Are rheumatoid arthritis and systemic lupus erythematosus inversely related diseases?

Medic;tl

Hypotheses

18:

.777-#o.

ARE RHEUMATOID ARTHRFL5 INVERSELY RELATED DISEASES?

1985

AND

SYSTEMIC

Anthony R. Mawson, Section of Rheumatology Medicine, Louisiana State University Medical Orleans, Louisiana 70112.

LUPUS

ERYTHEMATOSUS

and Rehabilitation, Department of School, 1542 Tulane Avenue, New

ABSTRACT Although rheumatoid arthritis (RA) and systemic lupus er,vthematosus (SLE) have certain features in corn mon, the literature suggests that the two diseases are inversely related to each other in at least eight major respects, viz., age of onset in relation to reproductive fertility; psychosis; kidney disease; nutritional status; and the differential effects of pregnancy, oral contraceptive use, jaundice, and penicillamine. It is suggested that associated with RA and SLE are differing blood and/or tissue levels of a common but as yet undetermined factor: deficient levels in RA, toxic levels in SLE. INTRODUCTION Rheumatoid arthritis (RAI and systemic lupus erythematcsus (SLEJ have long been thought to be related diseases (11, yet the nature of their relationship rem ains obscure. Although there are tvpical and easilv recognizable forms of both diseases, neither can be defined clinically with precision, and distinguishing between them in practice is often difficult, particularly in early and milder cases. RA and SLE have a number of features in corn mon (2). For instance, both are m ultisystem, connective-tissue diseases. Both preponderantly affect women, the sex ratio (f:m) being about 3:1 for RA and 9:1 for SLE. Both include arthralgia and arthritis among the diagnostic features (the latter taking a milder, generally non-erosive form in SLE), as well as pulmonary complications, pericarditis, the sicca syndrome, and many nonspecific symptoms such as fatigue, anorexia, and weight loss. An increased susceptibility to infection is seen in SLE and Felty’s syndrome, which comprises RA, splenomegaly, and leukopenia. Both diseases run a chronic, erratic course, marked by periodic exacerbations and remissions. RA and SLE also overlap serologicaIly; for instance, about 34% of patients with SLE have a positive reaction to rheumatoid factor (3), and the L.E. cell test is positive in up to 27% of patients with RA (If. ,4 number of observations suggest that RA and SLE not only are diseases, but also are inversely related to each other in certain respects These observations are of two types. First, certain features are highIp in one disease, yet compicuously\l rare in the other. Second, RA and inversely related in that RA tends to remit during jaundice and pregnancy, 377

different (Table 1). prevalent SLE are and

after the ingestion of certain drugs, whereas SLE (or a lupus-like disease) is precipitated or worsened by these same conditions and drugs, often in patients with RA. In keeping with the suggestion that they are inversely related diseases, the true co-existence of both diseases in the same patient is rare (4). The aims of this communication are to review the ‘inverse” aspects of RA and SLE and to speculate briefly on the implications regarding the cause(s) of both diseases. Age of OIlset in Relation to Reproductive Fertility. The onset of RA 1. typically occurs in the forties, with a markedly increased incidence in women between the ages of 50 and 55 (5). In contrast, SLE occurs most frequently in the childbearing years, especially in the late teens and early twenties (2). Thus, the risk of developing RA seems to be greatest at the time of declining reproductive fertility, whereas the risk of developing SLE is greatest at the time of peak fertility. 2. Psychosis. Schizophrenia is known to be exceptionally rare in patients with RA (6,7). In one study, 301 female schizophrenics aged 30 to 65 were tested for RA. The expected prevalence of RA was 7.796, yet not a single case was

Table

1

Some “inverse” aspects of rheumatoid arthritis and systemic lupus erythemattils (SLE)

SLE

-RA

Feature

(RA)

1.

Age at onset

40 yrs on average; marked increase in fern ales bet ween ages 50 and 55

peak in early twenties; mainlv in the childbearing years

2.

Psychosis

very rare

verv corn mon

3.

Kidney

rare

very corn m on

4.

Pregnancy

improves

often

5.

Jaundice

improves

may oroduce illness

6.

Oral contraceptives

improve

precipitate worsen

7.

Penicillam

improves

can produce like illness

8.

Nutrition

associated with undernutrition; supplementary zinc and/or vitamin A improve RA in humans and adjuvant arthritis in rats

associated with overnutri tion; reduced fat, protein, phenvlalanine, tyrosine, essential fatty acids, and zinc improve murine lupus

disease

ine

378

worsens lupus-like

or

lupus-

found (8). In contrast, 40% to 50% of patients with SLE have serious psychiatric disorders, episodes of which are especially likely to occur during disease exacerbations (9). The most common type of psychiatric disorder in SLE is a mixed syndrome corn bining organic and affective or schizophrenia-like symptoms (9). 3. Kidney Involvem ent. By general agreement, kidney dysfunction is far less common in RA than would be expected on the hypothesis that circulating immune complexes play a pathogenetic role in this disease, particularly because immune complexes are present in significant amounts both in RA and glomerulonephritis (2,101. In SLE, on the other hand, renal disease is a major cause of mortality and morbidity; virtually all patients undergoing renal biopsy demonstrate immune complex deposits within the mesangium (111, and membranous glomerulonephritis may be present for several years before the development of proteinuria, hypertension, or other clinical evidence of SLE (12). The signs and symptoms of RA subside in about 75% of 4. Pregnancy. patients during pregnancy and then recur postpartum (13,141. Concentrations of immune complexes decrease during pregnancy; and increase after delivery, whereas the concentration of rheumatoid factors shows no consistent change (15). Symptoms of RA also decrease during the postovulatory phase of the menstrual cycle, suggesting that some of the “spontaneous” fluctuations in RA reflect changes in the plasma concentration of estrogen or progesterone (16). Pregnancy is The reverse situation often applies to patients with SLE. associated with a worsening of the disease in a third of cases, with the onset of SLE in about 50% of cases, and improvement in some 20% of patients (17). Disease exacerbation in the immediate postpartum period is the most frequently reported adverse association between pregnancv and SLE. When exacerbation does occur during pregnancy, however, it tends to be severe and life-threatening (17). A further indication of the adverse effect of pregnancv on SLE is the high frequency of premature deliveries and spontaneous abortions, overall perinatal wastage being about 30% (18). The possible influence of estrogens on RA and SLE is discussed below (No. 6). 5. Jaundice. Although jaundice is generally associated with improvement in RA, it occurs in association with the aopearance of a luous-like disease in persons not having RA. Among patients with RA, a sudden remission of joint symptoms often occurs in spontaneous and artificiallv-induced liver disease and in obstructive jaundice, but not in hemolytic jaundice (19-211. In persons having no history of RA, however, jaundice is associated with the onset of a number of disease syndromes with manifestations closelv resembling those of SLE, viz., polgarthralgia, arthritis, and severe hyperqammsglobubnemia (chiefly I@). These syndromes include chronic active hepatitis C’hmoid hepatitis”), which overIan with the syndrome of primary biliary cirrhosis; “pill jaundice,” associated with the use of oral contraceptives; intraheoatic cholcstasis of pregnancy; and recurrent cholestasis of unknown origin (22-24). 6. Oral Contraceptives. These agents seem to reduce the risk of developing RA vet have the opposite effect of worsening the svmptoms of SLE. With one notable exception (2:5), mcst studies indicate a rifl% decreased risk of R.4 among oral contraceptive (OC) users as a group (26-28). Moreover, administration of estrogen at close to physiological levels produces s.ymptomatic relief from RA (291, enhances the anti-inflammatory activity of hvdrocortisone on skin disease (301, and reduces the rate and severity fo adjuvant arthritis in rats (311, while 379

ovariectomy increases the efficacy of estrogens in the (14).

severity treatment

of adjuvant arthritis (32). The clinical of RA nevertheless rem ains controversial

By contrast, patients with SLE tend to experience a worsening of symptoms within a few weeks or months after they start taking OCs (30,34). In a recent study, 43% of SLE patients suffered disease exacerbations as a result of taking estrogen-based OCs, whereas pure Qrogestrogens had no such effect (35). Hormonal studies also indicate: increased Qlasma estrogen levels in males with SLE (36); an increase in the extent of hydroxylation toward the I6 alpha urinary metabolites of &radial in male and female patients, resulting in a significant increase in estriol and 16 alpha-hydrouyestrone, both of which are potent estrogens (37); and increased testosterone oxidation, leading to reduced total androgens in patients with SLE (39). The fact that estrogens worsen murine lupus whereas androgens improve it (39,401 further supports the inference that the differential effects of OCs and pregnancy on RA and SLE are mediated by estrogens. However, the mechanism by which estrogens improve RA yet worsen SLE remains unknown. 7. Penicillamine. Although penicillamine has been shown in manv long-term double-blind studies to be of value in the treatment of RA (7), it also gives rise to an SLE-like disease in about 7% of all patients treated with the drug (42), and about 2% of RA patients treated over a S-year period (43). NIost penicillamineinduced syndromes occur between the 6th and 12th months of treatment (42). The chnical spectrum ranges from an asymptomatic serological condition to a severe illness with widespread joint involvement, sercsitis, rash, malaise, and weight loss (42). 8. Nutrition. Both underand overnutrition can adversely affect the functionin~immune system (44). Circumstantial evidence suggests that RA is associated with undernutrition, SLE with overnutrition. RA is associated with low blood levels of several specific nutrients, including vitamins A (45,461, C (45,47-49), and R6 (501, and zinc (50-55). These changes, including reduced dark adaptation asoaated with low vitamin A levels (46), were thought to be a result of RA or its treatment rather than a cause of the disease (561, became tests carried out many years ago indicated that dietary supplements of vitamins A (46) and C (47) failed to am eliorate RA symptomatology. In recent years, however, evidence has accumulated suggesting that zinc and/or retinoids (comprising vitamin A and synthetic vitamin A analogues) influence the pathogenesis of RA. Thus, dietary zinc prevents the joint symptoms that can occur in pigs with intestinal Clcetridium perfingers (57). Zinc sulphate, taken orally and evaluated in a double-blind trial (521, produced significant clinical improvement in a group of 21 patients with RA, associated5with an i Pease in serum zinc levels. Retinoic -Y acid in low concentrations (10 to 10 m 01/L) inhibited collagenase and Qrostaglandin E2 production by rheumatoid synovial cells in vitro (58). Isotretinoin (13-cis-retinoic acid) significantly reduced the inflamsasassociated with both neW~deVelOQing and established adjuvant arthritis in rats (a putative model of human RA), and reduced the amount of eollagenase secreted in tissue cultures by adherent cells isolated from inflammed synovia (59). Collagen arthritis, however, was worsened by three different retinoid compounds (SO). A further study by Brinckerhoff and her associates (cited in 61) indicated that the qmovitis induced by intraperitoneal injection of group A streptococcal cells, together with the associated increase in collagenase and prostaglandin E production, could be inhibited in a dose-dependent fashion by 4-hydroxyphenyl re ?-inamide.

Vitamin A (retinal) is esterified in the intestinal mucosa with long-chain fatty acids and taken to the liver for storage. From there, it is transported in plasma to the target tissues, bound to a specific carrier protein, retinol-binding protein (RBP) (62). Zinc interacts closely with vitamin A, and serve to mobilize RBP from the liver (63). Recently, zinc and 13-cis-retinoic acid combined were found to produce a greater reduction in the inflam=tion associated with adjuvant arthritis than either substance administered alone (64). In direct contrast to the above findings regarding RA, or animal models of RA, diets restricted in various substances that influence plasma vitamin A levels (65)--viz., fat, protein, essential amino acids, and zinc -- have the effect of reducing SLE symptomatology in the NZB/NZW mome, a hybrid species that spontaneously develops a disease resembling SLE in humans. Thw, murine lupus can be prevented or ameliorated, and longevity increased, by diets containing restricted amounts of fats (661, protein (67,681, phenylalanine and tyrosine (69), essential fatty acids (70), and zinc (71). Conversely, the pathologic signs of lupus can be accelerated in the NZB/NZW mo16e by diets containing a high proportion of fat (66). COMMENT The eight “inverse” aspects of RA and SLE, described above, are not readily explicable in terms of the conventional view, which attributes both diseases to infection or autoimmunity. As Morrow et al. (72) have noted in reference to SLE, research along these lines is at an impasse and a fresh approach is needed. One possibility is that RA and SLE reflect opposite states of metabolic imbalance; that is, just as mania and depression, or Parkinson’s and Huntington’s disease, are thought to reflect brain neurotransmitter imbalances (73,75), so RA and SLE could likewise be associated with different states or concentrations of a common physiochemical factor. If this is the case, then those conditions that improve RA -- namely, certain nutrients, pregnancy, estrogens, jaundice, and penicillamine -might be expected to do so by raising the concentration of the factor; conversely, the production or exacerbation of SLE by these same conditions may be due to the fact that they increase the already high background level of the factor beyond a critical threshold, thereby converting a state of subclinical toxicity into one of actual toxicity. In view of the above-noted nutritional-therapeutic data on RA and SLE regarding vitamin A and the fact that pregnancy, oral contraceptives, estrogens, and renal disease are all associated with increased plasma and tissue levels of vitamin A (76,77), I conjecture that RA is linked in some wav with a deficiency of vitamin A, SLE with vitamin A toxicity (78). ACKNOWLEDGMENT I thank Dr. Raj Marwah for his helpful Angela M. Jones assisted in the editing

comments. Mr. Charles Chapman and preparation of the manux!ript.

and Ms.

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