Many years ago, particularly around the turn of the century, rheumatoid arthritis was generally considered to be an infectious problem. The reason for this view was that there were a certain number of people who first had kidney trouble, a bad tonsil, or some other infectious complaint and developed arthritis soon afterward. It was assumed that the focal infection was the cause of the arthritis, and that if the focus were excised, the infection would go with it.
It was an era in which surgeons moved very quickly to take out all the removable parts that could be a source of infection, such as tonsils, the appendix, ovaries, the uterus, a kidney, the gallbladder—and often the synovial membrane from the affected joints. It was a devastating period for sufferers of arthritis because many of them were on the operating table within a day or two of complaining of the first twinge in a joint. The surgery did have an impact on the arthritic condition. Some patients improved markedly, but the results were not consistent, and many others got worse. As a result of unsuccessful joint surgery, some were crippled for life.
That draconian approach to arthritis quickly turned into unwarranted excess. It went on for ten or fifteen years, until finally, like each of the successive chemical treatments in the modern era, it ran its course. The principal reason for the demise of this particular approach to the disease was the rise of the American Rheumatism Association, which stood as a bulwark against unethical practices and treatments of arthritis that clearly didn’t work.
Unfortunately, when this kind of surgery fell into disrepute, the infectious theory was badly weakened as well. The baby, which was perfectly healthy, was thrown out with the bath water.
In the course of many decades of studying the disease as an infection, I have developed a theory for why some arthritics were improved by the surgery. I suspect that when some people got dramatically better after the surgical removal of a localized infection—in the gallbladder, tonsil, kidney, or wherever—it was because they were still in the early stages of the arthritic infection, and their bodies had not yet had time to become violently sensitized against the bacterial antigen. Conversely, those who did not do well after surgery were the ones who had suffered from arthritis so long that they were sensitized by exposure to the bacterial toxins—toxins that had been pouring into the bloodstream for months or years. When the focal area was attacked surgically, it released yet more toxins into the system of the already sensitized host, showing up in the form of a postoperative flare.
At about the midpoint of this century, the infectious theory went into a steep decline as the conceptual view of the arthritic mechanism took a sudden and unexpected turn. In the late 1940s, a researcher named Philip Hench at the Mayo Clinic announced several new extracts from the adrenal cortex, work that would win him (with E. C. Kendall and Tadeus Reichstein) a well-deserved Nobel Prize. Among those extracts was a substance he called Compound E, which had a startling impact on rheumatoid arthritis. The compound soon became known throughout the world as cortisone.
Cortisone was among the most miraculous of the new wonder drugs that followed World War II. It was absolutely astonishing to see its effects on patients who had been bedridden with crippling, advanced rheumatoid arthritis: they were suddenly able to rise and walk again without pain.
Most of America’s rheumatologists quickly decided that the natural cortisone production in the body of an arthritic patient was simply too low, much as natural insulin production is too low in the body of a diabetic. This concept of arthritis as a kind of deficiency replaced whatever was left of the infectious theory, and much of the medical world celebrated the conquest of the world’s most prevalent disease—even though the deficiency thesis was unproven and the cause of the alleged deficiency was still undetermined.
In fact, I knew from my own research that the thesis was not only unproven, but its basic premise was incorrect. The question of the role played by the glands in arthritis—the adequacy of the thyroid, the ovaries, or the adrenal gland, or the other endocrines—had been investigated extensively. It was known that the adrenal gland, where cortisone is made, was no different in arthritic patients than in patients without any trace of arthritis.
Yet the paradox remained that an excessive level of cortisone—far above what was being produced normally—would make an arthritic patient feel better. Supporters of the deficiency theory amended their thesis slightly to fit the results: they decided that although arthritics did indeed produce a normal amount of cortisone in their own bodies, it was of an inferior quality. No evidence was ever given to show in what way it was inferior or that it differed in any way from the cortisone produced by people who were perfectly healthy.
On the contrary, new evidence soon appeared that placed the deficiency theory in even more serious doubt. With a true deficiency, as in hypothyroidism, for example, replacement of the missing endocrine permits the body to keep functioning indefinitely at its normal levels; patients who take daily doses of thyroid to supplement or replace the production of a damaged or missing thyroid gland lead otherwise normal lives. But with this new “cure” for arthritis, it became apparent that after a relatively short time, usually within just a few months, the extra cortisone began to lose its effectiveness.
Hench’s work and the results his compound at first achieved so captured the enthusiasm of the medical world that even when cortisone’s effectiveness began to decline, almost nobody wanted to turn back from the new deficiency theory that its discovery had generated. Hench himself explained the failure as a problem of the kind of cortisone that was being used, and he exhorted the medical world to find a more effective type that would last indefinitely.
For the next decade, an enormous campaign of scientific research produced one steroid after another in the hope of finding such an ideal product. But after ten years of high promises followed by inevitably dismal disappointments, the great enthusiasm behind the quest for the perfect cortisone finally began to fizzle out.
A very big additional reason for the steroid fizzle was the discovery of numerous negative effects. These included stomach ulcers, high blood pressure, diabetes, and cataracts, among other things. It was observed that in many cases, prolonged and excessive use of cortisone resulted in the loss of calcium from the bones, a fact of particular concern to older patients already suffering from osteoporosis. If arthritis were really caused by a natural deficiency, we knew from our experience with hypothyroidism that the missing endocrine could be replaced for the rest of the patient’s life and no such side effects would ever arise. Even with the eventual shift away from steroids, however, the deficiency concept tarried on.
When Hench suggested the problems with cortisone were just with its form, I finally began to object in public. I was certain that the adverse effects arose from the cortisone itself, and not just because the compound needed some fine tuning. I believed that cortisone’s anti-inflammatory properties could still serve physicians who wanted to use the drug as an adjunct to some other form of treatment; indeed, I still use low levels to help patients through the initial stages of antibiotic therapy, or in cases where earlier misuse of steroids has destroyed the patient’s ability to produce the required natural amount. But I was certain that the ways in which cortisone had been used for the ten years following its discovery had produced far more serious problems than the ones it had resolved. And I was also sure, as was the rest of the medical world by then, that whatever good things cortisone seemed to do at first, the benefits didn’t last.
The impact of the discovery of cortisone on arthritis research was very similar to that of the discovery of insulin, in the early 1920s, on diabetes research. Both discoveries abruptly ended nearly all ongoing efforts to find the causes of their respective diseases. Nobody seemed to care what made arthritis or diabetes happen as long as they could control the symptoms. Years later, it was discovered that it wasn’t enough just to manage blood-sugar levels with insulin, that the long-term complications from diabetes, such as retinal damage, cataracts, infections, and abscesses, still occurred.
With the cortisone honeymoon approaching its end in the early 1960s, the American Rheumatism Association began to take a more prudent view of the use of steroids in large doses, but the medical community was still a long way from suing for divorce. Cortisone was still wonderful; it was just not as wonderful as it had been in 1950, and it had to be used in a more gingerly fashion. Although it was not said explicitly, there was a tacit recognition that what had been reluctantly identified as side effects of cortisone were not side effects at all; they were normal effects, part and parcel of using steroids in large quantities. And they could be disastrous.
Ironically, the effects of excessive cortisone had been identified and spelled out in detail a number of years earlier by the great neurosurgeon Harvey Cushing. Cushing’s syndrome is a condition in which the pituitary gland, which is at the base of the brain, becomes overactive. When that happens, it makes the adrenal gland overactive as well, and the result is that the body produces too much cortisone. The effects Cushing noted from the overproduction of natural cortisone include hypertension, diabetes, cataracts, ulcers, osteoporosis, and odd distribution of body fat so that the torso becomes very large while the legs and arms remain small. Diabetes, mellitus, impotence in men, and hirsutism in women were also features of the clinical pattern. Cushing never called these phenomena side effects because he knew that they weren’t side effects; they were the regular effects of too much cortisone. They had been an important part of the literature for decades.
For the whole field of arthritis research, there was a very costly long-term legacy from the introduction and spectacular early success of cortisone. That success was responsible for a nearly total commitment to the study and treatment of rheumatoid arthritis as a metabolic process, at the expense of any further study of the question of a primary infectious component. It was finally found that cortisone owed its effects to the fact that it interfered in some way with the autoimmune reaction, that it made people feel remarkably better almost immediately because it blocked the body’s natural defenses. When it became apparent that the benefits didn’t hold up over time, the medical profession found itself in the midst of a terrible dilemma. On one side was the immense early promise that had attached to a product that may well be the most highly publicized drug in the history of medicine. On the other was the growing body of evidence that it didn’t last, and that the patient could wind up worse off than when the treatment started.
That pattern—enormous early promise, followed by terrible disillusionment—was to be repeated over and over again as an endless succession of new metabolic compounds flowed from the research laboratories of America and the rest of the world. Indeed, it would characterize the course of arthritis research for most of the next thirty years.
I recognized that cortisone had some valuable properties in the treatment of arthritis, but from the very beginning I opposed the enthusiasm for large doses of any compound that would totally block the body’s immune defense system. Cortisone in those quantities was being used like a dam in a river, and I knew that the pressure would continue to build and that sooner or later the dam would break or overflow—usually with a peptic ulcer that would start to bleed, so treatment had to be stopped—and the rebound flare would create disastrous consequences for the patient. And that is exactly what happened. When the use of cortisone at these high levels finally failed, most of the medical world had subscribed too heavily to the autoimmune theory to switch back to the possibility of infection playing a role.
Meanwhile, my own group continued working in the same old direction. Even when cortisone was at its peak of popularity, before the failures had mounted into the millions, we assumed that if there were an infectious allergy from mycoplasmas or anything else, cortisone worked simply because it blocked the allergy, not because it supplanted any natural deficiency or cured a thing. Cortisone’s effect on allergies had already been well established; when people suffered from very severe status asthmaticus, for example, and were practically dead with breathing problems, cortisone would stop the attack right away by blocking the allergic reaction. Because rheumatoid arthritis responded so well, at first, to this anti-allergy substance, we began to speculate that the disease involved more of an allergic reaction than anyone had previously assumed, and we began to investigate that avenue as well. In regular allergies, the main offender is histamine release. In rheumatoid hypersensitivity, histamine is present in small amounts; the main offender is a mixture of proteolytic enzymes.
Despite its failures, over the course of the following years I frequently acknowledged our debt to cortisone for the redirection it had given to scientific thought on the question of hypersensitivity or the allergic state. It became well known that when a physician used cortisone in large quantities, and especially when that use led to dramatic remission, the disease got ten times worse when the cortisone was finally stopped. This backlash wasn’t just a subjective observation of patients; it was detectable in the sudden increases in rheumatoid factor, sedimentation rate, gamma globulin, and reactive proteins, in the fall in hemoglobin, and in all the other measurable indicators by which the disease is monitored.
Once the deficiency theory had finally run its course, the medical and scientific world slowly returned to an examination of some of the alternative causes of rheumatoid arthritis. The theory is now gradually reemerging that an infection or some other form of antigen creates a reaction which in turn causes inflammation in the joints, pain, weakness, and the other classic symptoms of the disease.
One of the first places medical researchers began to look after cortisone fizzled out was toward nonsteroidal anti-inflammatories. Suddenly a flood of such drugs appeared on the market: Naprosyn, Nalfon, Tolectin, Meclomen, Clinoril, and many more. They were designed to do what cortisone did in blocking inflammation, but without the side effects. All of these compounds passed the standard six-month double-blind screening requirements of the FDA, and they were all very promising. But over the course of longer experience, sometimes only after a couple of years of clinical use by hundreds of thousands of patients, many of the old, invidious side effects inevitably reemerged, along with some new ones. Some of these drugs caused stomach troubles; others have been discovered to cause kidney damage.
The primary impetus for the eventual turning away from cortisone, as indeed from all the other standard methods of symptomatic therapy, including gold and methotrexate in more recent years, has not been the doctors; it has been the patients. A lot of doctors resist the notion that there may be some democracy in medicine, and their resistance has slowed down the shift of arthritis research back toward treatments the patient can live with. The fact is that people are not going to tolerate medication that could easily destroy their health or their lives. Patients should be brought into the process of setting directions far sooner than they are, and they should be included deliberately, not just after everything has failed.
Most doctors pay lip service to the concept that patients should have some say in their treatment, but very few are really eager to see a system in which information about how medicines work is systematically shared and becomes the primary mechanism for setting the direction of treatment and research. A doctor feels that he is blessed with profound knowledge, as indeed he is. And he has been through the mill to learn what he knows: he’s suffered through incredibly hard work in four years of college, four years of medical school, and four years of hospital training. As a rule, the patient has little of this breadth of knowledge. Patients often have a particular understanding of their own disease, however, which they have acquired from extensive reading and from conversations with others who suffer from the same affliction. The patient has something else which is extremely valuable and which many doctors do not have: direct experience with the failure or success of the various medicines which the doctor prescribes. That knowledge is absolutely imperative to the process by which such products are refined and future medicines are developed.
For most rheumatoid arthritics, this long history of broken promises and misdirections has been one of the most painful aspects of their disease. And it has created a reaction: the problem of false hope has emerged as one of the most important factors in gaining a consensus and setting the agenda for arthritis research. Patients who have been told that wonderful things will happen, only to discover that the effects don’t last and that they often carry a terrible price, finally reach a point where they no longer believe in anything. That one problem, more than anything else, provides the best reason for directing research toward the cause of arthritis instead of toward its symptoms. Any medicine that eliminates the source of the problem cannot fail.
One of the things we have repeatedly demonstrated with our research on mycoplasmas is that when the treatment is aimed at the primary antigen that causes the arthritis reaction, a lot of the symptomatic drugs which had previously failed to be effective will come back to life again. An attack on the antigen itself even revives the efficacy of aspirin in patients for whom aspirin had stopped relieving pain many years earlier. Many new patients ask me what I can give them to supplant their most recent painkiller because, like all the others, it has stopped working. I tell them that I’ll do something even better than that; I’ll continue them on the old painkiller and make it work again.
The reason all such pain medicines eventually fail when the patient is treated symptomatically is not that the patient’s system is getting any weaker, but that the antigen is becoming that much more widespread. When any such medicine removes the inflammatory barrier from around the source of the antigen, it is like removing the coolant from a nuclear power core, and the eventual result is a meltdown. The inflammation is nature’s way of holding the reaction in check; it happens to be a painful method, but it is the only means by which the spread of the source of the antigen is contained. The fact that aspirin and other painkillers can be made to work again after the patient has started tetracycline therapy is more than a convenience for the management of discomfort. It is one further indication that the antibiotic is attacking the problem at its source.
Essentially, rheumatoid arthritis operates in the manner of a bacterial allergy, leading to collagen vascular disturbances. It is an allergic or hypersensitive state. The reaction is most intense in the connective tissue between the cells.
By itself, each of these pieces of the rheumatoid arthritis puzzle may be little more than a curiosity. But taken together, a complete picture has formed over time, and it now provides researchers with their first full portrait of the process by which rheumatoid arthritis occurs. Only with this portrait in mind can a plan for sustained control and ultimate elimination of the disease be designed.