RESULTS OF LONG-CONTINUED CORTISONE ADMINISTRATION IN RHEUMATOID ARTHRITIS

The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement.Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also.During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.     

Modern use of urinary antiseptics

Recent experimental evidence suggests that hydrocortisone (Kendall's Compound F) is probably the principal glycogenic steroid secreted by the adrenal cortex and that under conditions of stress it may participate more than cortisone in physiologic reactions. Laboratory studies indicate that hydrocortisone has greater physiologic activity, milligram for milligram, than cortisone and with certain assays its potency is twice as great.Two forms of hydrocortisone, the free alcohol preparation and the acetate, were given systemically to patients with rheumatoid arthritis and were observed to possess significant differences in ability to suppress the disease manifestations. When administered orally in large initial doses, hydrocortisone (free alcohol) appeared to produce greater suppressive effects, milligram for milligram, than either hydrocortisone acetate or cortisone acetate. Comparisons of potency made by determining maintenance dosage requirements for equivalent degrees of clinical control in the same patients indicated that the effectiveness of hydrocortisone (free alcohol) is more than 50 per cent greater than that of either the free or acetated forms of cortisone and approximately twice as great as that of hydrocortisone acetate. Certain observations suggested that the greater antirheumatic activity of hydrocortisone (free alcohol) is not accompanied by a correspondingly greater tendency toward endocrine complications. If more extensive future investigations support this observation, hydrocortisone (free alcohol), by producing equally efficient results with smaller doses, may prove superior to cortisone as a therapeutic agent.Intra-articular injections of hydrocortisone acetate appear to have only a limited place in the management of rheumatoid arthritis but may be used for temporary relief under certain conditions. In preliminary studies by the author it was noted that whereas improvement resulted in 80 per cent of the treated joints, the improvement was graded as pronounced or very pronounced in only one-half of the joints so injected. In almost all instances the benefits derived were quite temporary. Results observed in treatment of osteoarthritic joints by this method were decidedly poorer than in rheumatoid arthritis.     

NONSPECIFIC ANTI-INFLAMMATORY AGENTS—Some Notes on Their Practical Application,Especially in Rheumatic Disorders

A number of acute and chronic inflammatory disorders are amenable to varying degrees of therapeutic control with the administration of nonspecific anti-inflammatory drugs. An evaluation of these suppressive agents in the field of rheumatic diseases and practical suggestions regarding their administration are presented.Eight synthetically modified corticosteroid compounds are available commercially. Each of them exhibits qualitative differences in one or several physiologic actions, each has certain advantages and disadvantages in therapy, and each shares the major deterrent features of corticosteroids. Prednisone, prednisolone, methylprednisolone, fluprednisolone and paramethasone have similar therapeutic indices, and there is little choice between them for the usual rheumatoid patient requiring steroid therapy. Conversely, the therapeutic indices of dexamethasone, betamethasone and triamcinolone are lower than that of prednisolone; they are less desirable for routine use and should be reserved for specially selected cases.Salicylates are preferred to adrenocortical steroids in the treatment of the ordinary patient with acute rheumatic fever. Steroid therapy should be reserved for resistant cases and for those with significant carditis. Salicylates are mainstays for pain relief in rheumatoid arthritis, but with the analgesic doses usually employed their anti-inflammatory action is slight.Phenylbutazone is a highly useful anti-inflammatory agent, especially in management of acute gouty arthritis and ankylosing (rheumatoid) spondylitis; its metabolite, oxyphenylbutazone, does not exhibit clear-cut advantages.Colchicine specifically suppresses acute gouty arthritis. Its analogues, desacetylcolchicine and desacetylthiocolchicine, produce fewer unpleasant gastrointestinal symptoms, but may promote agranulocytosis and alopecia.A number of indole preparations with anti-inflammatory activity have been tested clinically. One of them, indomethacin, has received extensive therapeutic trial; with dosages that can be tolerated the drug is fairly effective in the symptomatic control of ankylosing (rheumatoid) spondylitis but it is of questionable value in peripheral rheumatoid arthritis.     

Rheumatoid arthritis; an evaluation of long-term treatment with cortisone

Fifty-six patients with rheumatoid arthritis were treated continuously with cortisone for periods ranging between 4 and 38 months, in daily doses of 15 to 100 mg. Concomitant therapy included periods of rest, physical therapy, and salicylates. The incidence of subjective improvement exceeded that of objective improvement. The incidence of objective improvement was higher in females; also, in those patients whose disease was in an early stage and of short duration at the time therapy was begun, and who required relatively smaller maintenance doses of cortisone. Therapeutic results were not affected by the age of the patient or by the presence of spondylitis. Despite precautions, the long-term administration of cortisone was, in some patients, productive of serious undesirable side-effects. Although cortisone usually suppressed the symptoms and signs of rheumatoid arthritis, progression of the disease was frequently noted during its long-term administration.     

PAGET'S DISEASE—Changes Occurring Following Treatment with Newer Hormonal Agents

From experience in six cases the anabolic steroid hormones, especially long-acting testosterone and estrogen preparations, are the treatment of choice in Paget''s disease, as in postmenopausal osteoporosis. Details of the management of three patients over a period of four years are presented.Roughly 4 per cent of the population, mostly persons over 40, show some evidence of Paget''s disease. Only a small number of them, however, have severe manifestations requiring treatment, such as pain, howing or fracture of the bones, pressure on nerves or heart failure. In rare cases malignant changes occur in the involved bone.Since the cause of Paget''s disease is not known, treatment in the past has been largely empirical. Reifenstein and Albright had advocated the therapeutic use of calcium, vitamin D and ascorbic acid, and, in postmenopausal women, administration of estrogens; but with fractures or immobilization, intake of calcium-containing foods, such as milk, must be restricted to avoid dangerous piling up of calcium and kidney stones, and fluids must be forced. In recent years anabolic steroid hormones, principally oral androgens and estrogens, have been employed by Gordan and others to promote bone repair, lessen bone pain and decrease urinary excretion of calcium. While these hormones probably do not arrest the disease, they seem to stabilize it and bring relief of symptoms.More recently, Albright and Henneman demonstrated that very large doses of corticotropin (ACTH) or cortisone resulted in immediate cessation of bone pain, decrease in urinary excretion of calcium and histologic evidence of regression of the disease process. The large doses required, however, also produce dangerous side effects, such as psychosis and osteoporosis, indicating that such treatment probably should not be continued over long periods.     

THE COLLAGEN DISEASES

The collagen diseases have in common certain relatively specific alterations in the tissues that are derived from the mesenchyme.In reviewing the development of this concept, the nature and the pathogenesis of these changes and the blocking effect of cortisone and ACTH are discussed.The term “diseases of the collagen system” includes a number of clinical states within a broad spectrum of variation in the basic alterations of collagenous and vascular tissues. In rheumatoid arthritis the modifications are chiefly in the somatic connective tissue; in periarteritis nodosa the blood vessel involvement is preeminent; dermatomyositis and disseminated lupus erythematosus present more intermediate mixtures of these changes.     

EXPERIENCE WITH CORTISONE AND ACTH IN A PRIVATE CLINIC

Cortisone and ACTH are valuable agents for treating a large variety of diseases. In appropriate situations they may save life. It may be possible to prevent loss of vision in eye disease or permanent damage to important viscera in generalized disease. With ready access to these agents through the pharmacist, it is important to know that cortisone and ACTH can be used in office practice provided patients are selected carefully and followed frequently and closely. Strict observation of criteria for selection of patients limited the size of the series of patients reported upon, but by the same token the incidence of complications from therapy was exceptionally small. Every physician who elects to employ these potent hormones must become familiar with their physiological effects and with the various methods of exhibiting them. Some of these effects are noted in this paper, but the experiences reviewed here provide an incomplete picture of the wide application of cortisone and ACTH.     

Rheumatologists,take heart! We may be doing something right

In the present issue of Arthritis Research & Therapy data are presented suggesting that antirheumatic therapies decrease the risk of cardiovascular disease in patients with rheumatoid arthritis. The QUEST-RA group, a large international collaboration, analyzed data on 4,363 patients in a cross-sectional manner. Traditional risk factors were all significantly associated with cardiovascular events, and the presence of extraarticular disease significantly increased the risk, confirming a previous publication. The most interesting analysis in this study suggests that effective antirheumatic treatment, with traditional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, or anti-TNF biologics, reduces the risk of cardiovascular disease in rheumatoid arthritis. Some methodological issues are discussed, however, and confirmatory studies are suggested.     

Induction of lactogenic receptors. I. In the liver of hypophysectomized female rats.

To identify the hormones which affect lactogenic receptors in the liver of chronically hypophysectomized female rats, hormones were injected s.c. for 7 days. Specific binding (%, SB) of labelled ovine prolactin (PRL) in liver membrane preparations (1000,000 X g pellet) of controls was 1%. Estradiol (E2), cortisone (Con), ACTH or bovine growth hormone (bGH) treatment did not induce hepatic binding sites for PRL. Human GH and a single dose of 2mg PRL (but not lower doses) increased SB of PRL. Treatment with oPRL plus ACTH was less effective than hGH plus ACTH (13 vs 28%); combinations of oPRL plus Con as well as administration of oPRL plus ACTH to hypophysectomized and adrenalectomized female rats did not induce SB for PRL. Therapy with oPRL plus hGH (26%) was more potent than oPRL plus bGH (2%). These studies suggest that PRL, GH, and ACTH induce and in concert with sex steroids, modulate the lactogenic receptors in the female rat liver. The effect of ACTH is not due to increased adrenal corticoid secretion.     

The Fluorescent Antibody Method in the Study of Immunopathologic Conditions

Histochemical studies of immunopathologic conditions were carried out, using Coons'' fluorescent antibody technique. Experimental conditions studied were: serum sickness, generalized anaphylaxis, the Arthus reaction and experimental glomerulonephritis. Human diseases studied were those referred to as “collagen diseases”. Specific immunologic reactants were localized in the lesions of all experimental conditions studied, thus offering objective evidence of a possible immunologic pathogenesis of the lesions. In human diseases, gamma globulin was localized in the lesions of rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus and amyloidosis. Although the finding of gamma globulin in human lesions might suggest that it is an antibody, such an interpretation should be made with care since the gamma globulin could be deposited on a non-immunologic basis.The tissue-localizing properties of sera from different disease states showed appreciable variability within a given disease, as well as similar localizing properties among sera of different diseases. It is suggested that these serum factors (“autoantibodies”) might result as a host response and are not primarily involved in the pathogenesis of the disease.     

Diagnosis of rheumatic fever and like conditions; evaluation of certain of the acute phase reactants in a single specimen of blood

CERTAIN OF THE ACUTE PHASE REACTANT TESTS WERE PERFORMED ON THE SAME SPECIMEN OF BLOOD FROM PERSONS WITH THE FOLLOWING STATES: Normal, acute respiratory disease, streptococcosis, acute rheumatic fever, acute glomerulonephritis, acute rheumatoid arthritis, inactive rheumatic fever, lupus erythematosus, malignant disease, obesity, asthma, and allergic rhinitis. Of the tests performed, the mucoprotein-tyrosine and the antistreptolysin-0 titer when done together appeared to be the most discriminating. It is suggested that the performance of such tests on the same sample of blood might aid in differentiating mild acute rheumatic fever and acute rheumatoid arthritis from each other and also from other disease states.     

DIAGNOSIS OF RHEUMATIC FEVER AND LIKE CONDITIONS—Evaluation of Certain of the Acute Phase Reactants in a Single Specimen of Blood

Certain of the acute phase reactant tests were performed on the same specimen of blood from persons with the following states: Normal, acute respiratory disease, streptococcosis, acute rheumatic fever, acute glomerulonephritis, acute rheumatoid arthritis, inactive rheumatic fever, lupus erythematosus, malignant disease, obesity, asthma, and allergic rhinitis. Of the tests performed, the mucoprotein-tyrosine and the antistreptolysin-0 titer when done together appeared to be the most discriminating. It is suggested that the performance of such tests on the same sample of blood might aid in differentiating mild acute rheumatic fever and acute rheumatoid arthritis from each other and also from other disease states.     

What epidemiology has told us about risk factors and aetiopathogenesis in rheumatic diseases

This article will review how epidemiological studies have advanced our knowledge of both genetic and environmental risk factors for rheumatic diseases over the past decade. The major rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, osteoarthritis, gout, and fibromyalgia, and chronic widespread pain, will be covered. Advances discussed will include how a number of large prospective studies have improved our knowledge of risk factors, including diet, obesity, hormones, and smoking. The change from small-scale association studies to genome-wide association studies using gene chips to reveal new genetic risk factors will also be reviewed.     

Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-α therapy and other novel approaches

Therapeutic options for patients with more severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is accumulating evidence that anti-tumor-necrosis-factor (anti-TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis and psoriatic arthritis. The major anti-TNF-α agents currently available, infliximab (Remicade^®) and etanercept (Enbrel^®), are approved for the treatment of rheumatoid arthritis (RA) in many countries. In ankylosing spondylitis there is an unmet medical need, since there are almost no disease-modifying antirheumatic drugs (DMARDs) available for severely affected patients, especially those with spinal manifestations. Judging from recent data from more than 300 patients with SpA, anti-TNF therapy seems to be even more effective in SpA than in rheumatoid arthritis. However, it remains to be shown whether patients benefit from long-term treatment, whether radiological progression and ankylosis can be stopped and whether long-term biologic therapy is safe.     

CALIFORNIA MEDICAL ASSOCIATION: C.M.A. PUBLIC RELATIONS SERVICE AVAILABLE TO COUNTY SOCIETIES

The collagen diseases have in common certain relatively specific alterations in the tissues that are derived from the mesenchyme.In reviewing the development of this concept, the nature and the pathogenesis of these changes and the blocking effect of cortisone and ACTH are discussed. The term "diseases of the collagen system" includes a number of clinical states within a broad spectrum of variation in the basic alterations of collagenous and vascular tissues. In rheumatoid arthritis the modifications are chiefly in the somatic connective tissue; in periarteritis nodosa the blood vessel involvement is preeminent; dermatomyositis and disseminated lupus erythematosus present more intermediate mixtures of these changes.     

Human pregnancy safety for agents used to treat rheumatoid arthritis: adequacy of available information and strategies for developing post-marketing data

For female patients with rheumatoid arthritis, the availability of a host of new disease modifying antirheumatic drugs has raised important questions about fetal safety if a woman becomes pregnant while she is being treated. In addition, there is limited safety information regarding many of the older medications commonly used to treat rheumatoid arthritis in women of reproductive age. Current summary pregnancy risk information for selected medications used to treat rheumatoid arthritis is reviewed in the context of the pregnancy label category. In addition, the strengths and weaknesses of post-marketing strategies for developing new pregnancy safety information are described.     

Emerging role of anti-tumor necrosis factor therapy in rheumatic diseases

Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine that has been implicated in a variety of rheumatic and inflammatory diseases. New understanding of the importance of TNF-alpha in the pathophysiology of rheumatoid arthritis and Crohn's disease led to the development of a new class of targeted anti-TNF therapies. Anti-TNF-alpha agents including etanercept (a fusion protein of the p75 TNF receptor and IgG1) and infliximab (a chimeric monoclonal antibody specific for TNF-alpha) have been approved for the treatment of rheumatoid arthritis. In addition, infliximab has been approved in the treatment of patients with active or fistulating Crohn's disease. A new appreciation of the importance of TNF-alpha in other rheumatic and inflammatory diseases has led to a broadening of the application of anti-TNF agents. Both etanercept and infliximab have been used in open-label and randomized studies in patients with psoriatic arthritis. Although larger randomized trials are needed to confirm early results, both these anti-TNF-alpha agents, etanercept and infliximab, have demonstrated activity in improving the signs and symptoms of psoriatic arthritis and psoriasis. Infliximab has also been shown to be effective in patients with other rheumatic diseases, including ankylosing spondylitis, and may be effective in adult-onset Still's disease, polymyositis, and Beh?et's disease. Further investigations will fully elucidate the role of infliximab in these and other rheumatic diseases.     

Role of infection in the pathogenesis of rheumatic diseases

Advanced immunological technology has revealed immunological abnormalities not only in some chronic and autoimmune connective tissue disorders but also in conditions like infective arthritis where infection apparently seems to play the only role. On the other hand role of infection in the pathogenesis of some connective tissue disorders has recently gained much importance from the observation of clinical, pathological and immunological similarities between these diseases and certain infectious diseases occurring in animal models. Meanwhile, knowledge gained into human leucocyte-A system and its association with certain diseases opens another angle in etiopathogenesis of certain rheumatic diseases. It has been postulated that adaptive mechanism of a microbe or the binding between the human leucocyte-A molecule and carbohydrate moiety of a microbe may set up an autoimmune reaction and in the presence of some triggering factors in the environment may lead on to disease manifestations. An attempt has been made to discuss the role of infection in the outcome of rheumatic diseases such as septic arthritis, polyarteritis nodosa, rheumatic fever, enteropathic arthritis, ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematoses in genetically susceptible individuals producing immunological abnormalities.     

Effect of coenzyme Q(10) supplementation in the rat model of adjuvant arthritis

Adjuvant arthritis (AA) is a model of chronic inflammation induced by Mycobacterium butyricum and characterized by similar pathophysiological and pathobiochemical changes as rheumatoid arthritis (RA) in humans. In this study the antirheumatic activity of coenzyme Q(10) supplementation was tested not only as to its capability to suppress the inflammation edema of the hind paw and to improve the body weight of the arthritic animals, but also to improve so important biochemical parameters as markers of inflammation and oxidative stress, and of mitochondrial bioenergetics. Despite the unfavorable effects on the rheumatic processes observed by monitoring biometric parameters (hind paw volume, relative body weight, relative weight of spleen), a significant protective effect was observed on the level of mitochondrial energetic and antioxidant disbalance. This finding speaks in favor of CoQ(10) supplementation in rheumatic patients, presumably as combinatory therapy with classical antirheumatics, e.g. NSAIDs.     

Aspects of early arthritis. Definition of disease states in early arthritis: remission versus minimal disease activity

With regard to rheumatoid arthritis, remission as currently used in the literature can have two meanings: either a state with persistent absence of clinical and radiological signs of disease activity without being treated for a specific time period, or it may point to a disease state with minimal disease activity during antirheumatic treatment. A risk factor for the first is absence of autoantibodies, with the anti-CCP-antibodies as best predictors, whereas risk factors for achieving a drug-induced state of minimal disease activity are not well defined. These definitions of remission refer to different disease states; therefore, we propose that the term remission is reserved for patients that are not treated with antirheumatic drugs.