Rheumatoid Arthritis Part 2: The Immunology of RA (Kremer, 8/26/2020)

This week, Dr. Lisa Kremer, a local Sutter Medical Group of the Redwood's Rheumatologist, gave Part 2 of her Grand Rounds presentation on Rheumatoid Arthritis (Part 1 from 2/26/2020 is available on this blog here)-- this one on the Immunology of Rheumatoid Arthritis (RA).

Dr. Kremer reminded us that RA is a symmetrical, poly-articular inflammatory process of small and medium joints on more than one occasion over more than six weeks (with supporting lab and/or x-ray findings and the absence of an alternative diagnosis).

• Of note, RA does NOT involve the low back or SI joints (can sometimes include the hips, shoulders and upper cervical spine)

RA has 3 phases (see image below):

• Pre-clinical
• Early "clinically evident: disease
• Chronic established disease

Source: https://www.sciencedirect.com/science/article/pii/S1074761317300419

RA has its roots in an environment of autoimmunity

• lung exposure: e.g. tobacco, silica, and textile dust (risk is increased with greater pack year, declines at 10 years after quitting tobacco
• increased citrillination of peptides
• oral mucosa: chronic gingivitis (inflammation)
• GI tract: microbiome, including inflammatory diets

RA is environment PLUS genetics

• production of antibodies recognizing citrillinated peptides that differentiates individuals at risk for developing RA
• monozygotic twins share RA 12-15% of the time
• fraternal twins and other 1st degree relatives share RA dx 2-5% of the time
• 40% of genetic influence is in MHC class IIa-DR4 alleles
• more than 90% of patients with RA express "susceptibility isotopes" on the DRB chain that are associated with increased disease severity

As RA moves from a pre-clinical to early RA, multiple autoimmune conditions are precipitated:

• macrophages in the synovium are activated
• cytokines are released, activating T cells and creating a positive feedback loop that leads to more cytokine and chemokine release
• T cells release inflammatory cytokines (TNFa, IL1, IL6)
• Fibroblast-like synoviocytes (FLS) and macrophages make up the thickened synovium of early RA
• FLS drive erosive bone damage

Our current therapeutics have been created in direct response to this immunology. Treatments for RA are named for their immune targets. Note that methotrexate is still mainstay treatment for RA and steroids should only ever be given for short-term management.

• Antimetabolites: Methotrexate, Leflunomide
• TNF: Adalimumab, Etanercept, Infliximab
• IL-6: Tociluzimab
• Co-stimulation (CD28-CD80/86): Abatacept
• B cell depletion (anti-CD20): Rituximab
• JAK inhibitors: Tofacitinib, Baricitinib
• IL-1: Anakinra

Untreated, RA shortens life by 5-10 years. Aggressive RA therapy decreased mortality due to CV disease, lung, alanto-axial subluxation, and drug toxicity (e.g. steroids, NSAIDs). Treatment reduces the need for joint replacements by 50%

Lifestyle matters!

• diet, exercise weight management
• tobacco cessation and limited alcohol
• stress management

COVID-19 in Pregnancy (Mason, 8/18/2020)

Many thanks to Dr. Antoinette Mason for her excellent review of the emerging literature on COVID-19 in Pregnancy. As Dr. Mason explained at the start of her presentation, much of the information regarding COVID in pregnancy is based on observational data with recommendations that are expert opinion at best. But as we continue to increase our understanding of this disease, we are gaining a better understanding of its impact on pregnant women and infants. I consider Dr. Mason one of our local experts-- herself having cared for several of our first OB patients with COVID locally this past month. With that, I will do my best to summarize Dr. Mason's key learning points.

Epidemiology

• In the US to date, there have been 16,798 documented cases of COVID-19 in pregnancy, 4,262 hospitalizations, and 37 deaths
• As is true across our country, OB patients of color are disproportionately affected by COVID (Reference: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/special-populations/pregnancy-data-on-covid-19.html)
• Here at SSRRH, we have had 9 total OB patients with COVID ( some only triaged, others admitted). In these patients:
• Gestational age ranged from 22-39 weeks
• 5 have delivered (2 returned later with PROM)
• 2 were picked up by admission screening (asymptomatic)

Is pregnancy a risk factor for COVID-19? Answer: We don't really know. 

The incidence of COVID-19 in pregnancy is similar to that of the general population. Several studies suggest that pregnancy and childbirth do not increase the risk of acquiring COVID-19. There is mixed data on whether or not pregnancy worsens the course of the disease. An MMWR from the CDC June 2020 showed the following: pregnant women were 5.4 times more likely to be hospitalized, 1.5 times more likely to be admitted to the ICU, 1.7 times more likely to receive mechanical ventilation, but no increased risk of death. (Reference: https://www.cdc.gov/mmwr/volumes/69/wr/mm6925a1.htm). Some of these stats are likely impacted by providers being more likely to admit and act more conservatively with sick pregnant women, but it is hard to see that in this data.

What is the clinical presentation of COVID-19 in pregnancy? Answer: The same as the general population

1/3-1/2 of OB patients with COVID-19 are asymptomatic

How to assess severity of disease in pregnant women? Answer: Oxygen saturation, consideration of comorbidities and close follow-up are key

• Oxygen saturation should be >95% on RA for pregnant women. This is a different standard than for non pregnant COVID patients (>92%). Also consider tachypnea (RR>30bpm).  
• Outpatient management is appropriate for pregnant women with COVID-19 with mild symptoms, but women should be monitored  (at least once within 1-2 weeks of diagnosis)
• should have home pulse oximeter if possible
• should have easy access to care if needed
• antenatal testing should be done as per standard recommendations
• Inpatient management: pregnant patients with moderate or severe disease (O2 sat <95% on room air, refractory T>39 despite antipyretics) and/or significant comorbidity (e.g. DM, CKD, immunosuppresion) should be managed in the hospital
• See diagrams below from ACOG and SMFM. Top diagram is indications for testing, bottom diagram is for triage in known COVID disease.

What are the maternal and fetal outcomes in COVID-19?    Answer: we don't really know.

From case reports, observational studies, and some reviews, there is concern that COVID may be associated with an increase in preterm birth, PPROM, cesarean delivery, and stillbirths. We do know that severe viral illnesses (e.g. influenza) have been associated with these outcomes.

One systematic review found aere possible increase in preterm delivery, including spontaneously and medically indicated preterm birth and c-section in pregnant women with confirmed COVID-19 infections. (Reference: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30190-5/fulltext). A UK study looking at outcomes pre and post pandemic preterm found a higher rates of still births-- the authors speculated that outcomes had more to do with access to care and comorbidities directly related to the virus rather than the virus itself.

Is there vertical transmission of COVID-19? Answer: Probably not.

While there is a theoretical risk of vertical transmission, most studies with significant number of cases have demonstrated no evidence of vertical transmission: looking at placenta, cord blood, amniotic fluid, and NP samples. There are a couple of case reports that call question to this, but the data is very limited. In addition, we have little to no data on the effect of COVID-19 infection on the first and second trimesters of pregnancy.

What is appropriate management of COVID-19 pregnant patients? Answer: Treatment for COVID-19 in pregnant women mirrors treatment of COVID-19 in non-pregnant women with slight modifications

• Remdesivir is considered safe in pregnancy (no known fetal toxicity, recommended by SMFM when indicated)
• Convalescent plasma is considered safe (currently under investigation for benefit)
• Steroids if indicated (NIH recommends for "patients needing oxygen")
• SMFM says maternal mortality benefit likely outweighs risk to fetus.
• Can do dexamethasone 10mg IV/PO as per the RECOVERY trial OR
• Some expert opinion recommending methylprednisolone  (see paper for details)(Reference: https://journals.lww.com/greenjournal/Abstract/9000/Corticosteroids_in_the_Management_of_Pregnant.97288.aspx)
• COVID-19 infection is NOT an indication for delivery;  mechanical ventilation is NOT an indication for delivery
• For severe disease, risks/benefits should be weighed
• Caution with magnesium sulfate because can increase risks of respiratory compromise (weigh risks/benefits depending on comorbidities)
• Most standard obstetrical management is safe: internal monitors, amniotomy, forceps/vacuum
• Might consider early epidural if symptomatic patient to mitigate risks of gen anesthesia for emergent c-section
• Nitrous oxide: not recommended for PUI/COVID+ patients (because of risk of aerosolization) but nitrous is okay to use in women who test COVID negative.

Does COVID-19 in combination with pregnancy increase risk of VTE? Answer: Yes, probably.

While there are only a few case reports of VTE in COVID in pregnancy, both COVID and pregnancy are hypercoagulable states and separately increase risk of VTE. Thus current recommendations for VTE prophylaxis: 

• All pregnant women admitted with COVID-19 should receive enoxaparin unless delivery is anticipated in <12 hours. 
• Also all hospitalized pregnant women should be 10 days of VTE prophylaxis after hospital discharge.

How should COVID-19 couplets be managed postpartum? 

• Moms with COVID-19 are prone to hypervolemia (keep strict Ins/Outs, watch respiratory status)
• Infants of COVID moms should be bathed after birth
• Breastfeeding should be encouraged!! 
• Separation of mother and infant is NOT recommended (likelihood of testing positive is the same if separated or kept together, if precautions maintained)
• infant should be tested once at 24 hours of life (no retest indicated)
• mom should use mask/hand hygiene
• baby should be in isolette when not breastfeeding

What about mental health in COVID in pregnancy? Answer: Ah, so much to say. . .

• Social isolation is associated with increased risk of depression and anxiety. Screen and ask!
• PTSD  has been recognized for those who are isolated/quarantined--> be sure to check in with new moms about the impact this may have on their postpartum period