You’re Asking ME??!?

Harry L. Gewanter, MD, FAAP, FACR

By Harry L. Gewanter, MD, FAAP, FACR

“Isn’t there something natural or a diet we can use instead of these poisons?”

This is a question all of us hear on a regular basis. And while we may believe we are recommending treatments utilizing the best evidence, that may not be the perception of some families. It is understandable that the parental desire to protect their child results in appropriate anxiety and fear over what they may believe to be overaggressive, or even experimental, treatment regimens. Similarly, anecdotes and subconscious beliefs may drive decision-making in these stressful situations more than evidence.

Our children do not respond well to our answers of “Because I told you so” and neither do our patients and their families. On the other hand, it is also difficult to answer beliefs just with facts. Like our offspring, patients and their families must often “discover” what we already know on their own. It is therefore important to have an understanding of their perspectives and provide valid information in an approachable format.

One problem with answering their questions is that there may not be sufficient (or any) comparable evidence to cite about the specific complementary, alternative or integrative intervention the families may be interested in trying. Responding with “more sleep and exercise are excellent natural interventions” or “work on reducing your stress”, while true, just ain’t gonna cut it. And essentially every article about both allopathic as well as non-allopathic interventions ends with the statement: “Ask your physician.”

So … what is “your physician” to do?

What caught my eye were recent posts by the NIH’s National Center on Complementary and Integrative Health (NCCIH). They have been working on trying to develop and/or report better evidence on integrative practices since their inception in 1998. While this will not necessarily provide you with the data you may want, it is an excellent place for valid information for both you and your patients. They have a clinical digest that they post monthly and the reports on “Musculoskeletal Inflammation and Natural Products” and “Complementary Approaches to Chronic Pain” are particularly relevant to our field. One can also subscribe to their Clinical Digest and other informative items, join or view their webcasts and utilize their site as a place families can go for more information. And, by the way, they also fund research projects.

These two reports can give you at least some evidence and suggestions that you can give to your families and you can direct them to the NCCIH website. In addition, MedlinePlus has material (http://medlineplus.gov) as does the UK’s National Health Service (http://www.nhs.uk/Livewell/complementary-alternative-medicine/Pages/complementary-and-alternative-medicine.aspx) and many US medical centers now have Integrative Medicine programs (www.imconsortium.org). The American Academy of Pediatrics also has a Section on Integrative Medicine (https://www.aap.org/en-us/about-the-aap/Committees-Councils-Sections/Section-on-Integrative-Medicine/Pages/default.aspx ) and its webpage within the AAP and/or its members can be a useful resource. For example, there is a handout for families (https://patiented.solutions.aap.org/handout.aspx?gbosid=156748) that can be personalized for your practice.

Beyond sending your families to the web for more information, here are a few things you can point out (beyond the obvious fact that there is even less data in children than adults):

  • Please tell me about everything your child/you are taking! We need to know so we can be sure we don’t think there is a positive or negative issue is from the wrong intervention(s).
  • There is good evidence that mind-body techniques help reduce pain and improve quality of life for people with rheumatic diseases and other chronic illnesses.
  • There is good evidence that sleep and activity is good for everyone. (Ideally everyone should try to “Eat, sleep & sweat” daily.)
  • Acupuncture has been shown to be effective in a number of musculoskeletal conditions, especially painful ones, but we are still learning about its impact on inflammatory conditions.
  • There is developing evidence on the effect of various diets on inflammatory conditions, but it is early and we have much to learn.
  • We are learning about the interactions between natural substances and our current therapies and there are situations where the combination can be helpful or cause problems.
  • While many of these interventions are helpful, there is not yet sufficient information to say they work as well in reducing the inflammation and preventing the damage as what I am recommending.

No single medical philosophy has all the answers and we must remain open to new information and insights. Not too long ago we did not think much of an infectious cause for ulcers or that our gut flora could influence health. Who knows what we pooh-pooh now may be beneficial in the future.

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Does Depression Cause Arthritis In Teenagers?

Mental illness is certainly an important aspect of many of our patients’ struggles, and I hope I’ve made the case earlier that it’s something pediatric rheumatologists should be paying attention to… There is a lot of good literature to show that patients with chronic disease, in general, are at higher risk for mental illness.

This makes sense to me, conceptually, that children and adolescents burdened with the stress and chaos of illness are at risk for psychological distress. Physical illness begets mental illness. I can also understand that this can be a bi-directional relationship, in which mental illness can in turn make physical illness worse. Perhaps this occurs in our patients when they are depressed if they are less likely to see their PCPs, or take their medications, or perhaps, as some have suggested, there are neuro-inflammatory effects that the brain has on the body that worsen physical inflammatory disease. But can mental illness cause inflammatory disease?

The authors of an article that recently came out in PLOS ONE suggest, yes. Specifically they suggest that affective disorders such as Major Depressive Disorder can cause arthritis in adolescents.

The article, more generally, is about links between mental and physical comorbidities, in which Tegethoff and her colleagues examined data from the Adolescent Supplement of the National Comorbidity Survey. In this survey, data was collected on demographics, mental illness, physical illness, and the reported timing of those.

The group previously published data showing associations between 5 different categories of mental illness and 8 different physical illnesses, in which there was a significant association between arthritis and mental illness, most notably anxiety (but also some association with affective disorder and substance abuse). In their most recent study, they examined timing to try to determine the direction of these associations. In terms of statistical significance and effect size, one of the most remarkable findings was the association of previous affective disorders with the development of arthritis, for which the hazard ratio was >3. In contrast, no significant hazard ratios were found the other way round, in terms of arthritis predicting mental illness.

While we’re cogitating on this, let’s review some important limitations to this study:

1) The presence and timing of physical illness was defined by a questionnaire administered to adolescent participants. The authors argue that this is a valid way of determining diagnosis, and they cite evidence showing that children are just as reliable as adults in describing their illness experience and health status. Perhaps one can use this to argue that they will be just as good at reporting physician-given diagnoses, but as one of their citations found, even in adults self-reported diagnoses agree well with physician diagnoses, except in the case of arthritis!

2) This brings up the question of how people interpret ‘arthritis’ (which is exactly as specific a terminology as was used in this study’s questionnaire ). To a rheumatologist this has a specific meaning and does not include joint pain without other findings, to a patient or even another researcher, this may be different. The US National Health Interview Survey used by the CDC collects data on arthritis with the following question: “Have you EVER been told by a doctor or other health professional that you have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia?”

Is it possible then, that the number of participants with JIA and other forms of chronic arthritis (what I thought of when I read “arthritis”) were few among this sample? And that others with joint pain or chronic pain syndromes were included and even drowned them out?

Looking at the authors’ previous paper about 2% of the total sample reported having had arthritis. This is at least 14 times what we would expect for the prevalence of chronic arthritis. On the other hand, juvenile fibromyalgia may be as prevalent as 6% and non-specific joint pain, more than that. Perhaps what is truly being observed here is the temporal relationship between affective disorders and musculoskeletal pain. This would be much less surprising and is congruent with all we know about amplified musculoskeletal pain syndromes, fibromyalgia, and their associations with mental illness.

So in my mind, the question of whether mental illness can cause chronic arthritis, whether JIA, lupus, or other, is still unanswered… but is it a far-fetched hypothesis? Certainly hypotheses that stress contributes to the development of autoimmune or inflammatory disease are not new, so perhaps this area is worthy of further research.

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Chicken Or Egg? The Relationship Between Sleep And Pain In Our Patients

Teenagers are notorious for poor sleeping habits. (And probably pediatric rheumatologists aren’t much better, at least not the ones I know.) The average teenager gets about 7 hours of sleep each night, but needs about 9 hours or more.

I’ve had a personal interest in sleep, especially its relationship with pain, in my patients for years. I’ve followed a large number of chronic pain patients who report poor sleep; for many of these children, formal sleep studies have shown abnormalities (often in the deep stages of sleep).

I suspect that this relationship (that is, between poor sleep and more pain) also exists for the inflammatory diseases that we treat. In fact, Yoni Butbul published a study with us showing that children with rheumatic illness often sleep poorly, and that poor sleep is linked to increased pain.

Can we improve children’s suffering by improving sleep? That’s really the important question, I think. It’s really a chicken and egg thing. Is the poor sleep somehow causing pain (for example, by lowering the threshold at which stimulae are perceived as being noxious), or is it the result of pain?

It was with this in mind, that I read with interest this report by Drs. Meltzer and colleagues, from National Jewish Health in Denver.

The group did a very interesting randomized, crossover trial in a small number of teens with asthma. For the first week, the patients went to bed and woke at their usual hours. Sleep was monitored by a wrist device, and the teens did flow meter readings morning and night. After the first week, half were randomized to go to bed earlier (in order to get 10 hours of sleep) and half were randomized to get only 6.5 hours of sleep each night. After that week they went back to their chosen bedtime for a weekend of ‘washout’. The two groups then switched for the third week, so that those who had a long sleep were now to go to bed late and have a short sleep, and vice versa.

Strikingly, during the ‘healthy’ (i.e. long) sleep week, the teens had the perception that their asthma bothered them considerably less than during the sleep-deprived week. While this may have been due to some ‘threshold of noxious stimulus’ adjustment (as mentioned above), their asthma also improved! FEV and peak flow improved significantly with healthier sleep. And, the asthma improvement was concordant with the symptom improvement.

It would seem, if these results can be replicated, that the chicken and egg thing may be solved. (At least, may be solved for asthma.)

Why did this happen? It could be that changes in sleep induce changes in the immune system. For example, many studies have shown unfavorable changes in IL-1 beta, TNF-alpha, IL-6 and CRP due to experimental deprivation of sleep. (However, many of these studies are small; also, the experimental protocols and results have not all been consistent.)

Can this knowledge help us in the clinic? Importantly, in the Meltzer study only 10 of 55 identified patients were finally enrolled and analyzed. There were a number of reasons for ineligibility (for example, 15% of their asthma patients had a BMI > 98th% …!) and patients were only analyzed if they actually did change their sleep.

But, it does seem possible to convince teenagers to change their sleep habits. In one Dutch study, in which healthy teens were given 30 Euro gift certificates for participating (so, maybe, bribing is the answer), a combination of progressively earlier bedtimes and sleep hygiene instruction improved sleep and depressive mood significantly.

Chicken or egg? I suppose time, and more studies like the Meltzer paper, will answer this for us. For me? I am certainly going to try to get my teen patients to sleep better, and – hopefully – it will do them some good.

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What Caught My Eye

By Kenneth N. Schikler, MD
Chief, Divisions of Pediatric Rheumatology & Adolescent Medicine
University of Louisville School of Medicine
Kosair Children’s Hospital

It is not unusual for pediatric rheumatologists to be asked to see a child with persistent fever, without arthritis, who may or may not have had rash. Usually by the time the rheumatologist is called, the child has often been treated with antibiotics, and bacterial cultures have been done and were negative, and serologic or PCR studies for tick related illnesses and other infectious etiologies are in process or negative. Viral studies are done, and how specific/ disease related is the finding of a positive recovery of a respiratory pathogen from a nasal swab?

In JAMA 2016   316 (8) 835, Herberg et al have published “Diagnostic Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children”. Their findings in a study that looked at the RNA expression signatures in febrile children who had:

  1. Bacterial syndromes with recovered/identified bacterial pathogens,
  2. Bacterial syndromes with no bacterial recovery,
  3. No classic syndrome nor recovery of infectious agent,
  4. Biral syndrome with virus identified,
  5. Biral syndrome without virus identified, and
  6. Henoch Schonlein Purpura or JIA.

The JIA patients were sampled at time of diagnosis or “early in disease”, but subtypes of JIA were not identified and median C-RP was 0.1. They also included in their analysis findings of the work of others in children with SLE.

Of interest to me, in their preliminary data they found two transcripts, IF144L and FAM89A showed reciprocal expression in viral and bacterial infection. In response to viral infection, mediated by type 1 interferon, IF144L was upregulated, while in children with septic shock FAM89A was upregulated.

In Arthritis and Rheumatology 2009, Barnes and colleagues reported on gene expression profiles in new onset JIA and in systemic JIA in addition to IL-6 and TLR/IL-1R pathways being activated, the Peroxisome Proliferative activated Receptor (PPAR) was identified.

FAM89A is reported to be one of the targets of PPAR gamma in an animal model reported by Tero-Pekka Alastalo et al in Journal of Clinical Investigation2011 Sep;121(9):3735-46. It would have been wonderful if the investigation could have included children with systemic JIA in active stages, to see if FAM89A expression discriminates septic children from innately toxic non-infected children. Still, the potential for being able to  eliminate a  viral etiology to rash and persistent fever would certainly be helpful.

 

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Some breast milk a day keeps the IVIG away?

Perhaps you missed the New York Times article published in October 2015,  “Overselling Breast Feeding” or the firestorm that erupted afterwards. I didn’t. I was up nursing my newborn on our first week home and reading resultant Facebook posts, emails, and even an article one of my friends had written. I stayed pretty silent from my glider and Boppy (a C-shaped nursing pillow), and told myself that I could comfortably keep to the sidelines for this one and let my general peds friends handle the unenviable job of correcting some of the more inflamed and misinformed comments.

But now, two recent articles in rheumatology are part of the library of evidence on the benefits of breastfeeding. Studies from France and Japan show protective effects in Ankylosing Spondylitis (AS) and Kawasaki Disease, respectively. The negative association with AS may not be surprising. If any of the diseases we see have a link to the gut microbiome and diet, it is the HLA-B27 arthritides. Montoya, et al, in May’s Annals of Rheumatic Diseases present a case-control study indicating that breastfeeding may lower the risk of AS.

They found that the odds of having AS compared to sibling controls were half as much in those who were breastfed. The study’s strength lies in the use of intra-family controls; important, as the authors point out, in examining a disease that clearly has a significant genetic component. The glaring limitation is that they had to rely on recall about breastfeeding status and duration for patients, some of whom were as old as 70. Remarkably, they report that only 7 of the 210 cases were not able to give breastfeeding data.

What impressed me even more were the findings in this month’s issue of Pediatrics, which features an article on the potential effects of breastfeeding in reducing the risk of Kawasaki Disease (KD). Yorifuji, et al, performed a very large, nationwide, prospective study in Japan, where there is a relatively high prevalence of KD. And also, apparently, a remarkably high rate of survey participation! Over 88% of the ~44,000 initial questionnaires sent out to families of six month old babies across the country were returned. If you have ever sent out a survey, more so, if you have ever been the parent of a six month old, you understand why this percentage is astounding. Perhaps this has something to do with Japan’s favorable maternity and child care leave laws, but I digress…

Larger than the effect seen with AS, the odds ratio of hospitalization for KD was 0.25 in breastfed and partially breastfed children compared to those who didn’t breastfeed. Moreover, the effect did not change much in models that controlled for multiple child and maternal factors. To put this in context, this effect size is in the same range as the effects of exercise in the prevention of death from cardiovascular disease. The authors suggest that this protection may be due to general “antiinfective” effects of breastfeeding versus the promotion of immune maturity, limiting the risk for dysfunctional inflammatory responses. In a disease that is potentially life threatening and whose treatment and management can be expensive and is not without risk, perhaps this piece of news is reason to raise a glass… or for some moms, a shirt.

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