Rheumination

Pneumocystis-

The patient was known to have dermatomyositis with minor muscle and skin involvement but a rapidly progressive pulmonary fibrosis for which he was taking moderate doses of prednisone and oral cyclophosphamide.He was admitted with a severe deterioration in pulmonary status and was shortly admitted to ICU and subsequently intubated. Bronchoscopy quickly confirmed a diagnosis of Pneumocystis and the young patient was able recover after a short but intense battle. Such is not always the case. The acute onset and rapidly progressive disease is the norm for this group, unlike the HIV population, but the outcome is not always this good. In fact,reports of up to 65% mortality in ICU admitted patients have been published. This case sent me scurrying off to review pneumocystis prophylaxis, something that I haven't really felt compelled to do since the nasty days of my residency when the first AIDS cases arrived on the floors and pneumocystis lurked everywhere.
Fortunately, just weeks ago there was a review on pneumocystis prophylaxis in the Mayo Clinic Proceedings. This was a meta-analysis of studies involving prophylaxis in non-HIV immunosuppressed patients. Among the studies pulled was a Mayo article from 1996. In that study they reviewed all cases of PCP in non-HIV patients over a six year period. They found 116 cases with a breakdown that showed highest risk among hematological cancers, followed by transplant patients and finally inflammatory diseases, including several rheumatological patients. This included five patients with temporal arteritis, three with RA and only two Wegeners patients. I suspect the low numbers in Wegeners is because prophylaxis was already fairly common among these patients. Their conclusion was that the patients who required prednisone of >16mg/d for longer than 8 weeks were at risk.
The meta-analysis itself also came up with some interesting numbers. Their discussion centered around the risk and benefit of PCP prophylaxis. They showed that the risk of adverse effects of Septra prohylaxis was small, 1 in 32 patients, and that the risk of serious side effects, such as Stevens-Johnson or marrow aplasia,was in the order of 7-8/100,000. They calculated that any diagnosis carrying a risk of contracting PCP of >3.5% was worth prophylaxing. This would include Wegeners patients but not the other inflammatory diseases. In no study, however, did I find any specific reference to cyclophosphamide, azothiaprine, mycophenolate mofetil or any other agents used in the rheumatological arena.
When I asked an infectious disease friend of mine about the matter, I was informed that the HIV patient population receives prophylaxis when the CD4 count falls below 200, and that this probably holds for our population as well. I looked into this and found two studies in Chest from 2000 and another from 2005. Both studies concluded that low CD4 levels were highly correlated with PCP infection, in all non-HIV diseases. In the first study, 91% of patients with PCP had a CD4 count of less than 300.
Overall then PCP prophylaxis would appear to be waranted in all treated Wegeners patients, and possibly all patients receiving prolonged high dose corticosteroids. This would include the majority of temporal arteritis patients as well as many sick lupus and vasculitis patients.This certainly isn't my practice at the moment. There is still insufficient evidence concerning the use of immunosuppressors, except in the case of methotrexate in RA where there appears to be little risk. CD4 counts may help us out here, if these preliminary studies should be replicated. It may well be that we can institute prophylaxis at the onset of treatment and reassess once disease activity has been controlled, based on the CD4 count.

Iron Overload?Wrenched Back?Subclavian Steel?

via Streetanatomy

Narrow Focus on Aortitis

This MR angiogram of a patient with Takayasu's vasculitis was presented by Radiology Picture of the Day with a caption suggesting that Takayasu's is the only vasculitis that causes aortic stenosis. I doubted this, given the well documented involvement of the aorta in Giant Cell Arteritis (GCA) and the even more common involvement of the aortic arch vessels with stenosis. I was pretty sure I could find at least one case on the net. My search did find many cases of aortic involvement with aneurysm, dissection and rupture, but I couldn't find any cases of aortic stenosis. MRI apparently shows aorta wall edema quite frequently but intimal hyperplasia with stenosis is apparently limited to smaller vessels. A good review of the pathology/pathophysiology of the disease can be found in the New England Journal from 2003.

Top 10 Prescriptions for Rheumatological Conditions

According to IMS, the top 10 prescriptions for rheumatoid arthritis in Canada, by diagnosis and therefore not necessarily by rheumatologists, are:

1. Methotrexate
2. Hydroxychloroquine
3. Folic Acid
4. Prednisone
5. Celecoxib
6. Leflunomide
7. Naproxen
8. Gold Thiomalate
9. Etanercept
10. Methylprednisolone

Weird eh. I can imagine that Arava ranks high because some provincial formularies require it's use before ant-TNFs, but gold higher than Enbrel?

Come On.....Calcium?

If there is one easy variable out there in clinical rheumatology, it has to be calcium. Calcium is good, even great. Sure sometimes it causes tummy upset, or irregularity, but how bad can it get. Apparently, quite bad. At least that is what a recent study in the BMJ is suggesting(free full text). Bolland et al have concluded that calcium supplementation, in typical therapeutic doses, might increase the incidence of cardiovascular events.
Previous evidence, although slim, has given hope that calcium may actually decrease cardiovascular disease by decreasing blood pressure and improving HDL/LDL ratios.(As discussed in their intro) Their own study was a secondary analysis of a calcium supplementation study for osteoporosis. 1490 patients were given 1000mg of calcium citrate or placebo and their cardiovascular events were recorded, initially by patient report and subsequently by verification. They recorded 45 events in the Ca group and only 19 in the placebo group which was significant. (p=.01) They tried to verify these findings and even searched the New Zealand database for unreported events, something that I don't think was planned intially but done largely because they were freaked out by their own results. This resulted in a decrease but not the elimination of cardiac risk. The relative risk was decreased from 2.12 to 1.47 with this hardy, but unsuccessful attempt at calming my nerves.
Now there was some serious problems with this study. Almost half of the patients dropped out before the five year study was over. It was after all a secondary analysis, and was pretty small by cardiovascular studies. Importantly, it was done in New Zealand and it is possible that the laws of physics are all topsy turvy when your upside down at that end of the planet.

But still. Come on. Calcium?

ARTritis

Demonstration of the new DAS 588 joint count:

The actual show is worth a few minutes.

via weirdasia (I think)

Judah Folkman

Judah Folkman died this week in Denver Colorado. Folkman is not a familiar name among rheumatologists but his legacy may well make inroads into the realm of rheumatology in the not so distant future. He was the father of the field of angiogenesis, a primarily oncological field which he pioneered despite considerable early skepticism.The idea that tumours may be inhibited by preventing the growth of blood vessels is now widely accepted and has spawned an entire industry. Other fields have taken notice, including rheumatology. In Boston, at the last ACR meeting, Folkman presented a summary of his work and how it may be of interest to rheumatologists. Among other things, it was interesting to see that he considers celecoxib to be one of the angiogenesis inhibiting drugs. It is obvious that we are far from applying his research to our own field but it was nice to hear it from the man who started it all. A nice summary of his life and accomplishments can be found at this Harvard Science site.

Bisphosphonates and Avascular Necrosis

You're going to hear about this one. In The Journal of Rheumatology there is a newly published article (online) concerning the risks of avascular necrosis (AVN) and bisphosphonate use. The results, that there is in fact an increase in the incidence of AVN with the use of all oral bisphosphonates, was presented on the CBC national news tonight.
The study was a database study using the Quebec medicare database. The cohort studied included 87,837 patients in which 196 cases of AVN was discovered, for an overall incidence of 26.7 per 100,000. Two important factors: the patients had all been admitted to hospital, and the authors were unable to distinguish between AVN of the jaw( a site thought to be fairly specific to this class of drugs) and AVN at other sites. The 196 cases were matched with 1960 controls to perform their analysis. Interestingly, 18.4% of the cases were also taking corticosteroids, another obvious risk factor for AVN, but so were 5.6% of the controls. Once this and other co-morbidities were controlled for the adjusted relative risk (RR) for all oral bisphosphonates was 2.87. Individually the risks were: alendronate 2.87, etidronate 2.43, risedronate 3.34. These differences were not significant. Further analysis showed that the risk was for both present and past users. The average time to the event was two years of treatment with bisphosphonates.
This is obviously an important study but of limited value to the clinician. The true incidence may be way off. I don't know how often AVN of the jaw is admitted to hospital, but often AVN of the hip is not. Even when they are, they are often admitted for total hip replacement and the admitting diagnosis would likely be OA rather than AVN. Secondly, there is a lot of corticosteroid on board and though this is accounted for in the analysis, I am still somewhat leary, Lastly, AVN of the jaw and other sites could not be separated and this is a big disappointment given that this condition is likely more specific to the use of bisphosphonates.
The numbers overall are rather encouraging though. An incidence of about 1 in 4000 is pretty rare, even if we bump up the numbers to account for the above-mentioned deficiencies. I can't see this competing with the gains of this class of drug. 18.4% of the cases were taking corticosteroids. Would anyone hold back bisphosphonates for this group? Perhaps though it might stop the the creeping overtreatment we've all witnessed . It seems to me that more and more patients are receiving these drugs with no clear indications, and the threat of a severe side effect may bring this practice back into line.

Synviscerated

There is no rationale for the continued use of hylan in patients with OA of the knee, either in practice or in clinical research.

I was discussing viscosupplementation with one of my patients today when this line came to mind.It's good to see a researcher willing to conclude with such conviction." Synvisc bad ". Case closed. But it's also a little odd to see a researcher assert that his/her research has definitively resolved a problem. Others can say it about the study, but the researcher themselves? But this is the case of Juni et al., in november's Arthritis and Rheumatism. And it is the kind of study we've been waiting for. A head to head comparison between Synvisc (crosslinked hylan) and two HA products, Orthovisc (from rooster comb) and Ostenil (bacterial source). No funding by pharmaceutical companies but rather the Swiss government, and including pretty good numbers, 660 patients altogether. They randomized the patients to the three treatments and evaluated them at three and six months, followed by a second cycle for those willing, up to 50%. (They couldn't afford to retreat everyone). The authors found no difference in the three treatments and a slight increase in the number of side effects of the synvisc, primarily post injection flares. Of interest is the fact that because no placebo was used, they couldn't say if any of the treatments were actually effective, only that they were equal in their effects or lack thereof.
I hardly think this is the last word, despite the author's assuredness. For one, I can't really see that this study is any less biased than the pharmaceutical funded studies, given that big government has as much financial interest as big pharma. The author's rather assertive tone makes me wonder if he didn't have it in for Synvisc all along, and of course, there are probably other studies in the pipeline. At the same time,given these results, paying a premium for Synvisc becomes a lot harder to rationalize.

Celebrex for Angina

Patients often believe that Celebrex was removed from the market at the same time as Vioxx. When I prescribe it for them they often look at me like I have just suggested arsenic or thalidomide. I have to decide whether or not a long explanation of the various NSAIDs and their toxicity profiles is worth it, or whether I should just move along to another drug. It was surprising then, to see an an article in The Lancet describing a study which looked at celecoxib treatment after stent implantation for coronary artery disease. I could just imagine the patient consent form and the ethics review procedure. Sure, all patients received both aspirin and clopidogrel as well, but it was still rather gutsy to add celecoxib. Interestingly, the reason for its use was the antiproliferative effects of the drug. It turns out that celecoxib, through a non-cox pathway, can inhibit the formation of vessel smooth muscle.
In the study, 136 patients received the celecoxib with an equal number of controls. At six months there was a significant decrease in the amount of restenosis as well as a decrease in the number of cardiovascular events. In the six month period, only one subject in the celecoxib arm suffered a non-fatal infarct, while there was a single death in the non-celecoxib group.
Celebrex for angina patients, who'd have guessed?