A fair point, but understand that many of the trials you cite were for registration purposes, and were constrained by regulators' desire for placebo or placebo-like control, and were not designed for comparative effectiveness.  Such studies are important but as you well know, very difficult to fund and enroll. 

Besides efficacy, how did the adverse event profile change with the combination and change in route of administration? While the combination may be better or slightly better, overall activity will drop off if compliance is not good. Low as welldose mtx is relatively safe and tolerable and efficacious.. Correct? To do a combination study of four agents against three agents might be asking for trouble (ddi and toxicity..)

Dear Shankar Sir, I fully agree with your point. Morever, with a background of methotrexate in most trials that have shown efficacy of biologic agents, it is difficult to say whether how much of the effect was due to methotrexate or due to biologic agent. For example, the PREMIER trial, which looked at adalimumab versus methotrexate. In the arms receiving mono therapy with adalimumab and methotrexate, responses at two years (ACR20, ACR50 and ACR 70) were similar for the mono therapy arms (in fact numerically superior ACR 20 and ACR 50 for the methotrexate mono therapy arm vs adalimumab mono therapy), and only the combination arm was better than either mono therapy arm. Also, until the tofacitinib vs methorexate trial published last year in NEJM, no trials had ever reached an ACR 70 response of 70% as had the TICORA trial. The recent TACTIC trial only reiterates the point that combination DMARD is as effective as biologic therapy, whilst being cost-saving. As Professor O'dell has repeatedly emphasised in various publications, it is more important to treat to target than to treat with a particular agent or group of agents. 

Dear Dr David H Mason,

I agree. Though the reason for the trials was for the registration, but the message across the rheumatology community is somehow to encourage biologics usage. 

The annual cost of conventional DMARDs ranges from US$ 20-US$ 120 in India while Biologics cost about USD 6000-8000 per annum with their Biosimilar versions costing between USD 3000- 4000 per annum. Thats almost a 40 to 80 fold increase in costs.  At least five trials from the last decade — TEAR, RACAT, BeST, Swefot, and TICORA — clearly show that intensive use of conventional DMARDs can produce results that are at least as good as those seen with biologics.

The advantages of biologics over conventional combinations is possibly very small and does not justify the greatly larger cost.

regards

Dear Dr Daniel Rossignol,

Very valid points. Safety is an issue with both types of therapy, but biologics are associated with a two-fold increase in serious infections. Yes, conventional agents are associated with higher rates of GI and other complaints. In the TEAR trial, for example, more than twice as many patients on conventional agents withdrew due to adverse events compared to patients on biologics. 

Most adverse effects with conventional DMARDs are "distressing" rather than serious and multiple approaches exist to mitigate them. A handful of preventive counselling, judicious usage of antiemetics and other symptomatic measures are any day preferable to choosing a therapy that is 2 logs higher.

I cannot comment about other countries, but India that hosts almost 17% of world population, has a per capita income of about US$ 1600 and due to the skewed distribution of wealth almost 80% live below this level (i.e mean income is significantly higher than the median income which is closer to $ 600).  Less than 3% Indian households earn enough to afford biosimilars (if they were to devote their entire income towards it) and less than 1% can afford Biologics on their own. This is because just about 20% of people have any kind of health coverage (the rest pay out of pocket).

So when looked at through this lens, combination DMARDs emerges a clear winner with ":treat to target " approach and the Biologics usgae gets restricted further.

regards

Dear Dr Durga Prasanna Misra,

Couldn't agree more. Well said.

regards

My question is about the trials with the biologics, after working in 2008 with a person with RA who had failed tx with MTX and was taking a biologic to block TNF-alpha, I tested her TNF-a which was high at 191 pg/ml (0-8.1). I spoke to the pharm company to ask about the trials on the drug and was told that no blood labs were used to evaluate the drug, only a symptom questionnaire. This seems incomplete as a drug trial.

I totally agree with Dr. Shankar, we in Pakistan using the same tripple therapy with low dose steroids and getting good results.

From a practical standpoint, most rheumatologists in the US still start RA treatment using MTX, and usually combining it with other oral traditional DMARDS, e.g., Plaquenil. A number of patients will respond well to this initial therapy. Biologics are introduced usually later when oral traditional DMARDS begin to fail the patient, either with insufficient response, or continuous progression of disease. It should be pointed out that even on a biologic, many patients continue to need MTX, with some exceptions of patients who do well on biologic monotherapy. Most of us have patients say on Enbrel or Humira, who actually do not do as well when the MTX is discontinued.  We are continuing the learn about RA and its treatment. RA is not one disease but rather a number of different clinical subsets, some driven by TNFa, other by other cytokines or immune mechanisms. Our current therapeutic approach is not yet based on the precise underlying immunogenetics. Someday, a more precise treatment will be developed based on individual patients' phenotypic profile, as is emerging now in cancer treatment. We are not quite there yet in treating RA.

This discussion continues to be interesting. thanks.

Cari, I am surprised you found TNF in the circulation, as from my understanding, it is typically at very low circulating levels in arthritis.  Even going back to sepsis, it was tough to measure in the circulation, but was at times measurable - and of course the therapy never worked in sepsis.  So ultimately, I think the reason TNF is not tested for in arthritis is that we are treating TNF generated locally at the site of inflammation, and, even if detectable in the general circualtion it would be low and of little use in predicting the course of disease.  In this case, the antibodies are given symptomatically.  

I am wiling to bet though, that a number of people never would have thought you can treat a disease that generates very low or no measurable TNF with and anti-TNF therapy. 

As for combination therapies- it is fortunate that the right combination of 3 or 4 drugs can reduce inflammation, but hitting that right combination is often a guessing game, and with adverse events possible with each drug in a combination, it must take some time to get everything right.  

"Where it can be afforded" is an expression not always used when we talk about  effective combinations of drugs, but it is real..  

I look forward to seeing how the new health care mandates with testing drugs and combinations under real-world conditions with huge databases will soon sort out the real value of meds. 

To Cari, RA drug trials don't consider just symptoms in the final evaluation of the potential efficacy or lack of it thereof of a given drug; there are validated measuring instruments such as the ACR20, 50, and 70, DAS28, etc, and these include objective measures such as swollen joint count and blood inflammatory markers, e.g., sed rates and CRP. Almost all biologic drug trials also include radiographic data of involved joints over time,

To Daniel: the treatment of RA and of any disease for that matter is best done on a individual basis, stemming from and based on an optimal doctor-patient relationship. Healthcare mandates and huge databases should have no place in the evaluation and treatment of individual patients. We are presently being inundated with non-sense health mandates that add nothing to the quality of the care provided; insurance companies for years have been trying to practice medicine without a license. I understand trying to save money; however, the real value of a given medical approach should be discussed and evaluated with the patient in front of you, based on individual patient response. Different people react differently to different medications. It is the treating physician who would know best that a given individual patient responds better to this particular TNF inhibitor and not to the next one or a biosimilar. Clinicians deal with this problem on a daily basis. I understand that administrators and CEOs of insurance companies would not know this (do they care?), but then again, they are not physicians treating patients. In the end, we don't treat just diseases; we treat human beings suffering from diseases; not two patients are the same,    

Fully agree with you.

If we really need to know what's better, safer and cheaper (not least) we have to randomize the first biologic! This kind of study would obviously be done by clinicians.

If it's not, all the informations have not statistical reliability.

I think there are already good studies that do show that triple therapy can have similar outcomes to biologic therapy e.g. SWEFOT, O'Dell, TACIT trials. So in countries where cost is a constraint, I think that triple therapy is the way to go for patients with severe disease.The problem is to persuade patients to take multiple medications all at the same time and be compliant, whereas MTX orally plus an injection of a biologic is much simpler. If cost was not an issue, biologics would be the easier option.

The other caveat with triple therapy vs biologic is the possibility that radiographic progression continues in the triple therapy group compared to almost no progression in the biologic arm. This may be because there is a lag in effect in the triple therapy group which gives time for the erosions to start, compared to the faster onset of the biologics.

It is disappointing that even with biosimilars on the market, the price of biologics have not reduced to an affordable level for non-re-imbursed markets. We can continue to hope!

I agree with Dr. Swan Sim Yeap; it appears that at first, the price discount for biosimilars would not be any more than 30%; later, perhaps, they will be more discounted, 

in a resource constrained setting like in india, we try to take a middle path in our clinic. we document failures of at least 3 DMARDs in full dosages before going to biologics. in case of affordability issues, we start second line DMARDs with low dose steroids.