By Santosh Vardhana, MD
A 36-year-old obese male with hypertension and hyperlipidemia presents to the ER with new knee pain, swelling, and erythema. Joint aspiration reveals negatively birefringent crystals. He is started on oral prednisone.
A 26-year-old woman with lupus presents to ER with edema, hematuria, and fevers. On exam she hypertensive, febrile to 100.4C, and has periorbital and lower extremity edema. Urine dipstick reveals 2+blood and protein. She is started on IV methylprednisolone.
A 60-year-old man with HIV on HAART presents to the ER with lower extremity weakness and a acute-onset loss of sensation below the umbilicus. He is started on IV methylprednisolone. IR-guided biopsy reveals diffuse large B-cell lymphoma, and he is started on R-CHOP.
An 8-year-old boy presents to his pediatrician complaining of a non-productive cough and shortness of breath. On exam, he is noted to have diffuse expiratory wheezing, as well as an erythematous, hyperkeratotic rash localized to his antecubital and popliteal fossae. He is started on inhaled mometasone and topical triamcialone cream.
What are the various mechanisms by which this class of drugs treats overactive immune responses, and how was their use for such conditions first discovered?
Part 1: The Origin Story
As is often the case with landmark discoveries, the search for the origins of therapy leads us to institutions that serve as the common docking sites for clinicians and researchers. In the case of steroids, the institution is the Mayo Clinic, the scientist is Dr. Edward Calvin Kendall, and the clinician is Dr. Philip Showalter Hench. Dr. Hench had been the head of the Department of Rheumatic Diseases at the Mayo Clinic since 1926, and had the unfortunate distinction of specializing in chronic arthritis. The tools at Dr. Hench’s disposal were diverse—from antihistamines to cobra venom to an ineffectual practice known as “liquor pumping” in which about 10 cc of CSF would be aspirated and re-injected about 20 times in 40 minutes . The standard of care at this point in time was biweekly doses of gold, for which there was some objective evidence of response (reductions in erythrocyte sedimentation rates ).
In 1939, Dr. Hench published a report in the Annals of Rheumatic Disease titled, “Recent Researches on Arthritis and Rheumatism in the United States” , in which he remarked on spontaneous remission of one patient’s arthritic symptoms following administration of cinchophen, an analgesic formerly used for arthritis which was discontinued in the 1930s after it was found to cause fulminant hepatitis . In what would ultimately prove to be a prescient remark, he noted,
“The strangely beneficial effect of jaundice may be more basic than simply an antirheumatic phenomenon. When one patient developed cinchophen jaundice a ‘momentous thing’ occurred: the patient was promptly relieved not only of his chronic rheumatic symptoms, for which the cinchophen had been taken, but also of symptoms of severe hay fever. The ‘anti-allergic’ effect apparently continued, so that the next year during hay-fever season the patient was able literally to romp in ragweed.”
By the following year’s report , Hench reported resolution of arthritic symptoms in patients with jaundice in nineteen cases, with remissions lasting over one year. As one patient of his noted, “When jaundice came in the front door, rheumatism went out the back door.” Hench noted that resolution of symptoms required significant jaundice; mild jaundice was ineffective.
At this time, Dr. Hench also noted a second condition leading to unexpected, spontaneous resolution of arthritic symptoms: pregnancy. Hench described twenty-two pregnant patients in which, in greater than ninety percent of pregnancies, symptomatic arthritis resolved by the fourth week of pregnancy and lasted until four to six weeks post-partum. At this time, he first suggested the possibility that pregnancy and jaundice might alleviate arthritis via the same mechanism, noting,
“It seemed reasonable to suppose that the agents responsible for both of these phenomena are closely related, perhaps identical. If the potent common denominator of these two phenomena can be discovered, progress in treatment may be expected…It behooves physicians to learn how to stimulate in a practical way the beneficial mechanism so effectively stimulated temporarily by jaundice or pregnancy.”
The dramatic responses to jaundice and pregnancy led Hench to believe that a biochemical, rather than microbiological, phenomenon might underlie the pathophysiology of rheumatoid arthritis. He wrote:
“It became increasingly difficult to harmonize the microbic theory of the origin of rheumatoid arthritis with the phenomenon of relief of the disease by jaundice or pregnancy. It became easier, rather, to consider that rheumatoid arthritis may represent not a microbic disease, but some basic biochemical disturbance which is transiently corrected by some incidental biologic change common to a number of unrelated events” .
In the years following, Hench proposed and discarded a number of potential candidates for what he referred to as the “biochemical denominator” of pregnancy and liver disease, including female hormones and bile salts. Ultimately, Hench began to suspect that the common factor might be an adrenal hormone. This was based on the discovery that the liver metabolizes circulating steroids, as shown by the accumulation of steroid metabolites in bile salts [7, 8] and later confirmed to occur via a cytochrome P450-dependent mechanism ) as well as the description of adrenal cortical hypertrophy in pregnant rats, although the latter was later refuted when assessed in properly controlled studies . Interestingly, while attenuation of metabolism of endogenous corticosteroids appears to explain the remission of RA symptoms in patients with jaundice, the same cannot be said for pregnancy, in which neither circulating cortisol nor sex hormone levels appear to explain the ability of pregnancy to ameliorate RA symptoms—yet another example of a landmark discovery aided by a case of mistaken identity.
Nevertheless, Hench’s search for the common ground between pregnancy and liver dysfunction led him to explore the potential value of adrenocortical hormones in alleviating chronic arthritis. Upon further investigation, he found further anecdotal evidence suggesting a potential therapeutic role for adrenal hormones; in a piece titled, “Potential reversibility of rheumatoid arthritis” , he described how transient improvements in arthritic symptoms occurred after both starvation (“…marked relief presumably resulted after two or three days after fasting, but disappeared as soon as the fast was discontinued…”) and surgery (“How often has bona fide, if transient, relief appeared to follow tonsillectomy, only to fade after two or three weeks!”)—two states known to stimulate the adrenal cortex. As luck would have it, Dr. Edward Calvin Kendall, the director of biochemistry at Mayo who was already known for isolating thyroid hormone, had recently succeeded in isolating several different steroid hormones from both the adrenal cortex and from bile acids .
In April of 1949, Hench and Kendall published the first report of therapeutic steroid administration, “The effect of a hormone of the adrenal cortex (17-hydroxy-11dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis” , in which they noted marked improvement in multiple subjective features of disease with steroid administration, including pain, tenderness, range of motion, swelling, functional capacity, and appetite. In another prescient comment, Hench also remarked on a concurrent sense of euphoria, sometimes “to the point of mild, ‘comfortable’ insomnia,” seen after initiating therapy. Symptomatic relief was accompanied by objective improvements, including sedimentation rate, paraproteinemia, and anemia. Hench and Kendall received the Nobel Prize for physiology of medicine in 1950 for their discoveries on the structure and biological uses of adrenal hormones.
However, the utility of prednisone as a widely applicable therapy was limited until cortisone became more widely available when researchers developed a way to isolate the compound from the mold Rhizopus nigricans. In the meantime, corticosteroids were tested and found to be efficacious in the treatment of a number of medical conditions, including but not limited to autoimmune disease, atopic disease, infectious disease, and neoplastic disease. As is so often the case, the broad and potent therapeutic efficacy of steroids resulted in clinical implementation that far preceded, and possibly retarded, careful examination of the mechanisms underlying their activity. This is reflected in the modern characterization of steroid activity in any of these conditions with a broad, but ultimately uninformative, term: immunosuppression. Further investigation reveals that steroids act via diverse mechanisms, on a number of pathways and on a variety of targets which at least in part explains their ability to achieve targeted efficacy against several different medical conditions.
Part 2: The Shape-shifter
The diversity of steroid activity can be addressed in many different ways: temporal (immediate versus prolonged effect), target-cell type (lymphocytes versus granulocytes versus endothelial cells), or molecular mechanism (transcriptional versus post-translational). After a quick introduction to the various pathways that are affected by steroid therapy, however, the best way to characterize steroid activity may be via a combination of the disease for which they are used and the primary effect they have in that regard.
Steroids and Signaling
The mechanism by which steroids act can be separated broadly into two main categories: canonical pathways, in which steroids alter gene transcription, and non-canonical pathways, in which steroids act outside of the nucleus to exert non-genetic effects. The canonical glucocorticoid signaling pathway begins with cytoplasmic binding of steroid hormones to intracellular hormone receptors . The resulting ligand-receptor complex migrates to the nucleus and exerts phenotypic effects primarily at the level of gene regulation, either by directly binding promoter regions of genes at sites known as glucocorticoid responsive elements (GREs)  or by affecting binding by other transcription factors . Steroids exert many of their effects by activating transcription of proteins that either suppress generation of inflammatory proteins or by shutting off inflammatory signaling pathways. Perhaps more than the genes that they turn on, though, steroids can be better characterized by the genes that they turn off. The most prominent of these are the gene for interleukin-2, the master regulator of immune cell activation and survival, and the gene for eotaxin, a potent inducer of allergic responses in the lung.
While many of these mechanisms are well-described, they all operate by regulating transcriptional activity, a process that requires at least thirty minutes to show phenotypic effects. Therefore, these slow mechanisms cannot account for the more rapid symptomatic responses to steroid administration. Most prominent, and perhaps least well understood among these rapid effects, is steroid mediated cytotoxicity, an effect that is prominently implicated in control of allergic, infectious, and most notably, neoplastic disease. While some of the known mechanisms by which this is regulated will be discussed below, the overall picture is far from clear.
Steroids and Atopy
Unquestionably, the most common indication for chronic steroid use is for the management of atopic disease, including asthma, allergic rhinitis, and eczema. It should come as no surprise, then, that targeted steroid therapy in patients with bronchial asthma [17, 18], allergic rhinitis , and atopic dermatitis  rapidly followed the demonstration of its efficacy in patients with rheumatoid arthritis. However, the mechanism by which steroids suppress allergic responses appears to be quite distinct. One of the first objective responses seen in response to steroid treatment was seen in 1951, when steroids were found to induce profound eosinopenia in both mice  and humans . This effect occurred within five hours, which paralleled the time course of symptomatic relief in patients with allergic disease. The mechanism of eosinopenia is not fully understood, but steroid-mediated suppression of the eosinophil survival factors IL-3, IL-5, and GM-CSF  and activation of caspase-mediated eosinophil apoptosis  appear to be critical.
In addition to inducing frank eosinophil apoptosis, corticosteroids inhibit the profound local tissue eosinophilia seen in allergic disease. This has been thought to be secondary to diminished eosinophil migration and vascular adherence  seen in experiments done thirty years ago. The underlying mechanism for this impaired chemotaxis has recently been elucidated with the discovery of eotaxin, a potent eosinophil chemoattractant that is secreted from pulmonary epithelial cells following allergic stimulation . Eotaxin production is potently suppressed by dexamethasone, which may prevent local eosinophil accumulation and propagation of the allergic response. In an intriguing convergence between allergic and infectious disease, eotaxin production is also upregulated by TNF alpha and IL-1b, which is produced by alveolar macrophages within the lung when exposed to infectious organisms. This may explain the benefit of steroid therapy in lung diseases of infectious etiology such as PCP, in which dexamethasone blocks the pro-inflammatory response of the alveolar macrophages that are responding to PCP, thus preventing a superimposed allergic response . Conversely, this would also explain the development of fatal disseminated strongyloidiasis in patients receiving corticosteroid therapy , as eotaxin-mediated eosinophil recruitment appears critical for both direct and antibody-mediated anti-parasitic cytotoxicity .
Steroids and Infection/Inflammation
This brings us to the next common indication for steroids: inflammation. The constellation of symptoms seen in inflammation was first described in the first century A.D. by the Roman scholar Aulus Cornelius Celsus in his multivolume text, De Medicina: “Notae vero inflammationis sunt quatuor: rubor et tumor cum calore et dolore.” (“The marks of severe inflammation, there are four: redness and a swelling with heat and pain.”) We now know that the cardinal signs of inflammation are largely attributable to byproducts of the arachidonic acid pathway; phospholipases A2 and C liberate arachidonic acid, which is then converted to prostaglandins via cyclooxygenases, and leukotrienes via 5-lipoxygenase. Prostaglandins potently induce sensitization of spinal pain neurons (dolore) and increase the hypothalamic setpoint (calore), while leukotrienes serve as powerful neutrophil chemoattractants, perpetuating fluid extravasation and inflammation that results in redness and swelling (rubor et tumor). The arachidonic acid pathway, in turn, is potently activated both by the hallmark pro-inflammatory cytokines IL-1b [30, 31], IFN-g , and TNF-a  as well as bacterial cell wall components .
Steroids potently prevent this inflammation both acutely and chronically. Acutely, they suppress the mediators of inflammation (prostaglandins and leukotrienes) by inducing production of lipocortin A now known as Annexin I , a small peptide that binds to and inactivates phospholipase A2, thus suppressing the arachidonic acid pathway . This directly reduces both neutrophil recruitment  and vasogenic edema . Chronically, steroids suppress the pro-inflammatory cytokines that activate the arachidonic acid pathway by acting on the two major arms of the immune response:
– The innate response serves as the first line of defense, responding to conserved pathogen-associated molecular patterns (such as bacterial flagella or viral DNA), and producing pro-inflammatory cytokines . Steroids suppress cytokine production by innate immune cells by interfering with pathogen-activated toll-like receptor signaling  as well as by inducing degradation of IL-1B and interferon mRNA transcripts [41, 42].
– The adaptive response acts through B and T lymphocytes, which recognize activate specific immune responses orchestrated by highly specific antigen receptors. Steroids primarily suppress T cell responses primarily by inhibiting production of interleukin-2, originally named “blastogenic factor” in 1965 due to its ability to stimulate T cell activation and DNA synthesis [43, 44] and found subsequently to be required for T cell survival  and differentiation . Steroids suppress IL-2 production both at the gene regulatory level (by blocking the activity of transcription factors required for IL-2 gene activation [47-50]) and at the non-genomic level (by causing degradation of T cell antigen receptors and preventing T cell activation ).
Steroids and Neoplasia
Last, but certainly not least, among the indications for steroid therapy is induction of lymphocyte death, which is of particular benefit for patients with lymphoid malignancies. Initial attempts to study pharmacologic effects of steroids on lymphocyte survival were initially unfeasible due to the inability to maintain viable cells in ex vivo cultures. However, in 1953, a new technique, in which cultured intact rat lymph nodes were incubated in media perfused with oxygen, allowed demonstration of lysis of 50% of lymphocytes with intermediate doses (1 ug/mL) and 99% with high doses (10 mg/mL) of prednisone . As this effect was not reversible by addition of androgens, nucleic acids, insulin, or potassium, and the cells were observed to undergo pyknotic degeneration, the authors concluded that steroid binding activated a process of autonomous cell death. Soon after this description, high-dose steroids were administered to patients with adult ALL, subsequently inducing profound remissions within 24 hours . Later studies showed that binding of the glucocorticoid receptor was essential for steroid-mediated toxicity, as the lympholytic potency of steroids correlated directly with their affinity for the receptor . The morphology of lymphocyte cell death after steroid treatment (nuclear pyknosis and membrane blebbing) suggested apoptosis. This was strengthened by demonstration of DNA fragmentation in CML and ALL lymphoblasts following steroid treatment  and confirmed by the ability of anti-apoptotic proteins Bcl-2 and Bcl-XL to reverse steroid-mediated T cell death . Beyond that, however, little is known about the mechanism by which steroids induce lymphocyte apoptosis. It appears that bound glucocorticoid receptors activate an internal, caspase-dependent apoptosis pathway rather than an extrinsic, Fas-mediated pathway [24, 56] and that activation of this pathway appears to be calcium dependent , but further studies are clearly required to elucidate the full mechanism by which glucocorticoid receptors activate the intrinsic apoptosis pathway.
We must truly be grateful to the Nobel laureates Hench and Kendall for their discovery and initial characterization of glucocorticoids, a class of drugs that are able to improve patient quality of life across a dizzying array of illnesses. Yet it is just as clear that vast work remains to elucidate the complex and multifocal mechanisms by which steroids ameliorate diseases of inflammation, allergy, infection, and malignancy. The future will bring new understanding of these molecular pathways, targets, and drugs, but even until then, steroids will remain a potent and effective weapon in the war against chronic disease.
Santosh Vardhana is a 4th year medical student at NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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