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Diseases and Conditions

Diseases and Conditions

How much alcohol is safe with methotrexate?

April 26, 2017
Is it safe to drink while taking methotrexate?

Can I drink alcohol when I take methotrexate?  This is one of the most often asked questions I’m asked in clinic when starting methotrexate.  I also suspect it is one of the reasons people sometime decline treatment with methotrexate.  This is a shame, because methotrexate the cornerstone medication for rheumatoid arthritis.

You would think the answer to this question is obvious.  Alcohol can cause liver failure and cirrhosis.  Methotrexate can also cause liver inflammation and fibrosis/cirrhosis.  So combining the two doesn’t sound like such a hot idea.  It turns out the answer to the question isn’t so black and white.

Yes, alcohol can cause liver failure, however, not everyone who drinks alcohol gets cirrhosis.  It tends to happen when someone drinks excessively for years.  The same goes for methotrexate.  Not everyone who takes methotrexate gets liver inflammation.

The real question is, how MUCH alcohol is safe to take with methotrexate?  Shockingly there was little if any data addressing this question until recently.  How much alcohol is too much?  How much alcohol is likely safe?

Science to the rescue!  A recent study from the UK specifically addressed this question¹.  But before I get into that, let’s quickly review what a standard unit of alcohol actually is.  “I drink alcohol socially” simply isn’t going to cut it.  “Social” is highly variable!


What is a standard unit of alcohol?

This depends on the country you’re talking about.  Every country defines a unit of alcohol differently.  Since I’m writing based from the US, I define a unit of alcohol as follows:

“NIH standard drink comparison” by the National Institutes of Health is in the public domain in the United States.  This file has been identified as being free of known restrictions under copyright law, including all related and neighboring rights.

Moreover, each country has their own definition for the maximum amount of alcohol per week.  Some countries are more permissive than others.  In the US, defines low risk drinking for women as no more than 3 drinks on a single day and no more than 7 drinks per week.  Men can drink no more than 4 drinks on a single day and no more than 14 drinks per week².

Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate

Researchers in the UK recently looked into this matter.  As I alluded to, our current guidelines actually offer no specific guidance about alcohol and methotrexate.  In the UK, “patients taking methotrexate should limit their alcohol intake to well within the UK national recommendations”… whatever that means.  The American College of Rheumatology offers similar non-specific guidance.  When I was training, some mentors would have a strict “no alcohol” policy and some would say, a glass of wine or two per week should be okay.

The aim of the recent study was to quantify the risk of alcohol consumption on hepatotoxicity (liver damage) in a contemporary group of methotrexate users with rheumatoid arthritis, in a large national primary care database.

Methods

The researchers recruited people from the Clinical Practice Research Datalink (CPRD) which is a large database of information gathered by primary care providers.  They looked at all patients identified as having rheumatoid arthritis and starting methotrexate after 1987 up until Feb 2016.  People were included if their liver enzymes were measured at least six times per year.

The researchers want to measure any episode of liver inflammation (transaminitis) defined as a level that was three times the upper limit of normal.  This was called the primary definition of transaminitis.  Since we know that persistently elevated liver inflammation can lead to liver fibrosis, the researchers were also interested in identifying people that that have three back-to-back levels that were above the upper limit of normal.  This was called the secondary definition of transaminitis.

Alcohol consumption was measured first by seeing whether the person drinks alcohol, yes or no.  Then the person’s alcohol consumption was categorized:

  1. Mild: 1-7 units per week
  2. Moderate: 8-14 units per week
  3. Moderate-high: 15-21 units per week
  4. High: > 21 units per week

Results

The researchers identified 44 586 people but only included 11 839 people in the study.  The people that were excluded typically were a little younger, were female, and tended to drink no alcohol or very little alcohol.

Using the primary definition of transaminitis, there were 530 first episodes in 47 090 person-years.  That’s about 11.26 per 1000 person-years.  This rate was similar between drinkers of alcohol and non-drinkers of alcohol.  There was no increased risk in the occurrence of transaminitis in drinkers compared with non-drinkers.  But this is pulling all the data together.  What about people who drank mildly vs moderately vs high?

After analyzing the data ever further, the researchers found, unsurprising, that the rate of transaminitis increased with increasing levels of alcohol consumption.  Drinking mild to moderate amounts of alcohol was not associated with transaminitis.  Drinking more than 21 units of alcohol per week tended to be associated with transaminitis.

Alcohol consumption below 14 units per week was associated with a very low probability (0.93%) of having clinically important risk of transaminitis.  Alcohol consumption in excess of 14 units per week was associated with increasing risk of transaminitis.  More specifically, the risk was 33% with moderate-high consumption (15 – 21 units weekly) and 81% with high (>21 units weekly) consumption.

When the researchers used the secondary definition of transaminitis, i.e., 3 or more consecutive episodes of increased liver enzymes above the upper limit of normal, they found similar data: Mild = 0.01%, moderate-high = 8%, and high 17%.

Limitations

No study is perfect.

First, the data came from a primary care database.  This means, it was the PCP or rather the general practitioner that was responsible for coding the diagnosis appropriately, not a rheumatologist.  That being said, some misclassification may have occurred inadvertently.

Another issue was that the amount of amount of alcohol consumption was self-reported.  Most people tend to under report their alcohol consumption, so we can kind of assume that the levels of alcohol reported by the people in the study were actually a lot more than stated.

Another limitation included the fact that many people were excluded because their liver enzymes were measured less than 6 times per year.  Things get a little muddled up here.  People that have their blood tested less often statistically have a decreased chance of having an abnormal test simply because they get tested less.  Then again, having your blood tested 6 times a year is a bit much, unless that person has risk factors that put them at increased risk of developing liver problems.

An important limitation is the fact that the dose of methotrexate was not included.  There could be an increased risk of hepatotoxicity if someone were to take 25 mg of methotrexate weekly versus someone who takes 10 mg.

It’s also unclear whether these results are generalizable to other autoimmune diseases.  Methotrexate is also used to treat psoriasis and psoriatic arthritis.  The study only included people with rheumatoid arthritis.  People with rheumatoid arthritis and psoriasis are not the same.  People with psoriasis tend to have more liver problems in general.  For example, they tend to develop fatty liver.  So the risk of hepatotoxicity with alcohol could be different.

Lastly, some people say that measuring liver function tests (AST and ALT) may be insufficient to actually assess long-term damage from methotrexate because some people develop liver fibrosis without having transaminitis.  The problem with the studies that look at methotrexate and liver fibrosis are for the most part, dated and most looked at people with psoriasis.  As I mentioned, people with psoriasis tend to have more liver problems than people with rheumatoid arthritis.  It’s also important to note that since the 80’s, we’ve changed the way we prescribe methotrexate as well as changed the way we check labs.  Measuring liver function tests, NOT performing serial liver biopsies to monitor methotrexate toxicity, remains current best practice.

On a side note, liver function tests is kind of misnomer because the AST and ALT actually don’t measure liver function.  They measure liver inflammation.

Conclusion

According to this study modest amounts of alcohol consumption when taking methotrexate may not be as harmful as once though.  I would like to remind you that the information provided today does not constitute medical advice.  Please talk to your doctor.  Everyone’s health is unique.  Please leave comments below!

References

  1. Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis.2017 Mar 23. pii: annrheumdis-2016-210629. doi: 10.1136/annrheumdis-2016-210629. [Epub ahead of print]
  2. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics
Diseases and Conditions

Will I get osteonecrosis of the jaw if I take medications for osteoporosis?

April 12, 2017

Foreword

As a rheumatologist, I regularly depend on the expertise and advice of pharmacists.  Medicine has gotten unbelievably complex.  I truly believe that using a team-based approach is the best way of providing quality-care.  In the clinic, I’m often asked questions about osteoporosis medications.  Bisphosphonates are a class of medications that are commonly used to treat osteoporosis and they’ve come under a lot of scrutiny lately. One of the potential side effects is osteonecrosis of the jaw.  For this week’s edition of RheumDoctor, one of our pharmacy students, Amy DeGennaro, teaches us: what is osteoporosis, what are bisphosphonates, and what is the real risk of osteonecrosis of the jaw.


Believe it or not, our bones are alive. Bones, in our bodies, are constantly renewing just like how our skin is constantly turning over. Our body’s ability to constantly build and breakdown bone is what allows us to grow and heal. This normal bone process over time results in our bones to get slightly thicker, however, we reach peak bone density in early adulthood.  As we age we gradually start to lose bone though.  Reduced bone mass puts us at risk for fractures which can be prevented by treatment.  One of our best treatments (a group of drugs called bisphosphonates) slows the breakdown of bone and reduces the risk of a fracture, which is exactly what we want when treating osteoporosis.

What is Osteoporosis?

Osteoporosis is a disease in which bone density and quality are reduced, which means our bones become more porous and fragile, increasing the risk of fractures greatly. However, this bone loss occurs silently. Often there are no symptoms you would experience until your first fracture. It’s estimated that 200 million people worldwide suffer from osteoporosis. In the United States and in Europe, about 30% of all postmenopausal women have osteoporosis, and even worse at least 40% of these women will sustain one or more fragility fractures in their remaining lifetime.

But it is important not to forget that men suffer as well from osteoporosis.1

What is Osteonecrosis of the Jaw?

Exposed bone, in our mouths, that has persisted for more than 8 weeks. If a section of bone is fractured and does not heal it can cause blood flow to the bone to be interrupted causing bone death.

What Type of Treatment for Osteoporosis is related to Osteonecrosis of the Jaw?

Bisphosphonates: alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), zoledronic acid (Reclast)

Bisphosphonates work very well at inhibiting the breakdown of bone which results in an increase in the density of bone. Bisphosphonates have FDA approved indications for the treatment and prevention of post-menopausal osteoporosis, osteoporosis in men, and glucocorticoid (steroid) induced-osteoporosis. All bisphosphonates on the market have demonstrated reductions in vertebrae fractures and the majority of bisphosphonates show additional reduction in non-vertebral and hip fractures as well.

Such strong inhibition of bone breakdown may theoretically lead to an accumulation of microdamage to the bone which might compromise bone strength or delay fracture healing. However, we have seen, from studying the bones of women on long-term bisphosphonates that there is no increased microdamage, and clinical trials of bisphosphonates did not show evidence of altered healing.2

What are Risk Factors for Osteonecrosis of the Jaw for Patients?

  • Drug-related risk factors
    • Bisphosphonate potency (oral therapies less potent than intravenous)
    • Duration of bisphosphonate treatment
  • Individual risk factors
    • Dental surgery
    • Concomitant oral disease
    • Periodontal disease
    • Ill-fitted dental prosthesis
  • Demographic factors
    • Genetic factors
  • Aggravating factors
    • Heavy smoking
    • Infection

What is the Real Risk of Osteonecrosis?

Osteonecrosis of the jaw (ONJ) is an extremely rare adverse event for patients taking bisphosphonates for osteoporosis.  Reports of bisphosphonate induced ONJ date back to the early 2000’s.  Reviews of current data support that up to 80% of ONJ cases occurred in patients with various cancers. These patients were also treated for a long period of time with high-dose injectable bisphosphonates. It is important to note that these doses were 10x higher than doses used to treat osteoporosis.3

Cases, of ONJ in osteoporotic patients, are extremely rare – not one case was found in more than 3000 patients participating in the clinical trials with zoledronic acid and alendronate. And no causal link between ONJ and bisphosphonate therapy, in these patients, has been convincingly demonstrated.4  

Although there are limitations to all studies, based on this information, the risk of ONJ in patients treated with bisphosphonates for osteoporosis is very low.

What does the American Dental Association Recommend?4

  • Routine Dental Care
  • Not modifying dental care solely because of bisphosphonates
  • Recommend AGAINST discontinuing bisphosphonates just before dental procedures

Conclusion

You should not stop taking your osteoporosis medication without talking to your medical provider. Osteoporosis is a serious but very treatable medical condition. The risk of fractures in people suffering from osteoporosis is very real and serious, while the risk of bisphosphonate-induced osteonecrosis of the jaw is rare. Also, there are  steps you and your doctor can take to help further reduce your risk by ensuring good dental hygiene and  preventive dental checkups  before starting and during treatment with these medications.    

 

Remember it’s always about benefit versus risk!

 

Author: Amy R. DeGennaro, Doctor of Pharmacy Candidate graduating May 2017 from Albany College of Pharmacy and Health Sciences.

Reviewed and approved by:  Jessica Farrell, PharmD.  Clinical Pharmacist, The Center for Rheumatology/Associate Professor, Albany College of Pharmacy and Health Sciences

 

References

  1. International Osteoporosis Foundation. Available at:  iofbonehealth.org
  2. Chapurlat RD, Arlot M, Burt-Pichat B, Chavassieux P, Roux JP, Portero-Muzy N, Delmas PD. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res. 2007; 22:1502-1509.
  3. Hough FS, Brown SL, Cassim B, Davey MR. The safety of osteoporosis medication. South African Medical Journal. 2014;104.4: p279.
  4. Florence R, Allen S, Benedict L, Compo R, Jensen A, Kalogeropoulou D, Kearns A, Larson S, Mallen E, O’Day K, Peltier A, Webb B. Institute for Clinical Systems Improvement. Diagnosis and Treatment of Osteoporosis.  Updated July 2013.
Diseases and Conditions

How do autoimmune diseases affect pregnancy?

April 5, 2017

By Jessica Chapman, M.D.

This past week I was asked to discuss the topic of pregnancy and rheumatic diseases.  This is a major issue as many people that develop autoimmune disease are young women.  If you so happen to be one of those young women and you thought that pregnancy was out of the question for you because of your illness… think again.

For the most part, most women with autoimmune disease can have successful pregnancies.  That is, with careful plan and coordination between your doctors.

General tips

It’s extremely important to have a frank discussion with your rheumatologist before thinking about conceiving.  If you have a hematologist, nephrologist, pulmonologist, cardiologist, or any other specialist that also plays a role in caring for your autoimmune, then they should be involved as well.  It’ll also me crucial for you to establish care with a high risk OB-GYN. I did say that it is possible to have a successful pregnancy, but it won’t be your average type of pregnancy.  All this should be done between 6 -12 months prior to attempting conception.

The following are typically recommended.

  • For best outcome, conception should be attempted during periods of low disease activity.
  • All high risk or teratogenic medications should be replaced with low risk medications.  This one can be tricky at times.  Remember that most of the medication have very very long washout periods.  So just because you stopped methotrexate a week ago, it’s still there lingering.
  • You should be assessed for high risk autoantibodies.  These include SSA (anti-Ro) and SSB (anti-La) antibodies as well as all the antiphospholipid antibodies.
  • If you plan on breastfeeding, the choice of medication should also factor into the decision.

Antibodies

SSA and SSB antibodies

These antibodies are typically associated with Sjogren’s syndrome but can also be present in a variety of different conditions such as lupus and rheumatoid arthritis.  It’s important to know whether you have these antibodies because they increase the chance of neonatal lupus.  Maternal SSA and SSB antibodies can passively transfer in utero to the baby.  The risk is small, 1-2% of cases but the risk significantly increases in women who have already borne a child with neonatal lupus.

Children that are born with neonatal lupus may have a rash, liver problems, and low blood cell counts but thankfully, these symptoms disappear completely after about six months.  I did not find research finding that have neonatal lupus increases the chance of the child developing systemic lupus erythematosus (SLE).  Research is research and things may change with time.

The most dreaded complication of neonatal lupus is complete heart block, which typically occurs at weeks 20 – 22.  It’s currently not recommended to use prophylactic steroids to prevent this from happening, but rather to get frequent cardiac monitoring.  This is where the high risk OB-GYN comes into play.

Antiphospholipid antibodies

There are three types of antiphospholipids: lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoproteins.  The presence of these antibodies, particularly at high titers, are associated with something called the antiphospholipid syndrome.  People that have this condition are  higher risk of developing bother arterial and/or venous blood clots.  Other complications include: miscarriage, stillbirth, pre-term delivery, and preeclampsia.  In an effort to try to prevent some of these complications, women that have antiphospholipids typically treated with prophylactic “pregnancy-safe” blood thinners.

High risk medications

Because it would be completely and utterly unethical to conduct a randomized controlled study on pregnancy outcomes and exposure to disease modifying agents (DMARDs), the vast majority of evidence regarding the safety of medications during pregnancy comes from animal models.  There are also a few registries that capture human data.  As we all know, not all pregnancies are necessarily planned and for some women having active disease may be worse for the baby or the mother, so the benefits of the medication may outweigh the risks.  Every situation is unique.

The American College of Rheumatology has a nice table listing medications that typically are used to treat rheumatic conditions.  Which is considered safe in pregnancy and breastfeeding.  In general the antimalarials, like hydroxychloroquine, are safe as well as azathioprine and sometimes sulfasalazine.  Mounting evidence also suggests that the TNF-alpha inhibitors may also be safe, but this isn’t set in stone.  Many rheumatologists are still on the fence regarding this one.  If a TNF-alpha inhibitor is absolutely required, it may be a good idea to use certolizumab as this medication is pegylated and technically should not cross the placenta.  It is VERY important to have a discussion with your rheumatologist regarding your medications!

How does pregnancy affect disease activity?

It all depends on the disease we are talking about.  Typically SLE becomes more active during pregnancy, whereas rheumatoid arthritis and psoriatic arthritis tends to improve.  Typically vasculitis, polymyositis, dermatomyositis, and systemic sclerosis are unaffected by pregnancy.

High risk clinical situations

HOWEVER, there are a few notable circumstances where pregnancy is risky for both the mother and the child.  It’s generally not safe to conceive during a period of very high disease activity.  This includes lupus nephritis.  It’s generally discouraged to conceive when lupus nephritis is active, but when things are controlled it’s okay with very close monitoring.  Patients with lupus nephritis commonly flare, are at higher risk of preeclampsia, and HELLP syndrome during pregnancy but these can be reversed with prompt treatment.

Another very important high risk situation is pulmonary hypertension.  This can occur in variety of disease such as systemic sclerosis, SLE, myositis, mixed connective tissue disease, Sjogren’s syndrome, and rheumatoid arthritis.  When pulmonary hypertension is caused by an autoimmune disease, we call it connective tissue disease-related pulmonary arterial hypertension.  For those who want to get technical, pulmonary hypertension is defined as a mean pulmonary arterial pressure higher than 25 mmHg at rest, associated with a pulmonary capillary wedge pressure lower than 12 mmHg diagnosed by right heart catheterization. Symptoms include:

  • Shortness of breath particularly while exercising.  Like more than what you would expect.  At one point the shortness of breath even when you are at rest.
  • Fatigue
  • Dizziness, passing out.
  • Chest pain
  • Swollen legs or swollen abdomen (ascites)
  • Palpitations
  • Bluish color

So why is this especially important for pregnancy-related matters?

A study by Qian et al. aimed to evaluate the survival of patient with SLE-associated pulmonary arterial hypertension.  This was a systematic review and meta-analysis.  They identified 6 studies which included a total of 323 patients.  They found that 1-, 3-, and 5-year survival rates were 88%, 81%, and 68% respectively.  The more severe the pulmonary hypertension, the worse the outcome.  These are not good odds.

High pulmonary hypertension peripartal mortality is not an isolated incident related to SLE alone.  It is elevated for all connective tissue disease-related caused of pulmonary arterial hypertension.

Conclusion

We’ve come a long way when it comes to rheumatic diseases and pregnancy.  Way back when, it was generally discouraged in practically all circumstances.  But things have changed.  With careful planning and monitoring, many women with autoimmune diseases can now have safe pregnancies.

References

Kelley and Firestein’s Textbook of Rheumatology, tenth edition

American College of Rheumatology

Pasut G. Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol.BioDrugs. 2014 Apr;28 Suppl 1:S15-23.

Moroni G, et al. Maternal outcome in pregnancy women with lupus nephritis. A prospective multicenter study. J Autoimmun. 2016 Nov;74:194-200.

Thakkar V, Lau EM. Connective tissue disease-related pulmonary arterial hypertension. Best Pract Res Clin Rheumatol. 2016 Feb;30(1):22-38.

Qian J, et al. Survival and prognostic factors of systemic lupus erythematosus-associated pulmonary arterial hypertension: A PRISMA-compliant systematic review and meta-analysis. Autoimmun Rev. 2016 Mar;15(3):250-7.

Diseases and Conditions

What do you mean by weight-bearing exercise?

March 22, 2017

Rheumatology primarily, and thankfully, deals with rare conditions with a few notable exceptions.  Osteoporosis being one of those.  According to the CDC

Percent of men 50 years of age and over with osteoporosis of the femur neck or lumbar spine: 4%

Percent of women 50 years of age and over with osteoporosis of the femur neck or lumbar spine: 16%

That’s a lot of people.  It’s also important note, that post-menopausal women are not the only ones that develop osteoporosis.  Men do.  People with inflammatory diseases do.  People that have GI absorption problems also do as well as people that don’t move a whole lot.

What is osteoporosis?

Osteoporosis is a condition that is characterized by weakening of bone.  People that have osteoporosis don’t feel they have osteoporosis.  It’s painless and there are no symptoms, until that is, something very bad happens like a fracture.  Bone strength is determined by bone mass and bone quality.  Think of a tree branch.  Branch A just fell off a healthy tree.  There was a bad storm and it just fell.  Structurally it’s normal.  Now you try to break it in half.  It’s a bit difficult to do.  Now you have Branch B.  This branch fell off a termite infested tree.  It’s partially hollowed out, i.e., the “wood” mass is significantly lower.  You try to break Branch B in half…easy peasy.  Osteoporosis = bone like Branch B.  Minor trauma in osteoporotic bone can result in a fracture.

Risk factors for osteoporosis

The next question is what are some of the risk factors that predispose someone to develop osteoporosis.  The good news is that some of these risk factors can be modified.  The bad news is that some risk factors cannot.

Things you CAN’T change

  • Advanced age
  • Ethnicity (white and Asian)
  • Early menopause
  • Slender build (< 127lbs)
  • Maternal history of hip fragility fracture
  • Certain medical conditions

Things you CAN change

  • Low calcium intake
  • Low vitamin D intake
  • Estrogen deficiency
  • Sedentary lifestyle
  • Cigarette smoking
  • Alcohol excess ( > 2 drinks/day)
  • Caffeine excess (> 2 servings/day)
  • Certain medications

Medical conditions

  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Lupus
  • Hyperthyroidism
  • Hyperparathyroidism
  • Alcoholism
  • Eating disorders
  • Inflammatory bowel disease
  • History of gastric bypass
  • Celiac disease
  • Renal failure
  • Multiple myeloma

There are a lot more conditions, but this is a quick list of the common ones.

Medications

  • Steroids!!! Like prednisone, methylprednisolone, dexamethasone, etc.
  • Excess thyroid meds
  • SSRIs
  • Proton pump inhibitors, used for heartburn

Before making any changes with your meds, please talk with your doctor. 

How to measure bone density?

Bone density is measured using dual energy x-ray absorptiometry (DEXA).  Just say DEXA, the first word is way too long and complicated.  Sometimes bone density can be measured with a special type of CT or ultrasound but this is not typical and usually is reserved for unusual situations.

The body parts that are typically measured are the lumbar spine, the hip, the femoral neck, and the forearm.  Sometimes the heel is also included.  These areas are best at predicting future fractures, which when you think about it, is what we’re trying to do: Prevent future fractures.

Typically, DEXAs are repeated every two years.  Again, there are some exceptions where DEXAs may be obtained more frequently.  For example, if I have a patient on a “boat-load” of steroids for systemic vasculitis for months and months on end, I may want to repeat the DEXA annually.

Why is it important to treat osteoporosis?

The answer to this question is very simple.  Prevention of fractures.  Other than the fact that fractures are incredibly uncomfortable, multiple studies have shown that fragility fractures particularly hip fractures, increase the risk of dying…  Yes you heard me, dying.  A recent article found that the one year risk of death was 23.6% after sustaining a hip fracture.  This finding is in line with most of the literature.  I don’t know about you but I don’t like these odds.

How to increase bone density?

The answer to this question is not simple.  The simple answer is eat a healthy diet, spend some time in the sun, if you smoke stop, supplement with calcium and vitamin D, regularly perform weight-bearing exercise, and medications.  The problem I have with this advice is that for the most part it is extraordinarily vague, except for the medication bit which will be covered in future posts.

What is weight-bearing exercise?

I’d like to focus on weight-bearing exercise, more specifically, what constitutes weight-bearing exercise.  I get this question a lot.

Before answering, “what is weight-bearing exercise”, we need to know what is NOT weight-bearing exercise.

Swimming is NOT weight-bearing exercise.

Cycling is NOT weight-bearing exercise.

Rowing is NOT weight-bearing exercise.

Don’t get me wrong, these exercises are excellent exercises for cardiovascular health, but they won’t help improve bone mass.  Weight-bearing exercises refers to exercises where you need to move your body against gravity.  These exercises can then be classified into high-impact and low-impact.  High-impact activities are better at building bone density but everyone has their own limits.  If you have severe osteoarthritis you may not be physically capable of performing high-impact activities.  Safety is a concern.  The National Osteoporosis Foundation has a nice list of activities.

High impact weight-bearing exercises are important but they are not the only factor in the equation.  Another major factor are falls, more specifically the prevention of falls.  Hip fractures almost always are directly caused by falls.  Having osteoporosis simply increases the risk of a fall that results in a fracture as opposed to a nasty bruise.  Some of the greatest fall risks include the following:

  • Frailty
  • Visual impairment
  • Cognitive impairment
  • Problems with your legs, this includes osteoarthritis of the knees
  • A cluttered home environment
  • A previous fall within the past 6 months.  This is actually number one on the list.

To help prevent falls, it’s important to try to correct some of the above.  It’s also important to perform activities that will help build muscle strength, balance, and mobility.  Most senior citizen exercise classes like the ones offered by the Silver Sneakers Program, focus on these types of exercises.

How much activity is necessary?

Again, this is difficult to quantify.

A recent Japanese study measured the number of steps per day continuously for 5 years and measured the bone density of participants’ heel on an annual basis.  They also measured the intensity of the activity.  After controlling for baseline density, age, and body mass, they found that bone health was optimal in elderly people who take at least 7000 to 8000 steps per day and/or spend at least 15-20 minutes per day at moderate activity.

It’s important to note that these people did not necessarily go to the gym.  Steps per day can be achieved in numerous natural different ways.  Blue Zone founder Dan Buettner has it as number #1 on the Power 9® list, MOVE NATURALLY.  If you’ve read some of my previous posts or actually heard me in clinic, you’ll know that I’m a huge fan of the Blue Zone Project.  We don’t need fancy supplements or gym memberships to achieve optimal health.  The following are a few examples on how to move naturally.

  • Walk, walk, walk.  Avoid using your car.
  • If you need to use your car, park further away.
  • Using stairs as much a possible, don’t use the escalator.
  • Start gardening.
  • Get rid of mechanical conveniences in the house.  I love my snow blower, but it has to go.

I hope that this has helped you.  If you retain only one thing, MOVE NATURALLY.  This is the secret to optimal bone health.

 

Disclaimer: the abovementioned information does not constitute medical advice.  Every case is unique.  Please contact your local rheumatologist or your physician for more information. 

References

CDC Osteoporosis Statistics

Rheumatology Secrets, 3rd edition

Guerra MT, et al. One-year mortality of elderly patients with hip fracture surgically treated at a hospital in Southern Brazil. Rev Bras Ortop. 2016 Dec 7;52(1):17-23.

National Osteoporosis Foundation

Shephard RJ, et al. Objective longitudinal measures of physical activity and bone health in older Japanese: the Nakanojo Study. J Am Geriatr Soc. 2016 Dec 9. doi: 10.1111/jgs.14553. [Epub ahead of print]

 

Diseases and Conditions

What are the risks vs. benefits of biologic therapy?

March 8, 2017

Some of you may recall one of my previous posts where I attempted to dispel some of the myths commonly associated methotrexate.  Don’t get me wrong, I frequently use methotrexate.  It is considered gold standard for the treatment of rheumatoid arthritis.  And this is despite the armada of new fancy medications coming onto the market.  The American College of Rheumatology doesn’t call it the gold standard for nothing.

But sometimes it isn’t enough.

It’s estimated that about 30% of people achieve either remission or very minimal disease activity with methotrexate alone.  That leaves the other 70%.  Maybe this includes you?  In this situation, your rheumatologist may either recommend you to combine methotrexate with another conventional disease modifying anti-rheumatic drug (DMARD) or either to combine it with a biologic DMARD.  The decision is very complex and will vary from person-to-person and from rheumatologist-to-rheumatologist.  Were there issues with the ability to tolerate the medication, allergies, other medical conditions, insurance coverage, safety profile concerns, etc?  And then there’s just style.

DMARDs

In the best of situations, ALL people diagnosed with rheumatoid arthritis should be started on a DMARD as quickly as possible.  For those who don’t really know me, the tone of this statement is very uncharacteristic of me.  I loathe dogma and authoritarian statements in general.  But when it comes to DMARDs and rheumatoid arthritis, people that receive these medications as soon as possible do better and have less joint damage.  It’s important to achieve remission or have very minimal disease activity as soon as possible and as long as possible.

So what is a DMARD? For a medication to be considered a DMARD it has to change the course of the disease, for the better:), for at least one year.  There should be improvement in either physical function, decreased swelling, or slowing/prevention of joint damage.

To understand why your doctor may want to start a biologic medication, it’s important to understand what is meant by a conventional vs. a biologic DMARD.

I would say there are two main differences between conventional DMARDs and biologic DMARDs: mechanism of action and cost.  Conventional DMARDs do NOT directly target a specific type of inflammation.  Biologics do.  This means that biologics are a lot more molecular complex.  This also means that they are A LOT more expensive.  Even in countries like Canada, where the single payer system has the ability to negotiate prices with pharmaceutical companies, the price is still very high.  I could on and on with this subject, but I’ll leave that for another post.

Conventional DMARDs

  • Often used
    • Hydroxychloroquine
    • Methotrexate
    • Leflunomide
    • Sulfasalazine
  • Not really used
    • Azathioprine
    • Mycophenolate, sometimes used for rheumatoid arthritis affecting the lungs
    • Cyclophosphide, used for life or organ threatening disease
    • Cyclosporine
    • Gold injections

Biologic DMARDs

  • Tumor necrosis factor inhibitors
    • Etanercept
    • Adalimumab
    • Golimumab
    • Certolizumab pegol
    • Infliximab
  • Interleukin-6 inhibitors
    • Tocilizumab
  • Co-stimulation inhibitors
    • Abatacept
  • JAK inhibitors
    • Tofacitinib
  • B cell depletion
    • Rituximab

There are other medications that are coming down the pipeline, but these are the ones that are FDA approved and commercially available for the treatment of rheumatoid arthritis.  There are other biologic medications like belimumab, apremilast, ustekinumab, and secukinumab that are used for other diseases like systemic lupus erythmatosus, psoriatic arthritis, and ankylosing spondylitis.

Triple therapy vs. methotrexate + biologic

Generally triple therapy refers to the simultaneous use of methotrexate + sulfasalazine + hydroxychloroquine for the treatment of rheumatoid arthritis.  A Cochrane meta-analysis recently found that triple therapy typically is just as effective as methotrexate + a biologic or tofacitinib alone.  So why is your doctor proposing going to a biologic medication instead of going to triple therapy?  It certainly would be cheaper.

This is where I would say is one of the potential benefits of biologics: the ability to tolerate treatment long-term.  Let’s put things into perspective.  When you take an antibiotic, you may end up with some GI discomfort, diarrhea, some nausea, etc.  You receive 7 days worth of treatment, the infection is gone, it usually takes a few more days for things to settle down, but then it’s done.  When it comes to the vast majority of rheumatic conditions like rheumatoid arthritis, some form of medication is consistently needed to keep the disease in remission. If you stop, the disease flares.  Don’t get me wrong, there are exceptions.  Sometimes the disease goes into permanent remission or “burns out”.  This is rare and definitely is not the rule.

The problem with triple therapy is that it tends to be very difficult to tolerate long-term.  Most people could tolerate a few weeks, but we’re talking years, decades, lifetime.  Many people stop one or more of the medications without telling their doctor, others take them sporadically.  Basically, there’s a lot of non-compliance with treatment when people receive triple therapy.

It isn’t necessarily because those people are irresponsible.  It’s that the medicines are making them feel sicker than their actual disease!

Simply put, biologics tend to be a lot easier to tolerate long-term and to bout SOME can be used as monotherapy i.e., you don’t need to combine with methotrexate.

Onset of action

I wouldn’t say that this is necessarily the most important factor when making a decision to go with a biologic instead of sticking to conventional DMARDs but I guess it could help tip the balance in certain situations.  In general biologic DMARDs tend to work a little more quickly that conventional.  This greatly varies from biologic-to-biologic.  Generally conventional DMARDs taking between 3 – 6 months to fully work.  It tends to be closer to the 3 month mark.  For most biologics it can take up to 3 months.  Certain ones like abatacept can take up to 6 months as well.

Cost

Most biologics cost over $ 1 100 per month.  Mind you, hardly anyone actually pays $ 1,100 per month.  Before starting a biologic medication, you doctor’s office will obtain authorization from your insurance company prior to prescribing the medication.  When the medication is authorized, your doctor will send it to your prescription mail-order company, and then it will be mailed to you.  Co-pays vary from $5 a script to a few hundred dollars in extreme cases.  It really depends on your insurance coverage.  It’s very important to keep your doctor but also your doctor’s medical secretary and if your doctor is extra lucky, your doctor’s patient advocate, appraised of all changes to your insurance.  It can mean the difference between a $5 co-pay and a second mortgage.  Most pharmaceutical companies have patient assistance programs.  Some are better than others… and some are better advertised than others.

Conventional DMARDs are a lot cheaper.  For example, methotrexate comes in 2.5 mg tablets.  20 tablets cost a little over $25.  This is the price if you had no insurance and were paying completely out of pocket.  Someone taking oral methotrexate will typical take between 24 to 40 tablets per month.  For most people this is doable even without any insurance.

Conversely, if you were receiving etanercept and had no insurance, your out of pocket cost would be about $3,500 per month.  Again, your doctor’s team will work to have the medication covered, but it’s still something to think about.

Method of delivery

This may be a non-issue for many people but it may be for some.  Most biologics need to either be injected or infused.  So far, only tofacitinib (rheumatoid arthritis) and apremilast (psoriatic arthritis) are taken orally.  There are pros and cons for both injections and infusions but generally, if your needle phobic, this may be a problem.  Infusions are time consuming because you need to come to the clinic to receive the infusion.  They typically last between an hour to half a day depending on the medication.  Some are dosed every month others every 8 weeks.  Rituximab is every 6 months but this is an exception.  Most injections are either given every week or every other week.  Some are a lot less frequent like ustekinumab, but again this is an exception.

Conversely, all the conventional DMARDs are oral except for cyclosphosphamide and gold.  I’ve never prescribe cyclophosphamide for rheumatoid arthritis… ever.  First, we simply do not encounter many people with life-threatening complications caused by rheumatoid arthritis anymore because the vast majority of people with the condition are treated with DMARDs very early into their disease.  Second, there are many other medications on the market that are a whole like better.  Don’t get me wrong, there are certain very serious indicated clinical situations.  Just wrote an order for it last week… my first in a year and it wasn’t for RA!

Infection risk

One of the big differences between conventional DMARDs and biologics is the infection risk.  Biologic medications generally are a lot more immunosuppressive than conventional DMARDs.  Again there are exceptions.  For example, abatacept is generally thought to have less of an infection risk.

I have to stress that this does not mean that people taking biologics get a ton of infections.  But it becomes extra important to keep up with routine vaccinations, adhere to proper hand washing, and try to stay away from high risk situations as much as possible.  It may also not be such a great idea to be on a biologic if you are prone to getting infections.  Let’s face it, no one wants 10 sinus infections in one year.  It also may not be such a great idea to be one some of these biologics if you have very serious lung problems.  I probably will try to avoid most biologics if someone has severe COPD requiring extra oxygen.  Pneumonia could be life-threatening in this situation.

Another important noteworthy point, certain biologics can re-activate dormant infections such as tuberculosis, hepatitis B+C, and zoster.  It’s important to screen for both tuberculosis and hepatitis B+C prior to initiation of therapy.   You may need to start therapy for these latent infection prior to treatment with biologics.  For zoster also known as shingles, you may benefit from the shot one month prior to treatment with biologics.  The shingles shot is a live vaccine and should NOT be given while taking a biologic medication.  Like I said, you need to wait a month.  Please contact your rheumatologist for more information.

Miscellaneous

There are a few other items of concern but these vary from medication to medication irrespective of whether that medication is a conventional DMARD or a biologic.  The following are items to consider when choosing the most appropriate medications.

  • History of hepatitis C
  • History of HIV
  • History of a demyelinating disease like multiple sclerosis
  • History of severe congestive heart failure
  • History of lymphoma or leukemia
  • History of melanoma
  • History of a solid cancer within the last 5 years (e.g., breast cancer)
  • History serious liver disease
  • History of a serious kidney disease
  • History of serious lung disease
  • History of serious diverticulitis or bowel perforation
  • History of gastric bypass surgery
  • History of macular degeneration
  • History of organ transplant
  • Allergy history
  • Current medications.  Are there any possible drug interactions? (e.g., azathioprine and allopurinol should not be combined)

Having one of these does NOT mean you cannot take any biologic medication safely.  It simply means that certain ones may not be such a good idea.  For example, tumor necrosis inhibitors should not be taken by people suffering from multiple sclerosis.

Conclusion

I hope this helps clarify a few concerns that you may have had regarding biologic medications.  Maybe I’ve caused you to think about things you had not thought about before?  Choosing the best course of therapy can be very complex.  There are so many things to think about and the down stream effects could be very serious.

Open communication and knowledge are key!

References

Rheumatology Secrets 3rd edition

Hazlewood GS, et al. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis. Cochrane Database Syst Rev. 2016 Aug 29;(8):CD010227. doi: 10.1002/14651858.CD010227.pub2.

https://www.drugs.com/price-guide/methotrexate

Diseases and Conditions When to see a rheumatologist

10 Warning signs you could have Sjögren’s syndrome

March 1, 2017
Sjögren's syndrome can cause dry eyes and dry mouth as well as many other symptoms. Read on to learn more!

Today is a most bizarre weather-related day.  It’s warm, like you don’t need a coat warm, and there’s a raging thunderstorm.  Did I mention it’s February in upstate New York?  In honor of this most bizarre day, I’d thought I’d write a few words on a somewhat bizarre and illusive autoimmune disease called Sjögren’s syndrome.

Henrich Sjögren gave Sjögren’s syndrome its name.  He was a Swedish physician who first described the disease in 1933.  Sjögren’s syndrome is a common autoimmune disease that primarily causes dryness.  But it’s a lot more complicated than that because Sjögren’s syndrome can involve almost any organ so can present with a myriad of symptoms.  The symptoms arise from infiltration of lymphocytes into glands and affected organs.  Simply put, Sjögren’s syndrome is on the differential diagnosis in any person who has a positive ANA presenting with unexplained symptoms.

10 Warning signs you may be suffering from Sjögren’s syndrome

The following are some of the common manifestations of Sjögren’s syndrome.  Believe me, there are A LOT more but these are some of the common ones.

  1. Dry eyes
  2. Dry mouth
  3. Swollen cheek(s) i.e., parotid gland enlargement
  4. Profound tiredness
  5. Joint pain, sometimes with swelling
  6. Swollen glands
  7. Numbness, tingling, burning of the skin
  8. Raynaud’s
  9. Shortness of breath with minimal work
  10. Having a child that suffered from congenital heartblock

Dry mouth symptoms

The following are some common symptoms of dry mouth.

  1. Difficulty swallowing dry foods
  2. Inability to talk continuously
  3. Change in taste
  4. Burning sensation
  5. Large dentist bill! – Cavities, cracked teeth, loose fillings
  6. Problems with your dentures
  7. Worsening heartburn
  8. Thrush

As you can see the symptoms are a little all over the place and quite frankly are kind of vague.  Furthermore, many different conditions can mimic some of these symptoms: dehydration, depression, various medications, uncontrolled diabetes, multiple sclerosis, hepatitis C, sarcoidosis, etc etc.  Literally.

Classification criteria

Now it’s important to note that the following classification criteria are used for research purposes, and not necessarily for the day-to-day clinic.  Although they are important, there is such a thing called the art of medicine.

As we all know, not everyone fits into a neat little box.

Recently the American College of Rheumatology and the European League Against Rheumatism came up with a new system to classify Sjögren’s.  Basically, a group of hot-shot Sjögren’s specialists got together, looked at the literature, probably had more than one heated discussion, and came up with the following.

To test positive you need to have a score ≥4.  There are five items but they are weighted differently.

  • 3 Points – Anti-SSA/Ro antibody positivity
  • 3 Points – Focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2
  • 1 Point – Abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4)
  • 1 Point – Schirmer’s test result of ≤5 mm/5 mi
  • 1 Point – Unstimulated salivary flow rate of ≤0.1 mL/min, each scoring = 1

The sensitivity of this score is 96% and the specificity is 95%.  The sensitivity tells you how likely you are to detect all cases of Sjögren’s syndrome and the specificity tells you how accurate you are with the diagnosis using these set of diagnostic criteria.  These are pretty good figures.

What does this mean?

As you can see, the diagnosis favors objective findings, NOT symptoms.  This is a huge change from the previous set of diagnostic criteria.  You’ll also note that positive ANA, rheumatoid factor, and positive anti-SSB/La antibody positivity are not included in the new classification criteria.

Now I don’t want people thinking that I think symptoms are unimportant.  They are VERY important.  It’s just that symptoms should prompt a workup looking for objective features of the disease.

Now, try to remember the 10 warning signs.  If you find yourself checking a few of these items, check-in to your local rheumatologist.

References

Rheumatology Secrets 3rd edition

Shiboski CH, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts.Ann Rheum Dis. 2017 Jan;76(1):9-16.

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