Joint Pain during Winter

Hardly anyone really likes cold, wet, and windy weather – there’s only one word in the world that really describes this condition: usselig – a word from the language spoken in and around my hometown Cologne (the city with the cathedral, the Kölner Dom). But people with inflammatory rheumatic disease and also people with osteoarthritis suffer even more during this season. And actually it isn’t “Hello darkness, my old friend” – quite a lot of people get the blues during the darker months, which also affects pain and not only mood disorders. Besides the joint pain (arthralgia), these people also suffer from pain in the muscles (myalgia).

It isn’t the lower temperature alone; as inflamed and painful joints are very responsive to the application of local, dry cold packs (ice and cold water in a plastic bag are suited best for the purpose). Decisive for the increased pain is the humidity and some people think also the lower air pressure.

E.M. Savage and colleagues addressed the question: “Does rheumatoid arthritis disease activity correlate with weather conditions?” As the authors are based in Belfast, they have enough humid weather. They concluded: “In this study, rheumatoid arthritis disease activity (as measured by DAS-28) was significantly lower in both more sunny and less humid conditions.”

W.R. Patberg and J.J. Rasker looked at: “Weather effects in rheumatoid arthritis: from controversy to consensus. A review.” They came to the conclusion: “The classic opinion, "Cold and wet is bad, warm and dry is good for RA patients," seems to be true only as far as humidity is concerned.”

Muscles and joints receive less blood during winter as other organs are favored. And the restrictions on movement per se add to lower joint mobility; the synovial fluid loses its lubricity and then pain intensifies – a vicious circle to be broken. Therefore patients should be encouraged to put on warm clothes (not forgetting gloves, hats and scarves) and walk a lot in fresh air. During daytime and especially, when the sun comes out of hiding as this counteracts the blues. However, Vitamin D isn’t produced in large enough amounts during the winter half year (in latitudes like Germany or higher up).

Links:

https://www.prisma.de/magazin/gesundheit/Rheuma-und-Gelenkschmerzen-im-Winter-was-tun,21316928

E.M. Savage and colleagues: https://www.ncbi.nlm.nih.gov/pubmed/25342437

W.R. Patberg and J.J. Rasker: https://www.ncbi.nlm.nih.gov/pubmed/15229951

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What new drugs do we need in Rheumatology?

Sometimes in workshops I have been asked about unmet needs for drugs in rheumatology. At the same time my colleagues and I were looking at new drugs, emerging principles to treat rheumatoid arthritis.

If you look at current pipelines there are several drugs like sarilumab, sirukumab, brodalumab, ixekizumab and biosimilars. We already have five TNF-inhibitors, two JAK- inhibitors, an IL-6-inhibitor, an anti-CD20-agent, a second-signal-inhibitor (CD80 or CD86). Any of these drugs is expensive. Do we need more expensive drugs? Maybe – I won’t rule out that there is a niche for a new principle, but I doubt it. We hear about “promising results” of mavrilimumab (a human monoclonal antibody inhibiting human granulocyte macrophage colony-stimulating factor receptor), but is it coming to the market?

It seems that nobody is working on a drug on the price level of leflunomide. 25 mg of iguratimod (manufactured as Careram by Eisai and as Kolbet by Toyama Kagaku in Japan) [1,2] cost around 1.20-2.40 € per day, which is much less than 52.36 € per day for tofacitinib (Xeljanz) in Germany right now [3].

Iguratimod’s mode of action includes the suppression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). It hasn’t been tested against tofacitinib or baricitinib. But iguratimod has been tested against and in combination with methotrexate [4]. Z. Xia and colleagues have writte in “Results”: “The combination of iguratimod with MTX was superior to iguratimod or MTX monotherapy”. Too bad, they didn’t comment on MTX vs. iguratimod. The “Study of Iguratimod Plus Methotrexate Compared to Leflunomid Plus Methotrexate in Patients With Rheumatoid Arthritis” is portrait as” “The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years” [5].

Maybe iguratimod isn’t the answer to our unmet needs. But I still hope for some drug to emerge that is cheaper than any of the current monoclonal antibodies or the small molecules that have been approved by FDA or EMA.

Links:

[1] http://rheumatologe.blogspot.de/2016/12/iguratimod-new-developments.html

[2] http://rheumatologe.blogspot.de/2014/06/iguratimod-at-eular-2014-meeting-in.html

[3] http://rheumatologe.blogspot.de/2017/05/tofacitinib-xeljanz-kommt-gerade-an.html

[4] https://www.ncbi.nlm.nih.gov/pubmed/26508503

[5] https://clinicaltrials.gov/ct2/show/NCT02275299

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TSORA, Trichuris suis ova in Patients with Rheumatoid Arthritis – Study abandoned

TSORA, there had been lots of interest in this study on patients with rheumatoid arthritis and inadequate response to methotrexate. These patients were randomized to Trichuris suis ova (2500 eggs in a capsule every two weeks vs. placebo). The study aimed at N=25 in each group and had been registered in October 2013. Primary endpoint had been disease activity measured by DAS28 after 24 weeks. The study was a pilot study at Klinik Immanuel Krankenhaus, a clinic for rheumatic diseases as well as natural medicine / phytomedicine in Berlin.

The idea behind is a suppression of immune responses by helminths like Trichuris suis in order to modulate inflammation in rheumatoid arthritis and other diseases.

What do we have? An abandoned study? I don’t know what stopped the study. EU Clinical Trials Register tells us that the study has been prematurely ended. No reasons given. I’ve tried to contact the person mentioned in the study for scientific enquiries, but I didn’t receive an answer so far.

M.A. Pineda and colleagues published a study last year: “From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis.” “ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae.” ES-62 inhibits Th17-cell dependent IL-17 production, but doesn’t affect NK and NK T cell IL-17 production, and therefore the authors think, ES-62 might make a particularly attractive therapeutic for RA. I have my concerns of IL-17 being a target in RA, but that’s another story. Link: http://www.ncbi.nlm.nih.gov/pubmed/25801883

As other scientific groups continue to look for clues in which helminthes may be helpful in fighting RA and other inflammatory diseases, I hope that we’ll get more information on what happened to TSORA.

I have enough space here to add any news!

03.11.2016:

I've just received an email by one of the investigators, who had been in maternity protection and therefore could not answer earlier. The study is incomplete because of insolvency of the sponsor. But she assured that the data, which had been accumulated, will be published. I'll look forward to discuss the results here. 

20.01.2017:

Last weekend I’ve met one of the principal investigators of TSORA. He told me that working on the statistics had just started, but that there’ll be a publication later this year.

 

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Integrative Rheumatology Care Program

The idea of integrative care programs isn’t new. Such programs should promote networks across sectors in health care (primary care physicians, specialists, hospitals) to improve the quality of patient care and to reduce health costs at the same time. It took decades until legislation formed the guiding laws to enable interested health care providers to build such programs and networks.

We’re in the 9th year with our Integrative Rheumatology Care Program. We are the Rheinisches Rheuma Zentrum, Inoges (Rehab facilities, physical and occupational therapy), the health insurance company BARMER/GEK, general practitioners of the region, and of course our patients. We developed a unique model of integrated care for all inflammatory rheumatic joint diseases. The result of our treatment are above average patient satisfaction and show excellent treatment results. We were one of the first clinics in Germany implementing such a program. Patients are treated the entire duration of illness in out-patient , day-clinic as well as in-patient or rehabilitation settings, always the one that is appropriate to disease activity and severity. So far about 700 patients have or still are being treated in our Integrative Rheumatology Care Program. Involved are also more than 230 practicing physicians as cooperation partners, who were all trained in the Rheinisches Rheuma Zentrum. The program already has offsprings at other locations.

A Case Manager (or Rheumatology Care Coordinator) is available on a hot-line for patients looking after quick first appointments and follow-ups, aids, rehab coordination and so on. Important is the involvement of GPs, who fax a screening questionnaire of patients and forwarding these patients to our out-patient clinic. It is only after verifying the diagnosis that patients enter the program.

The program has no restrictions as to drugs. Maybe it’s due to the fact that DAS28, HAQ, BASDAI, RADAI, and other tools are implemented to guide therapy decisions. Maybe the better care keeps the costs down; we hope to publish data on this together with the University of Duesseldorf.

All in all, we're happy with this program and hope that other insurance companies join us.

Typical screening questionnaire for GPs.

Flowchart on how patients enter the program  

Links: 
More on Integrated Care on Wikipedia: 
http://en.wikipedia.org/wiki/Integrated_care

The German text on Wikipedia is better, try to read it by machine translation: http://de.wikipedia.org/wiki/Integrierte_Versorgung

Rheinisches Rheuma Zentrum / Integrierte Versorgung (German text): http://www.rrz-meerbusch.de/de/kompetenzen/medizinische-kompetenzen/innere-medizinrheumatologie/integrierte-versorgung.html 

DMARDs and a proposal for a new nomenclature

J. Smolen and other European rheumatologists published a paper in the Annals of Rheumatic Diseases on proposing a new nomenclature of disease-modifying antirheumatic drugs.

Just now we distinguish sDMARDs, synthetic or chemical DMARDs (also called traditional or conventional DMARDs) and biological DMARDs. 

The authors propose:

-  boDMARDs for biologic original DMARDs (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab or tocilizumab, and also emerging ones like clazakizumab, ixekizumab, sarilumab, secukinumab or sirukumab)

-  bsDMARDs for biosimilar DMARDs (in principle the above mentioned ones, more particularly for the time being etanercept, infliximab, and rituximab)

-  tsDMARDs for targeted DMARDs (small molecules, protein kinase inhibitors), die authors specify “those [DMARDs] that were specifically developed to target a particular molecular structure (such as tofacitinib, fostamatinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib)”

-  csDMARDs for traditional DMARDs (methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts, azathioprin, and others)

Let’s see where the discussion leads us! I would be happy with this more stringent nomenclature.

Smolen JS, van der Heijde D, Machold KP, Aletaha D, Landewé R. : Proposal for a new nomenclature of disease-modifying antirheumatic drugs.

Ann Rheum Dis. 2014 Jan 1;73(1):3-5. doi: 10.1136/annrheumdis-2013-204317. Epub 2013 Sep 26.

http://www.ncbi.nlm.nih.gov/pubmed/24072562

Functionalism or Structuralism in Rheumatology?

What is needed more in rheumatology? An approach from the functionalism viewpoint or from the one of structuralism?

When I studied social anthropology I have been interested in the question of whether functionalism or structuralism would serve the scientific purpose more. Let’s apply a few thoughts of this field to rheumatology.

Of course, we need an approach from structuralism as we deal often in changes of joints and bones. On the other hand, what do we get out of this angle in terms of social functioning? I think that rheumatic diseases are far more than a definition in terms of structuralism. Pain and inflammation have an impact on body and mind. And this impact also works on social functioning and social role, in family, community, and/or work. Pain and inflammation are better looked at from the functionalism point of view. You can see structural damages on X-ray charts or MRIs for instance, but these charts don’t tell you anything about the impact on how the patient in interacting with the physical and social environment. Yet, on a visit at the rheumatologist looking at X-ray charts and talking about possible damages take a lot of time. Also we tend to talk more about lab results than on issues concerning social functioning.

So this short note is striking a blow for an approach from the functionalism angle of view! Let’s use structuralism more for background information, but talk more about the impact on the disease on functioning. In this way I hope that we can restore normality to people, who have been overrun out of a sudden by a disease that will stay and work against them. Let’s talk more about what is possible in term of social functioning and what still needs attention.