2013 was a year of major changes in healthcare reform with increasing numbers of rheumatologists adopting new methods of record keeping, prescribing and tracking patient progress. Whether motivated by mandates, reimbursement or the desire for improved patient care, the practice of rheumatology is changing as are the therapies we employ. There have been several notable advances or introductions in rheumatology management this year that will have an intriguing effect on patient care. These are presented in no particular order and were drawn from my ongoing review of news and literature germane to the optimal care of the patient with rheumatic disease.
Biologics Show Versatility and Growth. There are currently 13 FDA approved biologics for use in rheumatology – nine in rheumatoid arthritis, six in psoriatic arthritis, five in ankylosing spondylitis, three in juvenile idiopathic arthritis, one each for systemic lupus erythematosus and gout. These agents have substantially advanced treatment paradigms and provided insight regarding the immunopathology underlying these disorders. 2013, several of these agents were approved for new disease indications – certolizumab (Cimzia) for PsA and AS; ustekinumab (Stelara) for PsA; tocilizumab (Actemra) for polyarticular JIA; canakinumab (Ilaris) for systemic- onset JIA; and anakinra (Kineret) for the cryopyrin associated periodic syndromes (CAPS).
In addition to their biologic specificity and high expense, these biologics are notable for their parenteral administration and can be given by intravenous or subcutaneous injection. Interestingly, abatacept (Orencia), tocilizumab (Actemra) and golimumab (Simponi) have been further studied such that these agents can either be given as and IV or SC self injection according to patient or payor preference. Each of these have shown the IV and SC options to be equally effective and safe in RA patients. This versatility appears to be popular and important to patients and providers alike.
Tight Control in Psoriatic Arthritis. The TICOPA trial demonstrated results similar to that seen in RA; wherein achieving tight disease control with a treat-to-target strategy leads to super outocomes. Patients who received intensive, monthly joint assessments and protocol-driven drug changes to achieve joint counts <3, had 50-100% better ACR 20/50 (articular) and PASI75 (skin) outcomes compared to those receiving routine/usual assessments every 3 months (1). Clearly rigor promotes vigor!
Nutritional Strategies and the Microbiome. There is increasing popularity and adjunctive utility of probiotics and/or antiinflammatory diets (gluten-free, low carbohydrate, high protein, omega-3 or Mediterranean diets) in the control of inflammatory disorders like RA and psoriasis. One recent placebo-controlled randomized trial showed that probiotics improved disease activity and lowered proinflammatory cytokine levels in RA (2). Another exciting area of research has focused on the oral/intestinal microbiome that show quantitative and qualitative differences in flora based on activity or treatment. In my opinion, it is tempting to link these nutritional strategies with microbiome alterations in the gut, gingival or skin with parallel changes in immune responses (3, 4) in conditions like RA, psoriasis and Crohn’s colitis. Patients are asking about diet change and no longer accepting non-commital or perjorative advice like “eat right and exercise more” without specific guidance. The adage, “You are what you eat” may take on greater meaning if this research tracts becomes more revealing and merge.
Modifiable Lifestyle Factors and Rheumatoid Arthritis. Periodontal disease, smoking and obesity continue to be linked to the onset, risk and severity of RA. According to the CDC, periodontitis affects 47% of adults over the age of 30 years (approximately 65 million US adults) and is more likely with advancing age, lower education and lower socioeconomic status (5). It may be one of the factors underlying the long-held association between lower education and socioeconomic status with poor outcomes in RA. Smoking is a known risk factor for periodontal disease but has also been linked to multiple rheumatic disorders including RA, JIA, AS and SLE. Lastly, obesity has been shown to be a risk factor for developing osteoarthritis and RA, but has also been shown to impair responsiveness to conventional DMARD and aggressive biologic therapies – and is unrelated to fat mass and drug distribution. Presumeably, proinflammatory adipokines (eg, leptin) and mechanical factors combine to make usual drug responsiveness an uphill struggle. While smoking, fast-food and poor dentition may predispose to horrible outcomes in RA, there is, paradoxically, consistent evidence that regular alcohol consumption has a significant disease modifying effect (6). However, it seems irrational to hope for an alcohol advantage when there are so many other safer alternatives.
Biosimilars. 2013 saw the introduction of “Inflectra”, the biosimilar form of currently marketed infliximab, as the first EMA approved biosimilar for use in Europe. Biosimilars may revolutionize the treatment of rheumatic disease by showing equivalent efficacy and safety at a reduced cost. However, they are likely to impact in the rest of the world before becoming available in the US after 2016. The question remains, is a discounted biologic enough of a cost savings to motivate patients or physicians to use them? Or will their novelty be overshadowed by prescribers safety concerns and a history of using the parent compound for more than a decade? For those who aspire to a personal beauty or biosimilars - time and money will tell.
Spinning the Biologic Wheel. While biologics have increased the options and odds for disease control in RA, most rheumatologists have relied heavily on the use of TNF inhibitors, evidenced by nearly $25 billion in worldwide sales for Humira, Enbrel, and Remicade in 2012 alone. When the need for althernative therapy arises, the 2nd choice biologic is invariably another TNF inhibitor. In 2008, I surveyed 373 US rheumatologists about what they would use after their first TNF inhibitor failed and 74.5% preferred a second try with another TNF inhibitor. Such practices are based more on allegiance than evidence. This “dance with the one that brung yah” paradigm reflects practitioner preference more so than controlled trial data. However, by the end of 2013 we now have a many comparator trials that show after failing an initial TNF inhibitor, there is equivalent or better efficacy when targeting different mechanisms with abatacept, rituximab or tocilizumab, compared to another TNF inhibitor (7-11).
When/Which DMARD to Stop? The BeST study was the first trial since the step-down pyramid of Wilske (12) to examine the effect of withdrawing DMARD therapy over time in RA. In the BeST trial, patients treated with infliximab and MTX who achieved low activity by 9 months, were continued on MTX alone. Over half of the patients maintained their response without a TNF inhibitor. Several recent trials have furthered our ability to withdraw therapies appropriately (13-15). One take home message is the longer a patient is in remission or low disease activity (LDAS) the better his/her chances for sustained control on less therapy. Hence, DMARD withdrawal should not be attempted unless remission is present for 12 months or more. Next, for patients treated with MTX plus a TNF inhibitor, it is better to withdraw MTX rather than the TNF inhibitor, as flares and x-ray progression are more frequent with MTX alone. Lastly, for patients in long-standing LDAS or remission, lower or less frequent doses of a TNF inhibitor may be used without a substantial loss of disease control. In practical terms this means that patients in remission (or LDAS) can “space out” their TNF inhibitor injections by increasing or doubling the dosing intervals. When a newly diagnosed RA patient asks “how long will I have to take these medications or biologics”, I now have evidence to back up my response of “for a long time; When we achieve and maintain disease remission for more than 12 months, then we can talk about drug withdrawal (likely MTX) or less frequent dosing (of the TNF inhibitor).”
Small Molecules Have Small Impact. New trends in drug development include the development of small molecule inhibitors of intracellular mediators, such as Janus Kinase (JAK). These agents have the advantage of oral administration, rapid onset and biologic-like outcomes. The good news is that tofacitinib (Xeljanz) was FDA approved in 2012 (and approved in Japan and Switzerland in 2013) for twice daily oral use in RA. Unfortunately tofacitinib is expensive as its biologic competitors and has been twice denied the EMA (the FDA equivalent agency for the European Union) and not yet been approved in Canada. Another small molecule Syk-kinase inhibitor, fostamatinib was withdrawn from further development owing to significant but sub-par clinical efficacy. The uptake and use of tofacitinib in the US has been slow, presumably because of insufficient experience with the drug or concerns about its safety profile. These events are both sobering and challenging to the companies currently developing other JAK inhibitors and small molecule drugs for rheumatic diseases.
Triple DMARD Therapy. There have been two recently published large trials (TEAR & RACAT) that advocate for the equivalent utility of treating RA with MTX+Plaquenil+Sulfasalazine (triple DMARD therapy) when compared against MTX + Enbrel (etanercept). These trials show more rapid responses and better X-ray outcomes when MTX+Enbrel is used initially. However, if the primary goal is clinical effect 12 to 24 months down the road, both regimens are equal in efficacy and safety. Hence, if this was my mother I would suggest she take MTX+TNF inhibitor. However, if this were my irascible mother-in-law I would give her triple DMARD therapy and save the money (16,17)
- Coates LC, et al. The TICOPA protocol (TIght COntrol of Psoriatic Arthritis): a randomised controlled trial to compare intensive management versus standard care in early psoriatic arthritis. BMC Musculoskelet Disord. 2013 Mar 21; 14:101.
- Vaghef-Mehrabany E, et al. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition. 2013 Dec 17.[Epub ahead of print]
- Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol. 2014 Jan; 26(1):101-7.
- Bingham CO 3rd, Moni M. Periodontal disease and rheumatoid arthritis: the evidence accumulates for complex pathobiologic interactions. Curr Opin Rheumatol. 2013 May; 25(3):345-53.
- Thorton-Evans G, et al. Periodontitis among Adults Aged ≥30 Years - United States, 2009–2010. MMWR 2013; 62(03);129-135
- Jin Z, et al. Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies. Ann Rheum Dis. 2013 Jul 29. [Epub ahead of print]
- Finckh A, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum. 2007 May; 56(5):1417-23.
- Chatzidionysiou K, van Vollenhoven RF. Rituximab versus anti-TNF in patients who previously failed one TNF inhibitor in an observational cohort. Scand J Rheumatol. 2013;42(3):190-5
- Soliman MM, et al. Rituximab or a second anti-tumor necrosis factor therapy for rheumatoid arthritis patients who have failed their first anti-tumor necrosis factor therapy? Comparative analysis from the British Society for Rheumatology Biologics Register. Arthritis Care Res. 2012 Aug; 64(8):1108-15.
- Manders S, et al. Mode of action change not necessary after failing the first tumor necrosis factor Inhibitor: Preliminary Results of a Randomized Controlled Trial. ACR Abstract #1419, 2013
- Harrold LR, et al. The comparative effectiveness of abatacept versus anti-tumour necrosis factor switching for rheumatoid arthritis patients previously treated with an anti-tumour necrosis factor. Ann Rheum Dis. 2013 Dec 2 [Epub ahead of print]
- Wilske KR, Healey LA. Remodeling the pyramid--a concept whose time has come. J Rheumatol. 1989 May; 16(5):565-7.
- Smolen JS, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomized controlled OPTIMA trial. Lancet. 2013 Oct 25. [Epub ahead of print]
- Smolen JS, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomized controlled trial. Lancet. 2013 Mar 16;381(9870):918-29
- Pope JE, et al. The Canadian Methotrexate and Etanercept Outcome Study: a randomized trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis. Ann Rheum Dis. 2013
- O'Dell JR, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013 Jul 25; 369(4):307-18.
- Moreland LW, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012 Sep; 64(9):2824-35.