Life changes as etiologic factors in juvenile rheumatoid arthritis

Rheumatic diseases are a group of painful and often disabling systemic diseases that usually become chronic. The most frequent problems reported by those affected are complaints connected with the musculoskeletal system. From the wide range of rheumatic diseases, rheumatoid arthritis (RA), ankylosing spondylitis, fibromyalgia syndrome (FS), and psoriatric arthritis have the highest prevalence, with almost 1% to 2% of the total population affected by each of them. Because of the fact that these illnesses are usually chronic and disabling, they represent a major social and economic burden. RA, ankylosing spondylitis, and psoriatric arthritis are especially known to be immune-related diseases. Their etiology still remains unclear. Most commonly, multiple factors are suspected to be responsible for the initiation of these illnesses. Lack of knowledge as to the causes of most rheumatic diseases meant that a wide range of different approaches evolved. One of them is the field of stress and personality research.

As early as 1909, the first article suggesting an association between factors in everyday life like anxiety and worry and the provocation of RA was published.⁶³ Some years later, the personality of the RA patient was also taken into consideration as a possible risk factor for increased susceptibility to RA.¹⁸ In 1939, Cobb et al²⁵ summarized speculations dating back to 1880 that there is a relation between environmental or emotional factors on the one hand and the onset and exacerbation of RA on the other hand. Alexander¹⁰ classified RA as one of the seven classic psychosomatic diseases. Since the beginning of this field of research, a large number of articles focusing on stress and personality traits as provoking, predisposing, or modulating factors have been published. The results were often equivocal and caused considerable controversy.

This article reviews the role of psychologic stress as a factor that may precipitate or exacerbate rheumatic diseases. The most common and effective strategies for coping employed by patients with rheumatic diseases and the value of stress-reducing therapies are discussed.

The interactions between the immune system and psychological states are both intricate and intriguing. Research at a molecular level has thrown considerable light on the previously ill-defined area of psychoneuroimmunology. In this report, we explore the psychoneuroimmunology of autoimmune disorders, particularly rheumatoid arthritis and lupus erythematosus. Animal models of these diseases have provided a particularly useful window on complex psychoneuroimmunological interactions. Observations about the effect of stress on the onset and course of autoimmune disorders has added to our understanding of psychoneuroimmunological interactions. These interactions are bi-directional, as reflected in the autoimmune-mediated neuropsychiatric manifestations of systemic lupus. Exploring the role of various neurotransmitters and neuromodulators in the stress response may have important therapeutic implications for autoimmune disorders.

This study used the Life Events and Difficulties Schedule to assess whether an excess of life events occured prior to onset of rheumatoid arthritis (RA) in 60 consecutive out-patients. There was no evidence of an excess of events of any kind during the 12 months before onset of RA. There was no difference between seropositive and seronegative RA or between those with and without a family history. There was a non-significant trend for an excess of events before onset compared with after; this may be explained by the reduction of events after onset as a consequence of disabling disease. The prevalence of psychiatric disorder measured using the Psychiatric Assessment Schedule was 13.3% at the time of interview.

$\text{C3H}\text{HEJ}$ mice repeatedly exposed to rotational stress (45 rpm for 30 min) show a decreased immune response after challenge with sheep erythrocytes (SRBC) or multiple minor histoincompatible skin grafts (B10.BR) in association with the cues present when initially exposed to the physical stress. This conditioned immunosuppression is associated with diminished antibody production and enhanced skin graft survival. When previously conditioned mice were mated with normal (nonconditioned) males and reexposed to conditioning cues during pregnancy (days 13, 16, and 19 of gestation), the offspring of these mice were also found to produce a decreased antibody response (and decreased skin graft rejection response) when tested at 7 weeks of age. This altered immune response in the offspring occurred in the absence of any deliberate direct manipulation of these mice. In a further study a reciprocal crossover design was used to investigate whether altered immunity in the offspring was dependent upon the treatment of the biological mother and/or the fostering mother. The most marked immunosuppression was seen in offspring born to, and fostered on, conditioned mothers reexposed to cues previously associated with physical stress. However, even the offspring of normal $\text{C3H}\text{HEJ}$ matings developed a reduced immune response if they were fostered on conditioned mothers reexposed to stress-associated cues. These data imply that the developing immune system is regulated by factors in the colostrum/feto-placental unit which are modified by conditioning phenomena.

Interest in the field of neuroimmunoendocrinology is in full expansion. With regard to this, steroid influence on the immune system, in particular sex steroids and glucocorticoids, has been known for a long time. Sex steroids are part of the mechanism underlying the immune sexual dimorphism, as particularly emphasized in autoimmune diseases. Immunosuppressive and anti-inflammatory effects of glucocorticoids are now considered a physiological negative feedback loop to cytokines produced during an immune and/or inflammatory response. Psychosocial factors may play a role in the development of immunologically-mediated diseases, e.g. autoimmune diseases. The nonobese diabetic (NOD) mouse, that develops an immunologically-mediated insulin-dependent diabetes mellitus (IDDM) is an interesting model to study the role of endogenous steroids. Insulitis is present in both sexes, but diabetes has a strong preponderance in females. Hormonal alteration, such as castration, modulates the incidence of diabetes, whereas environmental factors, such as stress, accelerate the disease. In the present paper, we have reviewed the role of gender, sex steroid hormones, stress and glucocorticoids in autoimmunity as well as analyzed their different levels of actions and interrelationships, focusing particular attention on the immunologically-mediated IDDM of the NOD mouse.