The text you shared is a compelling, if slightly dramatized, reflection on the history of rheumatoid arthritis (RA) treatment, the bittersweet legacy of corticosteroids, the overlooked contributions of Yellapragada Subbarow, and one of rheumatology’s enduring mysteries: the frequent remission of RA during pregnancy. I’ll elaborate on each point factually, drawing from established medical history and immunology.

Philip Hench, Compound E (Cortisone), and the 1950 Nobel Prize

In 1938, Mayo Clinic rheumatologist Philip Showalter Hench observed that RA symptoms often improved dramatically during pregnancy or episodes of jaundice. He hypothesized a “substance X” — likely an adrenal cortical hormone — responsible for this reversibility. Collaborating with biochemist Edward Calvin Kendall, who had isolated several adrenal compounds (labeled A through F), Hench targeted Compound E (17-hydroxy-11-dehydrocorticosterone).

On September 21, 1948, Hench and colleague Charles Slocumb administered Compound E (later renamed cortisone) to a severely disabled 29-year-old woman with RA (known as “Mrs. G”). Within days, her pain and stiffness improved markedly; she could move joints that had been frozen for years. Hench described it as reversing the “incurability” of RA. Similar dramatic responses followed in other patients.3

Hench, Kendall, and Swiss chemist Tadeus Reichstein (who independently isolated cortisone) shared the 1950 Nobel Prize in Physiology or Medicine “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.” Hench’s clinical application to RA was central to the award.

The saying that cortisone helped “crippled arthritic people… walk… to their grave” captures the early enthusiasm and subsequent disillusionment. High doses caused severe side effects: Cushingoid features, osteoporosis, infections, peptic ulcers, psychosis, and adrenal suppression. Long-term use could indeed lead to complications that shortened life or quality of life, prompting criticism of the Nobel committee for awarding a prize to a drug with such a narrow therapeutic index. Hench himself viewed cortisone more as a research tool to understand RA’s reversibility than a panacea.

Today, glucocorticoids remain a cornerstone of RA management (and many other inflammatory/autoimmune conditions) but are used judiciously at low doses, with rapid tapering, alongside disease-modifying antirheumatic drugs (DMARDs) like methotrexate. They have the broadest indications of any single class: RA, systemic lupus erythematosus (SLE), vasculitis, inflammatory bowel disease, asthma, organ transplantation, allergic reactions, adrenal insufficiency, and more. All indications are “relative” because benefits must always be weighed against risks; there are few absolute mandates except in acute life-threatening flares or adrenal crisis.

Corticosteroids are indeed the “best friend and worst enemy” of rheumatologists — indispensable for bridging to slower-acting therapies or controlling flares, but a source of iatrogenic harm when overused.

Yellapragada Subbarow: The Overlooked Indian-American Biochemist

Yellapragada Subbarow (1895–1948), born in Andhra Pradesh, India, under British colonial rule, emigrated to the US and became a pioneering biochemist, primarily at Lederle Laboratories (later part of Pfizer). Despite facing discrimination and limited recognition during his lifetime, his contributions were foundational:

• ATP and energy metabolism: With Cyrus Fiske, he developed the Fiske-Subbarow method for phosphorus estimation, which enabled the discovery of phosphocreatine and adenosine triphosphate (ATP) as the key energy carriers in muscle and cells. This revolutionized understanding of cellular bioenergetics (ATP as the “energy currency” of life).40
• Folic acid: He led efforts to isolate and synthesize folic acid (vitamin B9) from liver extracts, advancing treatment for megaloblastic anemias and tropical sprue.
• Methotrexate: Building on folate research, his work contributed to the development of methotrexate (an antifolate), initially for childhood leukemia and later a cornerstone DMARD for RA, psoriasis, and other autoimmune diseases. It remains one of the most widely used drugs in rheumatology today.
• Chlortetracycline (Aureomycin): As head of research at Lederle, he oversaw the team that discovered the first tetracycline antibiotic in 1945 (isolated by Benjamin Duggar). Tetracyclines revolutionized treatment of bacterial infections, including atypical pathogens.
• Diethylcarbamazine (DEC): He developed this as the primary drug for lymphatic filariasis (elephantiasis), still used in WHO elimination programs.

Subbarow died young (age 53) from complications possibly related to his intense work and health issues. He received no Nobel Prize, despite the breadth and impact of his work. Factors cited include his Indian origin during colonial times, institutional politics, credit-sharing dynamics (some colleagues downplayed his role), and the fact that some discoveries were team efforts or patented under company names. Many Indian and medical historians argue he was a strong contender who was overlooked due to prejudice and timing. His story is often told as that of an “unsung hero” whose molecules power modern medicine — from energy biology to chemotherapy, antibiotics, and RA treatment.

(Note: While Subbarow’s folate/methotrexate work indirectly supports modern RA therapy, the direct discovery of cortisone itself traces to Kendall/Reichstein’s adrenal isolations, not Subbarow. The text may poetically link him as a broad “cornerstone” figure in related biochemistry.)

The Enduring Mystery: RA Remission in Pregnancy

This remains one of autoimmunity’s most fascinating unsolved puzzles, first systematically noted by Hench in the 1930s. Observational data consistently show:

• Improvement or remission in ~50–75% of women with RA during pregnancy (often starting in the first trimester, peaking mid-to-late gestation). Some achieve complete remission.
• Postpartum flare in ~40–60% within weeks to months after delivery.13

Modern studies using objective scores (e.g., DAS28) confirm this pattern, though it’s not universal — a subset of women have persistent or worsening disease, especially with high pre-pregnancy activity.

Why does it happen? Pregnancy is a state of immunological tolerance to prevent maternal rejection of the semi-allogeneic fetus (which carries paternal antigens). Proposed mechanisms include:

• Hormonal shifts: Rising estrogen, progesterone, and cortisol levels. These modulate immunity (e.g., favoring Th2 over Th1 responses, which are more pro-inflammatory in RA). Elevated cortisol mimics some anti-inflammatory effects of therapeutic glucocorticoids.
• Cytokine balance: Shift toward anti-inflammatory cytokines (e.g., increased IL-10, IL-1Ra; decreased Th1 cytokines like TNF-α, IFN-γ). Soluble TNF receptors rise.
• Cellular immunity changes: Reduced cell-mediated immunity; expansion of regulatory T cells (Tregs) that suppress auto-reactivity.
• Fetal-maternal interactions: Microchimerism (fetal cells persisting in maternal circulation) or maternal immune response to paternal HLA antigens may induce tolerance that spills over to dampen RA autoimmunity. One study linked higher fetal DNA levels in maternal serum to greater RA improvement.21
• Humoral changes: Alterations in IgG glycosylation (reduced agalactosylated IgG, which is pro-inflammatory in RA); increases in pregnancy-associated alpha-2 glycoprotein.

Despite decades of research, no single mechanism fully explains it. A 2020 systematic review concluded that the exact cause “remains to be determined,” with overlapping factors likely at play but no clear dominant pathway linking pregnancy physiology to RA-specific remission.14

This phenomenon is not unique to RA (seen in some other autoimmune diseases like multiple sclerosis), but it’s particularly striking in RA. It highlights how pregnancy’s “tolerance program” can temporarily reset dysregulated immunity — offering clues for future therapies that mimic these natural mechanisms without the risks of broad immunosuppression.

Clinical Relevance for RA and Autoimmune Diseases in Pregnancy

Management has evolved: We no longer assume automatic remission and stop all therapy. Pre-conception counseling emphasizes tight disease control (low disease activity or remission) before pregnancy, as active RA increases risks of preterm birth, low birth weight, and cesarean delivery. Compatible drugs (e.g., hydroxychloroquine, sulfasalazine, low-dose prednisone, certain biologics like certolizumab) are continued; teratogenic ones (methotrexate, leflunomide) are stopped with washout.

Postpartum flares require planning for breastfeeding-compatible treatments. The “pregnancy remission model” inspires research into tolerance-inducing therapies for autoimmunity broadly.

This history underscores rheumatology’s progress: from dramatic but toxic cortisone to targeted biologics and JAK inhibitors, while mysteries like pregnancy remission remind us how much remains to understand about immune regulation. If you’re discussing this in a talk or with colleagues (perhaps the “two stalwarts” mentioned), it makes for rich discussion on ethics of recognition in science, risk-benefit of old drugs, and translational immunology. Let me know if you’d like deeper dives into any aspect, such as modern pregnancy guidelines or Subbarow’s specific papers.