjögren’s and many other autoimmune diseases can be debilitating for anyone -- even for a star athlete.
“It’s been a journey, but it’s something that I had to do. And it’s made me stronger,” Venus remarked after defeating Yaroslava Shvedova in straight sets July 4th in the Wimbledon quarter-finals. “The most difficult part of the journey is just not being in control because when you’re an athlete, you’re used to being in control, being able to work for anything. Not being able to do that is a challenge,” she said during a post-match press conference.1
Primary Sjögren’s syndrome, the result of an autoimmune attack on moisture-producing tissues, is 10 times more common in women than in men, possibly affecting as many as 3.1 million Americans. That prevalence doubles in secondary Sjögren’s, coupled with other autoimmune and connective tissue diseases.2
An online survey of nearly 8,000 patients by the American Autoimmune Related Diseases Association (AARDA) in 2015 found that 98% experience fatigue that many describe as “profound,” preventing them from doing even the simplest of everyday tasks.3 At least 60% to 70% of women with Sjögren’s are beset by fatigue.4
On July 7, the Sjögren’s Syndrome Foundation (SSF) issued the first-ever U.S. clinical guidelines for managing the disease, including fatigue.2 In those guidelines, the SSF continues to recommend aerobic exercise for fatigue (details below).
A Difficult Diagnosis
Sjögren’s can be difficult to diagnose -- especially in cases like Venus Williams', when fatigue, painful swollen joints and shortness of breath are the most noticeable symptoms -- rather than the hallmark dry eyes.
Venus was initially told she had exercise-induced asthma. “I’d go to doctors, but I never got any answers, so there was nothing I could do but keep going,” she told the New York Times in 2011.5 “It was frustrating, always being in the dark and not having anything to help me but my own will.”
That’s an experience shared by millions of women with autoimmune diseases.
Data from AARDA show that among autoimmune diseases, Sjögren’s syndrome takes the longest time to diagnose – 6.5 years of multiple doctor visits. And almost 60% of Sjögren’s patients are told their disease was “imagined” or they were just being “overly concerned.”6
When a diagnosis finally comes, it’s a relief, patients often remark. At least you know what you’re up against and that you’re not crazy.
What Treatments Help?
Problem is, all FDA-approved treatments for Sjögren’s target dry eye, dry mouth and other signature “sicca” symptoms, but none are aimed at alleviating fatigue or joint pain.
A recent review from the division of rheumatology and immunology at Duke University notes that new drug development has focused on ways to modulate the immune system and dampen chronic inflammation. But “other mechanisms may be at play, such as neuroendocrine abnormalities, that affect some of the disease manifestations, such as fatigue,” and could be potential targets for therapy.7 At this stage, the Duke reviewers note “no disease-modifying drugs have been shown in randomized, placebo-controlled trials to be effective for the treatment of primary Sjögren’s syndrome.”7
While the anti-malarial hydroxychloroquine (Plaquenil) has been used to reduce fatigue and joint pain in primary Sjögren’s, a randomized controlled trial reported in 2014 that the oral drug “failed to “failed to significantly reduce symptoms of dryness, pain, and fatigue over placebo.”7
More recently, biological drugs -- the tumor necrosis factor (TNF) inhibitors infliximab (Remicade and etanercept (Enbrel) -- have been investigated for their efficacy and safety in patients with primary Sjögren’s syndrome. But neither was found to be effective for improving disease outcomes.8, 9
And the new clinical treatment guidelines from the SSF, published online in Arthritis Care & Research strongly recommend against the use of biologics for any aspect of Sjögren’s.2
However, the SSF says hydroxychloroquine, may be considered as an option for treating fatigue – a recommendation largely based on patient experience (in one study 1/3 of patients found it helpful).2 Even though the evidence for its use against fatigue is weak, the SSF notes that hydroxychloroquine is a safe medication.4
The guidelines do recommend hydroxychloroquine as the first-line treatment for musculoskeletal pain in Sjögren’s and, if that’s not effective, methotrexate may be added.
Short-term low-dose corticosteroids may also be tried if that approach isn’t helpful, with longer-term higher doses as an option.2
Other conventional disease modifying anti-rheumatic drugs (DMARDs), such as leflunomide (Arava) and sulfasalazine can be considered. (Venus is taking medications for her Sjögren’s.)
So what can you do about fatigue?
The SSF guidelines, drafted by a panel of experts with input from Sjögren’s patients, recommend daily exercise as an effective way to fight fatigue, citing a number of clinical trials (considered the gold standard of medical research) that found exercise an effective fatigue fighter.2
The SSF generally recommends women gradually work up to 25 minutes a day of aerobic exercise (and, no, you needn’t play tennis!).9
Other ways to fight fatigue from the SSF: pacing yourself and not taking on too much, giving yourself a 20-minute "time-out" every few hours, and getting enough sleep.9
Some women have found adopting an “anti-inflammatory” diet helps reduce joint pain and fatigue. Venus says she juices twice daily, and eats raw, unprocessed, vegan foods.
Another approach is to imitate the diet purportedly eaten by our prehistoric ancestors – meat, fish, vegetables and fruit, but no dairy, grain, or processed foods – often dubbed the “Paleo” diet. But there's no real evidence that it works. (We’ll talk about diet and anti-inflammatory foods in a future post.)
Other advice to combat fatigue from the SSF: pacing yourself and not taking on too much, giving yourself a 20-minute “time out” every few hours, and getting enough sleep.9
But sometimes the fatigue can be too much.
In “The Autoimmune Connection,” we quoted Sjögren’s patients who said that when fatigue hit “the body can stiffen up, become painful, and feel as if it had ‘run out of energy,’ ‘given up,’ or ‘had flat batteries,’ forcing them to put their life on hold.”10
Indeed, Venus briefly curtailed play after dropping out of the U.S. Open in 2011 because of fatigue and back pain. “The fatigue is hard to explain unless you have it,” Williams remarked at the time.5 “Some mornings I feel really sick, like when you don’t get a lot of sleep or you have a flu or cold. I always have some level of tiredness. And the more I tried to push through it, the tougher it got,” she told the New York Times.
But her passion for the game and her determination to win ultimately propelled Venus back into the game. Both qualities were on ample display at Wimbledon, both in her victory over Shvedova as well as in her defeat by Angelique Kerber in the semis July 8.
The very next day, she and sister Serena went on to win their 14th Grand Slam doubles match -- just a couple of hours after Serena captured her 22nd Grand Slam singles title against Kerber.
“It’s easy to be afraid. You have to let fear go,” Venus told the press at Wimbledon earlier in the tournament. “You’ve got to believe in yourself. No matter how things are stacked against you, you just have to every time.”1
Venus Williams defeated on the court? Occasionally. Defeated in life. Never.
That’s a lesson we can all learn -- even if we’re not tennis champs.
1 Venus Williams: Quarter Final. The Championships, Wimbledon 2016. Wednesday, 6 July 2016. http://www.wimbledon.com/en_GB/news/articles/2016-07-06-/venus_williams_quarterfinal.html
2 Carsons SE, Vivino, FB, Parke A, et al., Treatment Guidelines for Rheumatologic Manifestations of Sjögren’s : Use of Biologics, Management of Fatigue and Inflammatory Musculoskeletal Pain. Arthritis Care and Research. 2016; Jul 7. doi: 10.1002/acr.22974. [Epub ahead of print]. http://onlinelibrary.wiley.com/doi/10.1002/acr.22968/abstract. Accessed July 8, 2016.
3 American Autoimmune Related Diseases Association, Autoimmune Patient Survey on Fatigue, Released March 23, 2015. http://www.aarda.org/wp-content/uploads/2015/03/EMBARGOED+PressReleaseFatigueSurvey.pdf
4 Mengshoel AM, Norheim KB, Omdal R. Primary Sjögren’s syndrome: fatigue is an ever present,
fluctuating, and uncontrollable lack of energy. Arthritis Care & Research. 2014;66(8):1227–1232. doi:10.1002/acr.22263.
5 Crouse, K. Williams Says She Struggled With Fatigue for Years. New York Times, September 1, 2011.
6 American Autoimmune Related Diseases Association/National Coalition of Autoimmune Patients Survey Data, 2014.
7 Holdgate N and St. Clair WE. Recent advances in primary Sjögren’s syndrome. Version 1. F1000Res. 2016; 5: F1000 Faculty Rev-1412. Published online 2016 Jun 17. doi: 10.12688/f1000research.8352.1 PMCID: PMC4916986. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916986/ Accessed July 4, 2016.
8 Gottenberg JE, Ravaud P, Puéchal X, et al. , Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA. 2014;312(3):249–58. 10.1001/jama.2014.7682.
9 “Fatigue Fighters in Sjögren’s,” January 16, 2014. The Sjögren’s Syndrome Foundation, http://info.sjogrens.org/conquering-sjogrens/bid/331597/Fatigue-Fighters-in-Sj-gren-s
10 Baron-Faust R, Buyon JP. “The Autoimmune Connection, 2nd Edition,” 2016, McGraw-Hill, NY. Page 177.
July 5, 2016
Why “Autoimmune ConnectionS” plural?
Ongoing research is revealing new connections in autoimmunity, bolstering the more speculative links, and disproving others.
For example: a connection between lupus and an increased risk of cervical cancer has been suggested for years – it has now been confirmed. This is an important issue if you have SLE and possibly other autoimmune diseases.
The confirmation came at the recent European League Against Rheumatism (EULAR) annual meeting in London. A new study from Sweden found a doubled rate of cervical dysplasia or neoplasms – premalignant abnormal cell growth – among women with SLE in general and a greater risk among women treated with immunosuppressant drugs.
“We know that the therapies we use to treat lupus, particularly complicated lupus, are therapies that compromise normal immune function. They are also therapies we use in the organ transplant setting, where we know there are a number of malignancies that occur more often than expected, in particular premalignancies and frank malignancies of the female cervix,” explained study co-author Johan Askling, MD, PhD, a professor and senior physician at the Karolinska Institute in Stockholm at a EULAR press briefing.
“Is this driven by premalignant cell changes or frank malignancies or was the risk driven by the disease or the other things, such as the therapies we use? The aim of our study was to settle the controversy,” he commented.
Dr. Askling and colleagues examined medical data for 4,550 SLE patients in Sweden’s National Patient Register, separating them into two groups: 1,981 treated with immunosuppressants, such as azathioprine (Imuran), and 1,783 treated with anti-malarials, like hydrochloroquine. Then they compared the SLE patients to 28,113 age-matched women in the general population.
When the researchers looked at cervical cancer screening records between 2006 and 2012 from the Cervical Screening Registry and the Swedish Cancer Registry, they found the rate of cervical dysplasia or invasive cancer among women with SLE was 2.12 greater than for women in the general population.
Among lupus patients given antimalarials, the rate was 1.52 but it was 2.72 for patients on immunosuppressants (with or without antimalarials). The risk held up even when factoring in age and earlier cervical screening in the previous five years.
The study, published in abstract form in the June Annals of the Rheumatic Diseases, concludes that “SLE patients treated with immunosuppressants are at risk of cervical neoplasia and should be adequately monitored, regardless of whether the risk increase is due to disease severity or treatment.”1
The SLE-Cervical Cancer Connection
An elevated rate of cervical dysplasia among lupus patients has been reported for a number of years2,3 and associated with exposure to immunosuppressive drugs, including azathioprine.
“An altered clearance of cancer related viral agents in SLE (due to the disease and/or immunosuppression) may contribute to this risk and may also drive the risk for other cancers (such as vulvovaginal and hepatic carcinomas) in SLE,” the authors of a 2012 Canadian study note. 4 Immunosuppressive drugs may also be associated with increased susceptibility to human papilloma virus (HPV), which causes most cervical cancers and has been detected more frequently in women with SLE.4
The current Swedish analysis is significant because it’s large – almost 33,000 people – and analyzes results of cervical screening among women with and without SLE as well as SLE patients on anti-malarials or immunosuppressants, comparing then with women in the general population. So this analysis is able to quantify the risk.
However, we should stress that the Swedish data come from an abstract reported at a scientific meeting, are not final, and haven’t yet been peer-reviewed. Plus, population studies such as this can’t prove cause-and-effect -- just an “association” with increased risk.
Dr. Askling, who has been studying cardiovascular disease and cancer risk in rheumatoid arthritis and other autoimmune diseases, also notes that both RA and CVD are, in part, driven by inflammation. Studies of cancer in autoimmune diseases also show that higher disease activity may also increase risk.
Should SLE Patients be Alarmed?
Fortunately, screening tests using new liquid based cell analysis cytology) which can detect DNA from HPV are very sensitive. And, if cervical dysplasia or intraepithelial neoplasia (CIN) are found the condition can be treated with freezing or electrocauterization before it can progress to cancer.
Considering the potentially increased risk for women with SLE, is more frequent cervical screening needed? That’s something to ask your gynecologist.
Depending on a woman’s health history, 2016 guidelines from the American College of Obstetricians and Gynecologists (ACOG), the American Cancer Society (ACS), and other groups advise cervical cytology screening every three years for sexually active women ages 21–29 at average risk;5 the ACS recommends both cervical screening and HPV testing.6 Women ages 30–65 years are urged to have both tests every 5 years with high-risk HPV strains. Since cervical cancer is less common in older women, after age 65 screening can be stopped if consecutive Pap and HPV tests have been negative.6
Women with SLE are screened at about the same rate as women in the general population (around 89% ), Dr. Askling told interviewers at the EULAR meeting.7 “And we should keep encouraging women with lupus to be screened because it has “demonstrated true value. And here’s a group with an increased risk potentially more driven by the earlier stages of cervical cancer than by invasive cancer.”7
Also important: the Lupus Foundation notes that women with SLE also seem to be more vulnerable to the effects of certain cancer-linked viruses than the general population.8 A case in point: human papilloma virus. So younger lupus patients may also want to ask their doctors about the HPV vaccine.
New liquid-based cytology tests can detect DNA of HPV in cervical cells even before dysplasia or CIN occur. That’s another reason to be regularly screened. As we advised in “The Autoimmune Connection,” find a gynecologist familiar with ADs to help guide you in deciding how frequently to be screened.
Since immunosuppressant drugs like azathioprine appear to play a role in this increased risk, you may also want to discuss alternative treatments with your rheumatologist. Ultimately, the choice depends on the medication that best controls your SLE.
1 H. Wadström, E.V. Arkema, C. Sjöwall , J. Askling , et al., Rate of Cervical Neoplasia in Systemic Lupus Erythematosus: A Nationwide Cohort Study. EULAR Abstract: OP0189. Annals of the Rheumatic Diseases. June 2016. DOI: 10.1136/annrheumdis-2016-eular.2142.
2 Tessier-Cloutier B , Clarke AE , Ramsey-Goldman R, et al., Systemic lupus erythematosus and malignancies: a review article. Rheum Dis Clin North Am. 2014 Aug;40(3):497506, viii. doi: 10.1016/j.rdc.2014.04.005. Epub 2014 Jun 3.
3 Gayed M , Bernatsky S, Ramsey-Goldman R, Clarke A, Gordon C. Lupus and cancer. Lupus. 2009 May;18(6):47985. doi: 10.1177/0961203309102556.
4 Bernatsky S , Kale M, Ramsey-Goldman R, Gordon C, Clarke AE. Systemic lupus and malignancies. Curr Opin Rheumatol. 2012 Mar;24(2):17781. doi: 10.1097/BOR.0b013e32834ff258.
5 ACOG Practice Bulletin No. 157 Summary: Cervical Cancer Screening and Prevention. Obstetrics & Gynecology, January 2016; 127(1):185-187. doi: 10.1097/AOG.0000000000001256.
6 Sawaya GF, MD; Kulasingam S, Denberg TD, et. al., Cervical Cancer Screening in Average-Risk Women: Best Practice, Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;162:851-859. doi:10.7326/M14-2426.
7 Johan Askling profile page, Karolinska Intitutet. http://ki.se/en/people/johask. Accessed July 1, 2016
8 The Lupus Foundation, Cancer and Lupus, 15 Questions. www.lupus.org/resources/15-questions-with-Sasha-Bernatsky-cancer-and lupus/ Accessed July 1, 2016.