Can rheumatoid arthritis be prevented?

The discovery of elevations of rheumatoid arthritis (RA)-related biomarkers prior to the onset of clinically apparent RA raises hopes that individuals who are at risk of future RA can be identified in a preclinical phase of disease that is defined as abnormalities of RA-related immune activity prior to the clinically apparent onset of joint disease. Additionally, there is a growing understanding of the immunologic processes that are occurring in preclinical RA, as well as a growing understanding of risk factors that may be mechanistically related to RA development. Furthermore, there are data supporting that treatment of early RA can lead to drug-free remission. Taken as a whole, these findings suggest that it may be possible to use biomarkers and other factors to accurately identify the likelihood and timing of onset of future RA, and then intervene with immunomodulatory therapies and/or risk factor modification to prevent the future onset of RA in at-risk individuals. Importantly, several clinical prevention trials for RA have already been tried, and one is underway. However, while our growing understanding of the mechanisms and natural history of RA development may be leading us to the implementation of prevention strategies for RA, there are still several challenges to be met. These include developing sufficiently accurate methods of predicting those at high risk of future RA so that clinical trials can be developed based on accurate rates of development of arthritis and subjects can be adequately informed of their risk of disease, identifying the appropriate interventions and biologic targets for optimal prevention, and addressing the psychosocial and economic aspects that are crucial to developing broadly applicable prevention measures for RA. These issues notwithstanding, prevention of RA may be within reach in the near future.     

Rheumatoid arthritis: Evolving recognition of a common disease

Rheumatoid arthritis (RA) is a highly prevalent autoimmune disease and the most common form of autoimmune inflammatory arthritis. Studies of RA pathogenesis have contributed significantly to understanding the basis for complex immune-mediated disease, identified key steps in the development of autoimmune activation and joint damage in RA, and led to the development of targeted therapies that opened up the era biologic therapy. Current studies are linking differences in gene expression to abnormalities in cellular function that will help optimize therapy for individual patients and advance the goal of personalized medicine. Our evolving understanding and current important issues in RA are highlighted.     

Atherosclerosis and inflammation: insights from rheumatoid arthritis

Cardiovascular disease is a major health care problem and the most common cause of death among individuals from developed nations. Our understanding of atherosclerosis has evolved from a passive process resulting in narrowing of the lumen and consequent myocardial ischemia to a dynamic process that involves inflammation. The study of atherosclerosis in patients with chronic inflammation, such as rheumatoid arthritis (RA), will provide insights into the relationship between inflammation and atherosclerosis. We review the relationship between atherosclerosis and inflammation within the context of RA, providing evidence that patients with RA have increased cardiovascular morbidity and mortality and accelerated coronary and extra-coronary atherosclerosis. In addition, traditional and novel cardiovascular risk factors are discussed. Finally, actions that a rheumatologist can take to better control this cardiovascular morbidity are suggested. These can be summarized as follows: (1) careful assessment and treatment of cardiovascular risk, (2) better control of inflammation, and (3) individual risk–benefit evaluation of need for cyclo-oxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and high doses of corticosteroids. Presented as Medicine Grand Rounds at the University of Alberta. This review was supported by grants (HL04012 and HL67964) from the National Institutes of Health.     

Established rheumatoid arthritis – Redefining the concept

During the last few years, there has been a shift of focus in rheumatoid arthritis (RA) research towards earlier disease states. The terms early and established RA are inseparable, and having a clear definition of these two terms is crucial in conducting research and trying to understand the immunopathological mechanisms behind these different disease states. Established RA has been connected to chronic inflammation and a high burden of long-standing disease, with joint damage and comorbidities as a consequence of chronic inflammation. A chronological definition does not ensure us clear differentiation between early and established disease, because diagnosis can be delayed significantly. Similarly, a radiological definition does not ensure a clear differentiation either, as there is significant heterogeneity in the RA patient population, with some patients never developing structural damage, even after many years of disease. As the focus is now more on the early stages of disease, we propose to use the term established RA from the time of a definite clinical diagnosis of RA, irrespective of the symptoms’ duration or the presence of irreversible damage, to distinguish established disease to a stage of undifferentiated arthritis (UA) or risk for developing RA, which might never progress to RA.     

Familial rheumatoid arthritis in patients referred to rheumatology clinics of Tabriz, Iran

Background: The familial clustering of rheumatoid arthritis (RA) in first and second degree relatives of patients supports the role of genetic factors. The proportion of heredity in its development is roughly 60%; however, most individuals closely related to someone with RA do not get the disease. Considering the lack of sufficient data on the familial aggregation of RA in Iran, we designed this study for clarifying the familial prevalence of RA. Objective: To determine the prevalence of RA among relatives of patients with RA and to evaluate the mean disease onset age in relatives. Methods: In a longitudinal study from July 2008 to July 2010, we followed 210 unrelated patients with RA and their first and second degree relatives (FDR+ and SDR+), by interviewing and physical examination of those with symptoms, to ascertain prevalence. Familial RA was defined by presence of at least two siblings fulfilling the 1987 ACR criteria for RA. Results: We demonstrated that 17.6% of patients have at least one affected relative. The prevalence of RA in the family of studied patients was 0.83% (42 people). Thirty‐two in FDR+ and 10 people in SDR+ (2.53% and 0.26% of all family), also 1.12% in female relatives and 0.39% in male relatives had RA. The odds ratio for FDR/SDR was 2.52. The mean age at disease onset in relatives was 42.30 ± 1.51 years in FDR+ and 34.40 ± 2.10 years in the SDR+ group (0.03). Conclusion: The risk of RA is greatest in FDR+ and is likely to be due to a combination of inherited and environmental factors.     

Rheumatoid arthritis: a disease associated with accelerated atherogenesis

OBJECTIVES: Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with an increased prevalence of coronary heart disease and a high cardiovascular (CV) mortality. In this article, a review of mechanisms implicated in the development of accelerated atherogenesis in RA was performed. The potential role of treatment to reduce the incidence of CV events in RA was also discussed. METHODS: Retrospective review of the literature. The potential mechanisms implicated in the development of accelerated atherogenesis in RA, information on carotid ultrasonography, and the potential implication of treatment to prevent accelerated atherogenesis in individuals with RA were examined. RESULTS: Endothelial dysfunction, which is an early step in the development of atherosclerosis, has been observed in patients with RA. Deleterious effects resulting from persistent chronic inflammation may lead to endothelial dysfunction, insulin resistance, and a dyslipidemic pattern in these patients. Other mechanisms different from those related to classic atherogenesis risk factors, such as hyperhomocysteinemia and increased oxidative stress, are considered to be implicated in the pathogenesis of atherosclerosis in RA. Increased carotid intima-media thickness and carotid plaques have been found in RA patients compared with matched controls. Active MTX treatment of the disease has been associated with decreased CV mortality. Additional drugs such as statins may be considered in the management of these patients. CONCLUSIONS: The increased prevalence of CV mortality rate in RA cannot only be explained by the presence of traditional atherosclerotic risk factors. A chronic inflammatory response may promote the development of accelerated atherogenesis in these patients. Active treatment of the disease is required to reduce the risk of developing CV complications in individuals with RA.     

The recognition and assessment of cardiovascular risk in people with rheumatoid arthritis in primary care: a questionnaire-based study of general practitioners

Objectives. To investigate how well recognized the association between rheumatoid arthritis (RA) and excess cardiovascular (CV) risk is within primary care and the current assessment strategies being employed by general practitioners (GPs). Methods. Questionnaires were sent to all 376 GPs in the Worcestershire Primary Care Trust. Results. Thirty‐two per cent of GPs identified RA as an independent risk factor for CV disease. Fifteen per cent and 34%, respectively, assessed their RA patients for primary and secondary prevention of their CV risks. Of those GPs who made an assessment, 18.4% adjusted the calculated risk derived from standard charts. The frequency of assessment was greater among GPs who had received a form of education about the association between CV disease and RA. However, of the GPs identifying this susceptibility, only 40% performed any form of primary prevention risk assessment. Conclusions. At present, the excess risk of CV disease conferred by RA is under‐recognized and under‐assessed in primary care. Currently, educational resources on this topic targeted at GPs are lacking and may in part account for our findings. However, even when GPs did identify the risk of CV disease in RA or had received education about it, this did not consistently change their clinical management. Further work to promote knowledge and management strategies for CV disease in RA is therefore needed to improve the care of patients with this condition.Copyright © 2010 John Wiley & Sons, Ltd.     

Reducing work disability associated with rheumatoid arthritis: Identification of additional risk factors and persons likely to benefit from intervention

Objective. To study additional risk factors for rheumatoid arthritis (RA)-related work disability and to identify the groups of individuals at high risk and the potentially modifiable factors which place them at risk. Methods. A cross-sectional mail survey was conducted among 469 adults with RA. Work disability was defined as unemployment due to RA. A broad range of explanatory factors was examined, including sociodemographic, health, work, support given by others, and commuting difficulty. Employed and workdisabled subjects were compared by t-test and chisquare. Attributable fractions were calculated to assess the predictive value of factors. A recursive partitioning procedure identified individuals at varying risks for work disability, and their characteristics were defined. Results. The risk factors joint pain and functional status, commuting difficulty, physical demands of the job, and disease duration were important predictors of work disability in both the attributable fraction and recursive partitioning analytic models. Having a professional or administrative job was protective, provided the salary earned was not low. Younger individuals with RA of shorter duration were placed at high risk by potentially modifiable factors. While older persons with RA of long duration were at high risk, modifiable factors could not be identified. Conclusion. Commuting difficulty, a previously overlooked factor, is an important predictor of RA work disability. Younger individuals with RA of relatively short duration can be placed at high risk by potentially modifiable factors including commuting difficulty, physically demanding jobs, greater joint pain and poor functional status, and nonprofessional/nonadministrative jobs.     

New insights to the mechanisms underlying atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory circumstance, which has been associated with increased risk of cardiovascular disease (CVD). Although RA management has been promoted, mortality rate due to CVD remains remarkable. Approximately, 50% of premature death cases in RA are attributable to CVD. RA patients develop atherosclerosis in a greater amount than the general population. Moreover, atherosclerotic lesions develop rapidly in RA patients and might be more susceptible to rupture. The inflammatory condition of RA, such as cytokines, abnormally activated immune cells, play a role in the initiation, perpetuation and exacerbation of atherosclerosis. RA and CVD have genetic and environmental contributing risk factors in common, implying to potential coincidence of both disorders. Accelerated atherosclerosis in RA is attributed to inflammation, which carries its role out both through modulation of traditional risk factors and direct effect on the vessel wall. Hence, anti‐inflammatory medications in RA like tumor necrosis factor blockers might have a beneficial effect on preventing cardiovascular development. Increasing age, smoking, hypertension, male gender, hypercholesterolemia and diabetes are enumerated as traditional CVD risk factors. Hopefully, further understanding of the cardiovascular risk factors by perceiving the disease conditions behind CVD, will improve management of cardiovascular risks in patients with RA.     

Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: Baseline data of the CARMA Project

ObjectiveTo establish the cardiovascular (CV) morbidity and associated risk factors for CV disease (CVD) in Spanish patients with chronic inflammatory rheumatic diseases (CIRD) and unexposed individuals attending rheumatology clinics.MethodsAnalysis of data from the baseline visit of a 10-year prospective study [CARdiovascular in rheuMAtology (CARMA) project] that includes a cohort of patients with CIRD [rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)] and another cohort of matched individuals without CIRD attending outpatient rheumatology clinics from 67 hospitals in Spain. Prevalence of CV morbidity, CV risk factors, and systematic coronary risk evaluation (SCORE) assessment were analyzed.ResultsA total of 2234 patients (775 RA, 738 AS, and 721 PsA) and 677 unexposed subjects were included. Patients had low disease activity at the time of recruitment. PsA patients had more commonly classic CV risk factors and metabolic syndrome features than did the remaining individuals. The prevalence of CVD was higher in RA (10.5%) than in AS (7.6%), PsA (7.2%), and unexposed individuals (6.4%). A multivariate analysis adjusted for the presence of classic CV risk factors and disease duration revealed a positive trend for CVD in RA (OR = 1.58; 95% CI: 0.90–2.76; p = 0.10) and AS (OR = 1.77; 95% CI: 0.96–3.27; p = 0.07). Disease duration in all CIRD groups and functional capacity (HAQ) in RA were associated with an increased risk of CVD (OR = 2.15; 95% CI: 1.29–3.56; p = 0.003). Most patients had a moderate CV risk according to the SCORE charts.ConclusionsDespite recent advances in the management of CIRD, incidence of CVD remains increased in Spanish subjects with CIRD attending outpatient rheumatology clinics.     

Association of bone mineral density and vertebral deformity in patients with rheumatoid arthritis

The aim of this study was to investigate the association of vertebral deformities developed as a result of osteoporosis in female patients with rheumatoid arthritis (RA) with bone mineral density (BMD) and disease activity parameters. In the study, 100 female patients with the diagnosis of RA and 56 healthy subjects were recruited. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF) tests were performed and the number of swollen and tender joints, level of pain and health assessment questionnaire (HAQ) were recorded in order to evaluate disease activity. Anteroposterior and lateral thoracic and lumbosacral roentgenograms of all patients were taken for radiological examination and deformities of vertebrae were assessed. BMD measurements of patients were performed on vertebrae L1–4 of lumbar region and on total hip, femur neck, trochanter and Ward’s triangle of the right side. Vertebral deformity was established in 30% of RA patient group and 7.1% of control group and this was statistically significant. In the statistical analysis, no statistically significant difference was found between BMD measurements of RA and control groups. Patients with RA were divided into two subgroups with regard to using corticosteroids (CS) or not. Vertebral deformity was 32.4% in the subgroup using CS and 24.1% in the subgroup not using CS, and the difference was not statistically significant. There was a correlation between number of deformed joint and age and vertebral deformity incidence. RA is a risk factor on its own for the development of osteoporosis and vertebral deformity and this risk increases by age, excess number of deformed joints and severe course of disease. We think that precautions should be taken immediately to suppress the disease activity as well as to protect the quality and density of bone and to prevent the development of vertebral deformity and fracture while planning the treatment of patients with RA.     

Clinical significance of rheumatoid factor isotypes in seropositive arthritis

Summary In this cross-sectional study a comparison was made of rheumatoid factor (RF) isotypes in 203 RF positive patients with arthritis. Of these, 129 had rheumatoid arthritis (RA) and 74 a milder disease that would formerly have been classified as probable RA. The majority (74%) of the RA patients had elevations of two or three RF isotypes compared with only 34% of the patients with the milder form of arthritis. A striking feature was that combined elevation of IgM RF and IgA RF was found in 67% of the RA patients compared to only 20% of the patients with milder arthritis who most frequently had an isolated elevation of IgM RF (41%). RA patients with an isolated elevation of IgA RF were younger and had a shorter disease history than RA patients with an isolated elevation in IgM RF or a combined elevation of IgA RF and IgM RF. The prevalence of raised IgM RF was, furthermore, found to increase with age and disease duration. We concluded that a raised level of IgA RF is an adverse phenomenon in patients with seropositive arthritis while patients with an isolated increase in IgM RF may be expected to experience a relatively mild disease course.     

Cervical spine involvement early in the course of rheumatoid arthritis

ObjectivesCervical spine involvement in rheumatoid arthritis (RA) is considered a feature of long-standing disease. We describe two patients who presented with cervical symptoms as early features of RA.MethodsWe report two RA cases with cervical spine involvement as early features and use MEDLINE to review the literature concerning the frequency and disease duration of this manifestation and its imaging with plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI).ResultsAn 80-year-old man with cervical myelopathy from a C1–C2 rheumatoid pannus underwent decompression surgery before development of peripheral synovitis from RA. A 63-year-old woman presented with neck pain and polyarthritis at RA diagnosis, with imaging that confirmed a C1–C2 rheumatoid pannus. Onset of cervical spine involvement in RA is generally after 10 years of disease duration, ranging from 3 months to 45 years after peripheral synovitis among patients with seropositive erosive RA. Occurring in 9–88% of RA patients, cervical spine involvement may result in cervical instability due to either mechanical compression or vascular impairment of the spinal cord. Bone erosions and atlanto-axial subluxation on standard radiographs are two major signs of cervical spine involvement in RA. MRI identifies earlier signs of RA and has a higher sensitivity in detecting bone erosions compared to conventional radiography.ConclusionsCervical spine involvement in RA is not an uncommon condition but is rare at early disease onset. Symptoms of cervical pain and myelopathy should prompt a thorough neurological examination accompanied by imaging.     

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune‐mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so‐called cholinergic anti‐inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL‐6 production and improved RA disease severity, even in some patients with therapy‐resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.     

Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis

Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that are used to address the issue of gene-environment interactions in the etiology of RA, and discuss relevant examples of such interactions. We focus on how smoking, the best-known environmental risk factor for RA, interacts with HLA-DR shared epitope genes, the main genetic risk factors for RA, and result in a high risk of RA in individuals exposed to both of these risk factors. From these and other related findings, we can begin to define the distinct environmental risk factors (such as smoking) that in certain genetic contexts (for example, the presence of HLA-DR shared epitope alleles) can trigger immune reactions (such as autoantibodies to citrullinated peptides) many years before onset of RA, and consider how these immune reactions might contribute to clinical symptoms in a subset of affected patients. Increased knowledge about these and other events involved in the development of RA should enable the design of new tools for suppressing RA pathogenesis before the onset of disease.     

Risk factors for wrist surgery in rheumatoid arthritis

To assess the risk factors for wrist surgery in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 6 years. A linked registry study was performed using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women’s Medical University. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate Cox regression model that included variables such as gender, age, disease duration, a visual analog scale (VAS) generated by physicians, a patient-reported VAS for pain (VAS-pain), a VAS for general health, disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), erythrocyte sedimentation rate, and serum levels of C-reactive protein and rheumatoid factor as potential risk factors. Of the 5,497 patients registered at baseline, 122 (2.22%) had surgery on one or both wrist joints. Multivariate Cox regression analysis of the variables revealed positive coefficients for J-HAQ and VAS-pain and that advanced age and long RA duration were associated with a reduced risk of wrist surgery. The hazard ratios were: 1.515 for J-HAQ, 1.126 for VAS-pain, 0.985 for age, and 0.964 for RA duration. Advanced age and long RA duration were associated with a decreased risk of wrist surgery, while J-HAQ and VAS-pain were associated with an increased risk. The identification of the risk factors for wrist surgery provides important insights into the course of the disease and its impact on patients, as well as the potential consequences for health care resource utilization planning.     

Predictive factors in early arthritis: long-term follow-up

BACKGROUND: Because recent-onset inflammatory arthritis exhibits considerable clinical and prognostic variability, it is important to attempt to predict which patients are likely to have a poor prognosis as early as possible. Most prognostic studies have looked at patients who fulfilled proposed criteria for a definite diagnosis of rheumatoid arthritis (RA) or other well-defined conditions; less information exists concerning predictive factors for other types of early arthritis. OBJECTIVES: To examine prognosis in early arthritis, the authors assessed the long-term outcome in a cohort of patients who presented with inflammatory arthritis of short duration. Associations between outcome and patient clinical characteristics were analyzed to determine possible prognostic factors. METHODS: Since 1968, patients were selected to be followed up in 2 early-arthritis clinics if they had evidence of inflammatory joint disease and symptom duration was <1 year. Length of follow-up was variable, but was at least 1 year. At last follow-up, patients were classified as being in remission or as having persistent disease. Factors associated with a poor outcome were identified by using formal statistical methods. RESULTS: A total of 121 patients were included in this analysis. Mean disease duration to the first evaluation was 3 months, and median follow-up was 5 years (range, 1 to 30 months). Twenty-one patients (17%) had transient disease defined as total duration of <6 weeks. Sixty-three patients (52%) were in remission at final follow-up, with unclassified patients doing the best. Patients meeting criteria for RA or spondylarthropathies had more persistent disease. Polyarticular disease predicted more persistent disease (P <.05). In multivariable analyses, patients with initial hand involvement were much less likely to achieve remission of their disease (odds ratio, 0.18; 95% confidence interval, 0.05 to 0.66). Only 4 patients had either class 4 function or joint replacement. CONCLUSIONS: Our findings indicate that prognosis in early inflammatory arthritis is generally good, with more than half of all patients achieving remission in our cohort. Patients with unclassified arthritis fared better than those meeting criteria for RA or spondylarthropathy. Of the many clinical variables examined as possible prognostic factors, hand involvement was the strongest predictor of a poor outcome. RELEVANCE: The long follow-up of these patients with early arthritis provides clues for the clinician to the likely course and shows that many patients will do well.     

Cardiovascular disease in patients with rheumatoid arthritis

The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) is 1.5–2-fold higher than age- and sex-matched individuals from the general population. This excess risk is attributed to the systemic chronic inflammation which is a hallmark of RA. Challenges to optimizing CV risk management in RA include the need for improved methods to predict CV risk, and defining the target risk factor(s) to reduce CV risk. Lessons learned from RA studies can also inform CV risk prevention in the general population, where inflammation also has an important role in the pathogenesis of atherosclerosis.     

The −590 IL-4 promoter polymorphism in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The aim of the present study was to evaluate the –590 IL-4 promoter polymorphism in patients with RA and its association with disease activity and severity. We enrolled 94 patients with RA diagnosed according to the criteria of the American College of Rheumatology. Polymerase chain reaction amplification was used for analysis of the polymorphism at position –590 of the promoter of the IL-4 gene. The distribution of IL-4 genotypes in RA patients did not differ from control subjects. Nevertheless, the active form of RA was more frequently diagnosed in patients with T allele (genotypes CT and TT) as compared with homozygous CC patients. Moreover, in carriers of the T allele, parameters of disease activity (DAS 28 score, ESR, number of swollen and tender joints) were significantly increased. We suggest that the IL-4 –590 promoter polymorphism may be a genetic risk factor for RA severity.     

Mortality in rheumatoid arthritis: time to take it seriously

Rheumatoid arthritis (RA) is often regarded as benign and not a serious disease. Yet patients with RA have a substantially reduced life expectancy. Patients with RA are particularly at risk of death from cardiovascular disease, infection and renal disease. A few variables are now recognized as important predictive markers, such as disease duration, severity, sex, educational level and treatment.