Spectrum of rheumatoid arthritis and initial assessment of inflammatory arthritis

The term ‘rheumatoid arthritis’ (RA) describes a spectrum of diseases which, in their more severe forms, may lead to several outcomes (related to each other) that substantially influence important aspects of the afflicted individuals’ lives: the disease(s) are associated with pain, stiffness, fatigue, impairment to perform everyday tasks, disability, loss of gainful work (paid or unpaid) or employment, loss of quality of life and even premature death . Given these possible sequelae, it is evident that it is the most important goal of treatment to substantially influence the course of disease and thus to avoid or at least delay these outcomes. Observations on patient cohorts as well as advances in genetic knowledge have provided insights in the variability in the course of the disease as well as the factors contributing to more favourable as well as severe outcomes and/or responses to treatment . From these studies, it has become clear that there are subsets of patients, particularly those with lower inflammatory activity, negative rheumatoid factor or anti-citrullinated peptide-antibodies (ACPAs) and/or absence of genetic risk factors , that do comparatively well even without aggressive treatment, whereas another group of individuals will have progressive disabling disease with high risk of joint destruction and substantial and rapid loss of quality of life. Therefore, it seems necessary, particularly in the very early periods of the disease, when the usual ‘classification criteria’ are not applicable, to apply some kind of risk assessment in order to estimate the likelihood of a given patient to develop RA. One of these risk-assessment strategies incorporating the type of clinical involvement, sex, age and autoantibodies has been recently proposed and validated independently . However, these scores allow the correct classification of only about 70% of early-arthritis patients–a considerable amount of uncertainty remains, particularly in the light of having to decide to start possibly harmful treatments. Nevertheless, it has been clearly demonstrated that the time frame within which these decisions should be made is rather short . Most rheumatologists defined ‘early’ arthritis as a disease with no more than a 3-month duration of symptoms .

Cure and prevention

Conceptually, ‘cure’ of a disease means that, after a period of ‘absence of health’ the affected individual regains full health without continuous treatment. RA is regarded as a chronic inflammatory disease whose causes are still unknown but appear to be multifactorial with genetic, environmental, nutritional, behavioural and social factors contributing and accumulating their impacts on any given susceptible individual over a period of time until the disease emerges with its first symptoms. Thereafter, RA progresses with cumulative damage to joints and, sometimes, soft tissue and internal organs. In this framework, ‘cure’ appears to be a very ambitious goal with relatively low probability of ever occurring. ‘Prevention’, however, has several stages: ‘primary prevention’ refers to methods designed to avoid the occurrence of disease or impairment (e.g., the provision of a balanced diet to avoid malnutrition or immunisations to avert infections and their sequelae); ‘secondary prevention’ (sometimes referred to as ‘intervention prevention’) is usually directed at those identified within the targeted population as ‘at risk’ and thus refers to early diagnosis and treatment to shorten illness episodes and to limit disease sequelae; tertiary prevention involves both the treatment of the identified problem or disease and restoration of the individual to a full state of functioning within the targeted population . Definitions of both secondary and tertiary prevention imply that some limited amount of impairment might remain and, thus, are the more likely scenarios when discussing outcomes of interventions in (rheumatoid) arthritis. Moreover, as the bulk of the literature on RA implies, even if only minimal disease activity is reached (frequently referred to as ‘remission’) most patients appear to be in need of at least some amount of treatment . This article focusses on secondary and tertiary prevention, because primary prevention (i.e., risk avoidance or modification of lifestyle, social, economic or environmental factors) is beyond its scope.

Cure and prevention

Conceptually, ‘cure’ of a disease means that, after a period of ‘absence of health’ the affected individual regains full health without continuous treatment. RA is regarded as a chronic inflammatory disease whose causes are still unknown but appear to be multifactorial with genetic, environmental, nutritional, behavioural and social factors contributing and accumulating their impacts on any given susceptible individual over a period of time until the disease emerges with its first symptoms. Thereafter, RA progresses with cumulative damage to joints and, sometimes, soft tissue and internal organs. In this framework, ‘cure’ appears to be a very ambitious goal with relatively low probability of ever occurring. ‘Prevention’, however, has several stages: ‘primary prevention’ refers to methods designed to avoid the occurrence of disease or impairment (e.g., the provision of a balanced diet to avoid malnutrition or immunisations to avert infections and their sequelae); ‘secondary prevention’ (sometimes referred to as ‘intervention prevention’) is usually directed at those identified within the targeted population as ‘at risk’ and thus refers to early diagnosis and treatment to shorten illness episodes and to limit disease sequelae; tertiary prevention involves both the treatment of the identified problem or disease and restoration of the individual to a full state of functioning within the targeted population . Definitions of both secondary and tertiary prevention imply that some limited amount of impairment might remain and, thus, are the more likely scenarios when discussing outcomes of interventions in (rheumatoid) arthritis. Moreover, as the bulk of the literature on RA implies, even if only minimal disease activity is reached (frequently referred to as ‘remission’) most patients appear to be in need of at least some amount of treatment . This article focusses on secondary and tertiary prevention, because primary prevention (i.e., risk avoidance or modification of lifestyle, social, economic or environmental factors) is beyond its scope.

Remission

Because, in RA, ‘cure’ according to the definition given above is regarded to be rare, several definitions of ‘remission’ (a state of minimal disease activity assumed to be close to cure, albeit under treatment) have been put forward . However, even patients with RA in remission have been shown to show substantial progression of radiographic damage and synovitis detectable by magnetic resonance imaging (MRI) and ultrasound .

Evidence for effectiveness of treatment

The currently available drugs (disease-modifying anti-rheumatic drugs (DMARDs), including glucocorticoids) have been shown in numerous studies to effectively reduce signs and symptoms of RA and to be able, in the longer term, to prevent or at least significantly slow down the joint destruction that is the hallmark of the disease. This effectiveness exists for biological and non-biological drugs alike–observations over the past few years point to the importance of adjusting the intensity of treatment (by adjustments of dosages, addition of medication or change of drugs) to the success as estimated by well-validated measures such as the various versions of the disease-activity scores (DAS, DAS28, DAS44, Clinical Disease Activity Index (CDAI) and similar others). The as yet incompletely answered question is whether achieving ‘remission’ as judged by these scores is superior in long-term outcomes to ‘only’ attaining ‘low disease activity’. It is still not clear whether a certain degree of minimal disease activity or a degree of (low) disease activity which has been termed ‘patient acceptable disease state’ is sufficient, at least in patients without risk factors for destruction , to prevent later joint destruction or disability. Likewise, it is doubtful whether ‘remission’ equals ‘cure’ (probably not) and whether long-lasting drug-free remission (or ‘cure’) is (1) attainable and (2) necessary. Given the relative safety and long-term tolerability of modern biological and non-biological agents used to treat RA and other inflammatory arthritides, a modest frequency of periodic drug intake (once weekly in the case of methotrexate (MTX)) or application by injection (once weekly to approximately twice a year in the case of the new biological DMARDs) does not seem to pose an undue burden on the individual patients. On the other hand, even ‘remission’ may, at least in established RA, not be adequate to prevent ongoing or newly occurring damage to joints as has been shown in up to 15% of patients fulfilling remission criteria continuously for over 2 years .

What has become clear, not only on theoretical grounds (given the additive nature of damage in chronic destructive arthritis) but also supported by observational and interventional studies, is that the treatment effects appear to be better, the earlier effective treatment starts. Some observations in early inflammatory arthritis (also referred to by some authors as ‘undifferentiated’, because ‘RA-criteria’ are not fulfilled) even suggest that some patients may even be prevented from developing clear-cut RA by early glucocorticoid and/or DMARD treatment . Early adequate (i.e., more intense) treatment even appears to be able to counteract the effects of genetic and/or serological ‘high-risk factors’ in terms of intermediate–term outcomes .

Evidence for treatment-induced (near) remission

It has already been pointed out that very low disease-activity states or ‘remissions’ may be achieved in early (undifferentiated) arthritis, in early RA and in ‘established RA’ in a certain proportion of patients. Both intensive treatment (including glucocorticoids, combination therapies and biologicals early on) and tailoring treatment intensity to response with rapid adaptation of dose and/or number of drugs (preferably in combination) have been convincingly demonstrated to be quite superior to the more ‘cautious’ approaches in (early) RA. Most of these studies demonstrated that the percentage of patients in ‘low disease activity’ or ‘remission’ approached 75% in the intense-treatment groups (with combination therapy and/or biologicals), whereas more conventional or ‘cautious’ approaches consistently resulted in success rates (patients fulfilling criteria for low disease activity or remission) of substantially <50%. Importantly, several of these trials employed a ‘response-driven’ strategy. These strategies call for adaptation of the intensity of treatment to the observed response. This response is judged by structured assessments, which yield an individual score for the patient at the time of assessment, such as the DAS or the DAS44. Whenever the pre-defined goal (‘remission’ according to the validated cutoffs) is missed, medication is intensified. In the case of the Tight Control for Rheumatoid Arthritis (TICORA) trial , remission thus could be achieved after 18 months in 65% of the intensely treated individuals, remarkably without the use of biologicals. The Behandel-Strategieen (BeSt) trial strategy achieved remission after 12 months in approximately 40% of the patients, with the more intense treatment reaching these goals significantly earlier .

Much less evidence exists for diseases which are not classified as ‘RA’ (mostly referred to as ‘undifferentiated arthritis’ or ‘inflammatory oligo-/polyarthritis’). In this setting, definitions of diseases become quite problematic, with a wide range of inclusion criteria and/or definitions of types of joint involvements used in studies dealing with management of these patients ( Table 1 ). Furthermore, whereas the former studies attempted to prevent further progression in (presumably, due to fulfilment of classification criteria) established RA (‘secondary prevention’), the latter explicitly or implicitly aim at both induction of remission and ‘primary prevention’ of development of RA, as judged by various criteria, such as deferring use of DMARDs, absence of clinical arthritis, etc . Some of these trials hint at the possibility of delaying, but not averting, the development of RA, which was achieved by treating early inflammatory arthritis with glucocorticoids as well as with MTX . The PRObable RA: Methotrexate versus Placebo Treatment (PROMPT) Trial found that, in patients with early undifferentiated arthritis followed up over 30 months, treatment with MTX (which was, in the case of remission, discontinued after 1 year) delayed the fulfilment of American College of Rheumatology (ACR) RA criteria significantly during treatment as compared to placebo ( p = 0.04); however, development of RA was not prevented, it only occurred at a later time (after cessation of MTX treatment). Remarkably, a preventive effect on the development of RA in the anti-cyclic citrullinated peptide (CCP)-positive individuals (24% of the trial population) was seen, which was not demonstrated in anti-CCP negatives. Remission, however, was more frequent in the anti-CCP negatives (in the vicinity of 30%) as compared to the anti-CCP-positive individuals (7–17%), although this difference was not statistically significant, probably due to the number of patients. Interestingly, the studies which employed biological DMARDs (infliximab and abatacept), presumably the most potent RA medications to date, did not show effectiveness in significantly delaying RA development or MTX use . Conflicting results were reported with regard to the utility of glucocorticoid (monotherapy) in this ‘early (undifferentiated) arthritis’ setting: one study reported a somewhat delayed necessity to start DMARDs in the glucocorticoid-treated patients , whereas this was not the case in a second, somewhat larger trial . Both investigations found remission rates (without DMARD treatment) of less than 20%, which were lower than the previously reported rates of remission in early-arthritis cohorts , probably due to more stringent criteria for remission used.

Table 1

Intervention studies in “early arthritis”: Inclusion criteria and outcomes

Study title/reference	Inclusion criteria	Intervention	Primary outcome(s)
Green 1999	synovitis of ≥2 joints, symptoms ≤12 months	Intramuscular methylprednisolone	Remission at 6 months
Green 2001	synovitis of ≥5 joints, symptoms ≤12 months	Intra–articular injections of methylprednisolone	“complete response”
Quinn 2003	Hand arthritis Symptoms ≤12 months Excluded: RA or spondylarthropathy	Sequential NSAID–glucocorticoid–DMARD	Persistence of synovitis over 12 months
Karim 2007	Inflammatory hand pain, <5 joints, >3 months duration	Intramuscular methylprednisolone	50% improvement in pain and stiffness at 4 weeks
Van Dongen 2007 (“PROMPT”)	ACR 1958 criteria for probable RA (definite RA excluded) symptoms ≤24 months	Methotrexate vs. placebo	Diagnosis at 2 years, radiographic damage at 2 years
Marzo-Ortega 2007	Oligoarthritis: synovitis in ≤4 joints symptoms <12 months	Intramuscular methylprednisolone followed by sulfasalazine vs NSAID followed by later methylprednisolone and sulfasalazine	Absence of synovitis at 12 months
Emery 2008 (“COMET”)	synovitis of ≥2 joints symptoms ≤18 months	Abatacept vs placebo	Diagnosis of RA at 12 months
Saleem 2008	Undifferentiated arthritis of >1 joint symptoms ≤12 months	Infliximab vs placebo	Remission, progression to RA
Machold 2008 (“SAVE”)	Inflammatory arthritis ≥1 joint, symptoms ≤16 weeks	Intramuscular methylprednisolone vs placebo	Remission at 12 and 52 weeks
Verstappen 2008 (“STIVEA”)	Tenderness and swelling ≥2 joints, duration 4-10 weeks	Intramuscular methylprednisolone vs placebo	DMARD use at 6 months

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