In last month's Musings, I reflected on the need for rheumatologists to learn how to "turn and keep down the heat" related to the inflammatory processes that burden our patients in order to protect them not only from immediate joint and organ damage but also from long-term collateral damage: functional limitation, lymphoma risk, premature osteoporosis, early mortality. I reviewed the advances in our knowledge of the pathophysiology of rheumatic diseases and looked forward with hope to our new biologic therapies.
Now, we come to the question of when to use our broad array of new drugs. This month, we focus on the first "window of opportunity" - the critical nature of early disease.
The early phase of RA is of key clinical and pathogenetic importance because the inflammatory process is at its height of activation and the "at risk" level of joint inflammation and rate of bone loss are maximal. Thus, this is clearly the "window of opportunity" and is critical to the future of the patient's joints and internal organs. Emery has noted that treatment has a contrasting effect on inflammation and function. Inflammation responds to intervention with disease-modifying anti-rheumatic drugs (DMARDs) with a steady improvement that is largely independent of the duration of disease. In contrast, the final functional status is determined by the duration of symptoms before institution of therapy. (See Figure 1) "There is a level of disability in an individual above which reversibility is unlikely". Thus, early intervention is vital if long-term functional limitation is to be avoided.
Note the differences between the responses of inflammation and function to DMARD institution.
Wrestling with Ambiguity
Making a decision on treatment is much easier for the person with "difficult" RA - go full speed ahead and use your cruise missiles because so much is clearly at stake; you know your enemy and are meeting him head-on. But the situation is ambiguous very early on during the initial "stirrings" of joint inflammation, when there isn't even a universally accepted name for the illness other than undifferentiated polyarthritis, an illness that has many potential destinies. It can resolve on its own by running out of steam or move on to a more chronic and damaging disorder.
In order to make optimal treatment decisions, important facts must be appreciated about the presentations, personalities and outcomes of inflammatory joint disorders. And that requires answering more questions:
The initial stirrings of inflammatory joint disease
Early arthritis clinics in Europe, and some studies in the U.S., have generated critical information about the very earliest and embryonic phases of inflammatory joint disorders, only some of which eventuate in what we all call - and ACR criteria define as - rheumatoid arthritis. In those patients who present within a few months of the onset of joint inflammation in two or more joints, nearly 50 percent who are followed for up to 5 years have a complete remission of their arthritis, never evolve into full-blown RA and are free of joint damage; they do this with or without DMARD, NSAID or steroid treatment. Various names have been given to these patients including undifferentiated polyarthritis syndrome or early inflammatory polyarthritis.
When first entered into the Norfolk Arthritis Register, only 38% of these patients could be classified as having RA using the ACR RA criteria. However, 66% of patients satisfied the criteria when applied cumulatively over 5 years from symptom onset. This demonstrates that early inflammatory polyarthritis is indeed frequently undifferentiated at onset and may remain so for some time. It is "impossible to specify a time by which differentiation will be complete, or before which it cannot of have occurred." Fifty percent of these early polyarthritis patients are seronegative for rheumatoid factor and have normal or low ESRs and CRPs. Some of them may satisfy ACR criteria for RA early on but later on they do not.
It is important to appreciate that the 1987 ACR revised RA criteria were developed by employing patients with classical, definite longstanding (7 years) RA, many of whom already had developed erosions, rheumatoid nodules and clearly had elevated acute phase reactants such as ESR and CRP. Thus, these ACR RA criteria cannot and should not be employed in patients with early RA or undifferentiated polyarthritis. The use of such standard criteria is clearly inappropriate since, by the time the criteria are satisfied, the opportunity for early treatment would have been missed.
In this group of patients, diagnosis is less relevant than risk prediction. Very early arthritis may very well be a symptom of a spectrum of different diseases, with a heterogeneous outcome. Predictive constructs to define those patients who will or will likely not go on to develop progressive, joint-damaging and functionally-limiting seropositive RA have included positive rheumatoid factor (RF) or combinations of RF with anti cyclic citrullinated proteins (CCP), elevated CRP, early development of erosions, and certain patterns and extent of joint inflammation. The early use of MRI and MRA or ultrasound may very well be helpful in this context because they can give us an "early warning sign" of already present damage or the development of erosions despite treatment.
Risk prediction is essential to identify which patients with early inflammatory polyarthritis have the potential to develop persistent destructive disease -- in order to treat them as early as possible, while avoiding inappropriate treatment of those with other forms of arthritis or those destined for spontaneous remission. Unfortunately, foolproof predictive algorithms do not exist.
Thus, while some authors adopt a "wait and see" approach to treatment in these undifferentiated polyarthritis patients, employing short courses of steroids and NSAIDs, others employ antimalarial drugs, sulfasalazine or methotrexate along with NSAIDs and steroids to bring down the inflammatory thermostat.
Clearly, duration and severity of the polyarthritis and its attendant functional limitation should be factored into this decision, made in partnership with the patient. Since the "window" may very well be invisible and the personality of RA is well-known, decisions have to be made on a patient-by-patient basis. However, some studies do titillate us with the likelihood that aggressive DMARD treatment in the very earliest phases of disease may help to abort it; whereas, later treatment may not. Studies are needed to elucidate the inflammatory, immunologic, clinical and predictive characteristics of this stopping off point for polyarthritis on the way to either seropositive RA or remission. Figure 2 defines the various routes that early polyarthritis can take, and figure 3 shows results of Wolff's 1993 important study that nicely describes the issues at hand2. The use of microarrays, cytokine profiling and correlations with clinical outcomes will likely advance our knowledge about this important problem.
Potential outcomes of early inflammatory arthritis.
Results of the Wichita cohort study of patients who present with polyarthritis.
Initiating DMARDs in Early Rheumatoid Arthritis
Accumulating evidence suggests that inflammation and destruction, and thus disability, may be more effectively treated and prevented if the underlying inflammatory and immunologic processes are stopped early in the course of the disease. However, RA is often difficult to diagnose in its early phases because it may have atypical presentations, serologic markers like RF may be absent, and plain X-rays may not show erosions. In the early arthritis populations from the Leiden early arthritis clinic, the arthritis had disappeared in 60% (self-limiting disease) after 2 years. In 40% of the patients, however, arthritis was still present at 2-year follow-up or had extended. Of these patients with persistent arthritis, 60% had already developed joint erosions at 2-year follow-up.
It is important to note that all features of chronic synovial inflammation can be observed in so-called early RA. This suggests that no arguments exist for the effect of therapeutic intervention on synovitis varying in different phases of RA.
It is for this reason that RA patients should be started on a single DMARD therapy within the first 2-4 months of symptom onset, this being rapidly stepped up with regard to both dose and the addition of other conventional DMARDs, in an attempt to suppress all disease activity. Nothing less than the attainment of no evidence of disease (NED) is acceptable because inflammation needs to be thought of as an inherently damaging process if left to its own devices. Only with time and new information might we be able to correctly characterize the true personality and intent of the illness.
The use of low-dose steroids as a bridge therapy until DMARDs take over is also appropriate and generally safe. If patients do not show a satisfactory response after 3 months of maximal dose methotrexate in combination with other conventional DMARDs (sulfasalazine, hydroxychloroquine, leflunomide), anti-TNF medications should be considered.