Thursday, November 7, 2013

Carpe Diem's Revise that haiku #2, Basho's famous 'old pond'

Rain falls into pond
Tears of ancient sorrows
Frog leaves 

Windy night
Moon hovers above the pond
Frogs won’t jump

The muddied pond
They only jump after sunset
These lazy frogs

Carpe Diem's Tan Renga Challenge Month #VIII, MMT's ''even candent days''


even candent days
cannot drive the willow leaves
from their homing place
Magical Mystery Teacher

silence is called golden
leaves fall silently

the wind talks loud and louder
but leaves keep their silence

PS. Will be on vacation during the next weeks, most probably the last entry before returning from New Zealand.

Wednesday, November 6, 2013

Influence of Weather on Rheumatoid Arthritis Disease Activity

It's still a big question, but we're getting closer to an answer. People with rheumatoid arthritis often complain about the influence of weather an disease activity. There were two studies at the ACR 2013 Meeting in San Diego addressing the issue.

T. Sawada and colleagues presented the following study [Abstract #1356]: "Disease Activity Of Rheumatoid Arthritis Is Influenced By Seasonal Change, As Analyzed Based On a Nationwide Japanese Cohort Database." This study looked more at seasonal variations than weather and found, that "RA disease activity, as assessed both subjectively and objectively, was lowest in fall." Sorry, that won't get us any further, though one would have to take this account, when doing studies in Japan.

E. Savage and colleagues presented the second study [Abstract #1359]: "Does Rheumatoid Arthritis Disease Activity Correlate With Weather Conditions?" The authors come mostly from Belfast, Northern Ireland, but one also from St. Vincent’s Hospital, Melbourne, Australia, where I had the pleasure to do some research on DRGs. I guess that the data has been collected in Belfast. 133 patients either on stable etanercept or adalimumab were recruited for this study. The authors lokked at "three weather components from the seven quantitative variables (maximum temperature, minimum temperature, hours of sunshine, mm rainfall, relative humidity, wind-speed and pressure)." Conclusion: "This study demonstrates statistically significant lower DAS-28 scores in sunny and dry conditions. A non-significant trend to higher DAS-28 scores in times of low temperature, and dull, wet and windy weather was also noted." I'm surprised to hear about sunny and dry weather in Belfast, but now we have statistically significant results that prove patients complaints.

Weather and inflammatory rheumatic diseases

It is not uncommon that patients with rheumatic diseases report an increase of symptoms under certain weather conditions. Some of my patients feel that it will rain soon based on their symptoms. Other patients with rheumatoid arthritis report that cold, wet weather conditions or changes in air pressure will worsen their symptoms, such as pain, stiffness or joint swelling.
The results of studies on the effects of weather on the rheumatoid arthritis haven’t been conclusive, but there’s a new study that proved a link between weather and symptoms, which has been presented at the ACR 2013 Meeting in San Diego. See link below.

Weather sensitivity - findings from the last few weeks:

"Not the weather itself, but the change no matter which direction leads to more complaints." (female, RA)

"If there’s a change in weather. But I don't know if it isn’t in the mind. If a rain front comes. When the sun shines, I feel better." (female., RA)

Weather sensitivity: no (female, PsA)

"Maybe it was because poor weather. I thought the heat was really agreeable. You can’t always blame the weather. If it wouldn’t come so suddenly, but if the temperatures would go down gradually, so peu à peu." (female, RA)

"The cold and wet weather is not conducive. But it's then not particularly severe. The warm weather is good to me, I don’t get not much flares." (female, AS)

"Really bad. Such a weather [wet, cold] is fatal." (female, AS)

"Sweating in hot weather, nothing else." (female, RA)

"Since the weather swings back from warm to cold, I have more complaints again. But maybe I just feel it in my head.” (male; RA)

Weather sensitivity: "I'd say no." (male; RA)

"It depends on the weather. If it’s wet and cold, I've got more complaints again. I notice 100%, if the weather turns." (female, RA)

"I immediately notice the change in the weather in my back." (male; PsA)

"There is a comfortable temperature. It should be not too hot and not too cold." (female, RA)

"The hands are swollen since the change in the weather. More fatigue. More sluggish. As usual, when the weather swings." (female, SLE)

"With the change in the weather last week I put on a splint, because the whole right hand hurts very badly. I’ve put the hand immediately at rest. Then again, the next day, it's alright. I can tell you, if it's hot, because then my right little finger points to the outside of my hand." (female, RA)

"When it rains, or when the weather changes, the pain gets stronger." (male; AS)

"With the rain, it's worse. I have more pain if it’s damp. (female, RA/SLE)

"I had the feeling for the first time that it is related to the weather. I've never experienced  t this way. The rain." (female, RA)

"It has to be the humidity. Saturday was my date for the injection, I noticed it two or three days before." (female, RA)

"I'm always weather sensitive. More problems with damp and cold weather. Even in air-conditioned rooms. Running is more difficult and breathing, and my heart is racing." (female, RA plus lung involvement)

"Since Thursday I have more complaints on the back. The rain, the cold." (female; RA)

"Complaints from time to time. Once the moisture hangs out in the air." (female; AS)

"In the rain all joints hurt. In wet weather, I notice it immediately, then I can not run. In the summer, it is better. Now it hurts everywhere." (female; RA)

"Especially now with the weather [it’s worse again]. Before the weather change arrives. The other day we have rain. Then I can not sleep." (male; PsoA)

"When the weather change comes, if it gets wet, when the extreme weather change comes, then stiffness lasts much longer; then, you don’t want to put the elbow onto somewhere. No matter whether it turns from good to bad or vice versa." (male; RA)

"Last change in the weather a fortnight ago led to a swelling under my right foot, lasted 2 and 2½ days. Cooling with ice also didn’t help. Right hand starting from the outer edge, until it covered the entire hand." (male; RA)

"When it gets so cold, I've always cold hands; feet also." (female; RA)

(RA - Rheumatoid arthritis, PsoA - psoriatic arthritis, AS - ankylosing spondylitis, SLE-Systemic Lupus Erythematosus)

When the weather is particularly rainy and cold weather seems to increase joint pain and stiffness. But there are lots of differences.

Here’s the link to the blog post on the ACR 2013 Meeting:

Tuesday, November 5, 2013

Carpe Diem's Tan Renga Month #V, Sara McNulty's "Life completes circle''


life completes circle
at the end of the journey
death draws the last line
Sara McNulty

gloomy words on epitaph
butterflies fly by and rest

between abodes of death
a creeper finds place to bloom

Mavrilimumab at the ACR 2013 Meeting in San Diego

Mavrilimumab is a human MAB for the treatment of rheumatoid arthritis. It targets the GM-CSF receptor-alpha. More at:
Usually we are talking about T and B cells in rheumatoid arthritis or maybe dendritic cells, but now neutrophils and macrophages come into focus. GM-CSF controls activation, differentiation, and survival of macrophages and neutrophils.
I've just been to an ACR review/update course here in Germany and the colleagues were very much in favour of this new drug.

There have been three studies on mavrilimumab at the ACR 2013 Meeting in San Diego.

G.-R. Burmester and colleagues presented the following study [Abstract #1733]: "Early and Sustained Improvement In Pain and Physical Function As Measured By Visual Analog Scale and Short Form-36 Physical Component Summary Score In Rheumatoid Arthritis Patients Treated With Mavrilimumab, An Investigational Anti-GM-CSFR-Alpha Monoclonal Antibody, In a Phase 2a Study." Conclusion: "Treatment with mavrilimumab 100mg resulted in an early onset and sustained improvement in pain relief and physical functioning as measured by VAS and SF-36 PCS, respectively, in moderate-severe RA patients. These findings are consistent with improvement in the disease activity (DAS28-CRP) and support further investigation of the blockade of the GM-CSF receptor with mavrilimumab in Phase 2b studies conducted in both DMARD-IR and TNF-IR patients."

W. White and colleagues presented the second study [Abstract #2377]: "Biomarkers Associated With Rheumatoid Arthritis Disease Activity Including Joint Damage Correlate With Changes In Clinical Response In Subjects Treated With Mavrilimumab At Doses Above 10 Mg." Conclusion: "Promising clinical safety and efficacy results of mavrilimumab support further clinical development at doses greater than 10 mg. Mechanistically, the drug suppressed both acute phase and inflammatory blood markers. Tracking of disease activity by MBDA showed a clear biomarker-based dose-response relationship. The association of MBSD decline with radiographic damage will be assessed in an on-going phase 2b study."
But there hasn't been any data on radiographic changes up to now.

P.C. Ryan and colleagues resented a study on monkeys [Abstract #2378]: "Safety Of Mavrilimumab In Cynomolgus Monkeys: Relevance Of Nonclinical Findings In Lung To Human Safety." Conclusion: "These results suggest that suppressing macrophage activity by targeting GM-CSF receptor alpha may be a novel approach with an acceptable safety profile for the treatment of RA."
Interestingly in "results" the results of a study published at the EULAR 2012 Meeting in Berlin has been quoted: "In EARTH,
mavrilimumab demonstrated good clinical activity with no clinically significant or persistent changes in the lung function tests performed. Likewise, the serum biomarkers of lung damage, SP-D and KL-6, showed no clinically significant changes following mavrilimumab treatment." The study at the EULAR 2012 had been by S. Spitz and colleagues [Abstract AB0576]; "Evaluation Of Surfactant Protein-D And Kl-6 As Potential Pulmonary Safety Biomarkers During Mavrilimumab Treatment".
It is like in a detective story - the inspector frowns if someone gives an alibi without being asked for it. Though as macrophages are involved the side effects on the lung should be monitored.

The recent data looks much better than what has been presented last year, but still we lack a study of longer duration with data on radiographic progression. And as the studies EARTH explorer 1 and 2 look at other dosages (also 150 mg) and test against golimumab for 24 weeks, results on radiographic progression still have a long way to come.

Summing it up: it looks better for mavrilimumab than a year ago, but still we don't know if there's going to be a new drug.


Monday, November 4, 2013

Carpe Diem's Tan Renga Challenge Month #III "morning shimmer" by Bjorn Rudberg

morning shimmer
dew frosting on furze
a single leaf falls
Björn Brudberg

a yellow remnant of spring
while the furze is shivering

Carpe Diem's Tan Renga Challenge Month #IV Becca Givens River Stones

river stones
caressed by flowing water
pale moon shines
Becca Givens

stars glitter on the river
until the morning rises


Lodotra (modified or delayed release prednisone) at the ACR 2013 Meeting in San Diego

Let me talk again about modified or delayed release prednisone (Lodotra) as two studies have been presented at the ACR 2013 Meeting in San Diego.

F. Buttgereit and colleagues presented this study [Abstract # 2255]: "Threshold Analysis of Patient Reported Morning Stiffness Where Delayed-Release (DR) Prednisone Was Compared to, and Replaced, Immediate Release Prednisone in Rheumatoid Arthritis (RA) Patients Receiving Conventional Disease-Modifying Antirheumatic Drugs (DMARDs) Over 1 Year." IR-prednisone, taken in the morning, is compared to DR-prednisone, taken once daily at bedtime (e.g. 10pm). Conclusion: DR prednisone, as compared to IR prednisone, produces significantly higher MS response rates as defined by 25/50/75% improvement thresholds.  [...]."
The same patients were analysed in this study, which had been presented by R. Alten and colleagues [Abstract # 2265]: "Switching From Immediate Release (IR) Prednisone To Delayed Release (DR) Prednisone Improves Patient Reported Outcomes In Rheumatoid Arthritis (RA) Patients On Conventional Disease-Modifying Antirheumatic Drugs (DMARDs)." Conclusion: "This analysis demonstrates that RA patients on stable DMARD therapy, who have not adequately responded to IR-prednisone with respect to morning stiffness, showed statistically significant and clinically meaningful improvement in this symptom when switched to DR prednisone [...]."

Where's the catch? There's more than one. First: would you call a patient, who suffers two hours of morning stiffness, stable? Second: the advocates of Lodotra claim chronotherapy for their therapy, but we're already doing chronotherapy. We give immediate release prednisone in the morning to optimize (reduce) side effects. Lodotra is given in the evening to be released during the night to optimize (increase) therapeutic effects. In any study designed as this study DR prednisone will be better than IR prednisone. This is due to the time, when the drug is given. So the study shows that prednisone given at different times has different effects on morning stiffness. If you really want to test, if the DR mechanism has any advantage over IR prednisone, you would have to give both at the same time in the evening. My guess is that significance dwindles to a trend. Unless I see such a designed study, I won't prescribe DR prednisone.

Osteoarthritis Satellite Symposium at the ACR 2013 Meeting in San Diego

Very near to the end of the ACR 2013 Meeting in San Diego I went to a Satellite Symposium with the full title of "Prognosis and Treatment of Knee Osteoarthritis Update 2013". Let's have a closer look at some of the data presented at this event.

V. Byers Kraus presented a cell study that concluded: "Chondroitin sulfate ... suggesting that it may inhibit an inflammasome component, assembly, or action" and "this mechanism may also play a role in Osteoarthritis ...“ Too much suggesting and may!

J. Martel-Pelletier presented: "Effects of Glucosamine and Chondroitin Sulfate on Knee Osteoarthritis Structural Changes over Time: Data from the OAI Cohort". It isn't a blinded trial but retrospective data was used. Out of 1300 patients 600 were selected. The presentation showed charts with an extreme amount of numbers. Comparing joint space width (JSW) in patients not taking analgesics two parameters showed a significant difference, but ... 13 other parameters didn't show a significant difference! If you looked at MRI changes and JSW you also had some effects, but these were different, when examined at 12 and at 24 months! Conclusion: "Data from this study provide support for the structure-modifying effects of Glu/CS combination in knee osteoarthritis subjects. [...]". Please no; these effects are more likely to be due to chance. Besides, how can you tell if people taking glucosamine and chondroitin sulfate aren't more health orientated and do more exercises, change diet, and so on?

C.W. Wu presented a study on oral hyaluronic acid for the treatment of osteoarthritis knee pain. The study was small sized and of 51 patients only 40 completed the study. The WOMAC has been non significant or even identical at month 2 and conveniently made a big leap in the next four months to show a significant difference; now explanation for this inconsistent data. A comparison between hyaluronic acid turnover in placebo and verum group has been made, but only in nine placebo patients and ten verum patients. I'd be more careful with conclusions on this set of data. A test on 12 cytokines and chemokines has been done, placebo had an increase and verum a decrease in ALL parameters, but no values were given. Role of each in osteoarthritis? Significant changes or not?

There were other studies, but only on comorbidities, drug utilization, and a DNA-based test.

I don't think that the studies, which I've outlined above, prove anything that warrant the use of glucosamine and/or chondroitin sulfate in knee osteoarthritis. Or maybe they prove indirectly how in vain the drug companies try to find something to base their advertisements on.

Saturday, November 2, 2013

Carpe Diem's Tan Renga Challenge Month #II Mark M. Redfearn's "by the garden path"

by the garden path
an upside down flowerpot
cottage for a toad
(Mark M. Redfearn)

the toad’s too lazy to jump
pond rests in tranquillity

sad song of the rippling rain
but toad hears a happy tune

Carpe Diem's Make the Haiku Complete #3


chanting and humming
gongs immerse the green valley
butterflies at ease

chanting and humming
gongs immerse the green valley
smell from the kitchen

chanting and humming
gongs immerse the green valley
scarecrow sighs deeply

Pain Fallacies

„And pain is all around” ~ Simon & Garfunkel, Bridge Over Troubled Water
Rheuminating pain / As fog and rain return / But the foliage ~ Haiku

The most stupid thing a physician can do, when treating pain patients, is to doubt pain. Pain is a subjective feeling and only the person experiencing pain can tell you if it hurts, where it hurts, and how much it hurts. Doubting pain hurts, too!

1st Fallacy: “I don’t see anything on the X-ray!” – so you shouldn’t complain about pain. I call it the orthopaedics’ fallacy, because lots of patients with low back pain encounter such an attitude. But there’s another trap: any degenerative sign in an X-ray chart may serve as an explanation for pain; often too easy an explanation for chronic pain, which is complex.
2nd Fallacy: “But there’s no inflammation!” – and so you shouldn’t complain about pain. I call it the rheumatologists’ fallacy, because that’s a trap we might fall in. Sometimes inflammation is below detection limit, sometimes we haven’t used all technical equipment like high frequency ultrasound or MRI. Sometimes there isn’t any autoimmune driven inflammation, but there might be pain due to mutilations or post arthritic osteoarthritis. All need extra care!
3rd Fallacy: “If there’s pain, there has to be something wrong!” I might call it the chronic pain fallacy. It’s a trap for physicians and patients as well. After a good diagnostic one shouldn’t turn to more aggressive diagnostic procedures, as this might more harm than yield results. Chronic pain is a disease of its’ own, which gets worse, when there’s input by acute pain, but which doesn’t need this input to hurt badly all over. A good example is fibromyalgia.

Some pains are due to undetected inflammation and need more anti-inflammatory measures.
Some pains might need a change of drug.
Some pains might need a change of attitude.

Let us physicians keep in mind to believe in the pains that patients bring to us!