Psoriatic Arthritis

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

Key clinical point: Pre-existing radiographic damage was substantially prevalent in patients with psoriatic arthritis (PsA), with secukinumab therapy being associated with the inhibition of joint tenderness and swelling; however, high baseline radiographic damage reduced the likelihood of achieving minimal disease activity (MDA).

Major finding: Overall, 86% and 60% of patients had erosion and joint space narrowing (JSN) scores of >0, respectively. At week 16 and 52, 150 and 300 mg secukinumab reduced tender and swollen joint counts across all values of baseline erosion and JSN scores; however, patients with higher baseline erosion and JSN scores were less likely to achieve MDA.

Study details: This was a post hoc analysis of two phase 3 trials, FUTURE 1 and FUTURE 5, including 1554 patients with PsA who received 300 or 150 mg secukinumab with or without a loading dose.

Disclosures: This study received funding from Novartis Pharma AG. Four authors declared being employees of or owning stocks in Novartis. Seven authors declared ties with various sources, including Novartis.

Source: Mease P et al. Quantification of pre-existing radiographic damage and its relationship with joint activity and long-term clinical outcomes with secukinumab therapy in patients with psoriatic arthritis. Arthritis Res Ther. 2022;24(1):283 (Dec 28). Doi: 10.1186/s13075-022-02944-1

Key clinical point: Pre-existing radiographic damage was substantially prevalent in patients with psoriatic arthritis (PsA), with secukinumab therapy being associated with the inhibition of joint tenderness and swelling; however, high baseline radiographic damage reduced the likelihood of achieving minimal disease activity (MDA).

Major finding: Overall, 86% and 60% of patients had erosion and joint space narrowing (JSN) scores of >0, respectively. At week 16 and 52, 150 and 300 mg secukinumab reduced tender and swollen joint counts across all values of baseline erosion and JSN scores; however, patients with higher baseline erosion and JSN scores were less likely to achieve MDA.

Study details: This was a post hoc analysis of two phase 3 trials, FUTURE 1 and FUTURE 5, including 1554 patients with PsA who received 300 or 150 mg secukinumab with or without a loading dose.

Disclosures: This study received funding from Novartis Pharma AG. Four authors declared being employees of or owning stocks in Novartis. Seven authors declared ties with various sources, including Novartis.

Source: Mease P et al. Quantification of pre-existing radiographic damage and its relationship with joint activity and long-term clinical outcomes with secukinumab therapy in patients with psoriatic arthritis. Arthritis Res Ther. 2022;24(1):283 (Dec 28). Doi: 10.1186/s13075-022-02944-1

Key clinical point: Pre-existing radiographic damage was substantially prevalent in patients with psoriatic arthritis (PsA), with secukinumab therapy being associated with the inhibition of joint tenderness and swelling; however, high baseline radiographic damage reduced the likelihood of achieving minimal disease activity (MDA).

Major finding: Overall, 86% and 60% of patients had erosion and joint space narrowing (JSN) scores of >0, respectively. At week 16 and 52, 150 and 300 mg secukinumab reduced tender and swollen joint counts across all values of baseline erosion and JSN scores; however, patients with higher baseline erosion and JSN scores were less likely to achieve MDA.

Study details: This was a post hoc analysis of two phase 3 trials, FUTURE 1 and FUTURE 5, including 1554 patients with PsA who received 300 or 150 mg secukinumab with or without a loading dose.

Disclosures: This study received funding from Novartis Pharma AG. Four authors declared being employees of or owning stocks in Novartis. Seven authors declared ties with various sources, including Novartis.

Source: Mease P et al. Quantification of pre-existing radiographic damage and its relationship with joint activity and long-term clinical outcomes with secukinumab therapy in patients with psoriatic arthritis. Arthritis Res Ther. 2022;24(1):283 (Dec 28). Doi: 10.1186/s13075-022-02944-1

Key clinical point: Uveitis related to psoriatic arthritis (PsA) had a prevalence of approximately 5%, presented as an acute and recurrent disease with anterior and unilateral involvement, and was associated with impaired quality of life and increased functional disability.

Major finding: Uveitis onset was acute in all cases, with 50% being recurrent and 80% being anterior and unilateral. Patients with vs without uveitis had a higher PsA impact of Disease Score (P  =  .001) and Bath Ankylosing Spondylitis Functional Index (P  =  .01) and a higher prevalence of HLA-B27 (P < .0001), sacroiliitis on magnetic resonance imaging (P  =  .027), and ocular surface pathology (P  =  .021).

Study details: This retrospective longitudinal study included 406 patients with PsA, of which 4.9% of patients experienced ≥1 episode of uveitis.

Disclosures: This study did not receive any specific funding. Several authors declared receiving grants, research support, consulting fees, or honoraria for participation in company-sponsored speaker's bureaus from various sources.

Source: De Vicente Delmás A et al. Uveitis in psoriatic arthritis: Study of 406 patients in a single university center and literature review. RMD Open. 2023;9(1):e002781 (Jan 12). Doi: 10.1136/rmdopen-2022-002781

Key clinical point: Uveitis related to psoriatic arthritis (PsA) had a prevalence of approximately 5%, presented as an acute and recurrent disease with anterior and unilateral involvement, and was associated with impaired quality of life and increased functional disability.

Major finding: Uveitis onset was acute in all cases, with 50% being recurrent and 80% being anterior and unilateral. Patients with vs without uveitis had a higher PsA impact of Disease Score (P  =  .001) and Bath Ankylosing Spondylitis Functional Index (P  =  .01) and a higher prevalence of HLA-B27 (P < .0001), sacroiliitis on magnetic resonance imaging (P  =  .027), and ocular surface pathology (P  =  .021).

Study details: This retrospective longitudinal study included 406 patients with PsA, of which 4.9% of patients experienced ≥1 episode of uveitis.

Disclosures: This study did not receive any specific funding. Several authors declared receiving grants, research support, consulting fees, or honoraria for participation in company-sponsored speaker's bureaus from various sources.

Source: De Vicente Delmás A et al. Uveitis in psoriatic arthritis: Study of 406 patients in a single university center and literature review. RMD Open. 2023;9(1):e002781 (Jan 12). Doi: 10.1136/rmdopen-2022-002781

Key clinical point: Uveitis related to psoriatic arthritis (PsA) had a prevalence of approximately 5%, presented as an acute and recurrent disease with anterior and unilateral involvement, and was associated with impaired quality of life and increased functional disability.

Major finding: Uveitis onset was acute in all cases, with 50% being recurrent and 80% being anterior and unilateral. Patients with vs without uveitis had a higher PsA impact of Disease Score (P  =  .001) and Bath Ankylosing Spondylitis Functional Index (P  =  .01) and a higher prevalence of HLA-B27 (P < .0001), sacroiliitis on magnetic resonance imaging (P  =  .027), and ocular surface pathology (P  =  .021).

Study details: This retrospective longitudinal study included 406 patients with PsA, of which 4.9% of patients experienced ≥1 episode of uveitis.

Disclosures: This study did not receive any specific funding. Several authors declared receiving grants, research support, consulting fees, or honoraria for participation in company-sponsored speaker's bureaus from various sources.

Source: De Vicente Delmás A et al. Uveitis in psoriatic arthritis: Study of 406 patients in a single university center and literature review. RMD Open. 2023;9(1):e002781 (Jan 12). Doi: 10.1136/rmdopen-2022-002781

Key clinical point: Targeted musculoskeletal ultrasound performed by trained dermatologists improved the accuracy of early psoriatic arthritis (PsA) diagnosis and may eventually decrease referral to rheumatologists.

Major finding: Use of musculoskeletal ultrasound changed the sensitivity and specificity of early PsA screening strategy from 88.2% (95% CI 58.1%-94.6%) and 54.4% (95% CI 44.8%-64.1%) to 70.6% (95% CI 38.4%-81.9%) and 90.4% (95% CI 83.9%-95.6%), respectively. Overall, 45 of the 46 patients were cleared of preliminary diagnosis-based PsA suspicion after musculoskeletal ultrasound.

Study details: This was a prospective study including 140 patients with psoriasis who presented to dermatologists with arthralgia, of which 19 patients were diagnosed with PsA by a rheumatologist.

Disclosures: This study was supported by Novartis Pharma. The authors declared no conflicts of interest.

Source: Grobelski J et al. Prospective double-blind study on the value of musculoskeletal ultrasound by dermatologists as a screening instrument for psoriatic arthritis. Rheumatology (Oxford). 2022 (Dec 22). Doi: 10.1093/rheumatology/keac702

Key clinical point: Targeted musculoskeletal ultrasound performed by trained dermatologists improved the accuracy of early psoriatic arthritis (PsA) diagnosis and may eventually decrease referral to rheumatologists.

Major finding: Use of musculoskeletal ultrasound changed the sensitivity and specificity of early PsA screening strategy from 88.2% (95% CI 58.1%-94.6%) and 54.4% (95% CI 44.8%-64.1%) to 70.6% (95% CI 38.4%-81.9%) and 90.4% (95% CI 83.9%-95.6%), respectively. Overall, 45 of the 46 patients were cleared of preliminary diagnosis-based PsA suspicion after musculoskeletal ultrasound.

Study details: This was a prospective study including 140 patients with psoriasis who presented to dermatologists with arthralgia, of which 19 patients were diagnosed with PsA by a rheumatologist.

Disclosures: This study was supported by Novartis Pharma. The authors declared no conflicts of interest.

Source: Grobelski J et al. Prospective double-blind study on the value of musculoskeletal ultrasound by dermatologists as a screening instrument for psoriatic arthritis. Rheumatology (Oxford). 2022 (Dec 22). Doi: 10.1093/rheumatology/keac702

Key clinical point: Targeted musculoskeletal ultrasound performed by trained dermatologists improved the accuracy of early psoriatic arthritis (PsA) diagnosis and may eventually decrease referral to rheumatologists.

Major finding: Use of musculoskeletal ultrasound changed the sensitivity and specificity of early PsA screening strategy from 88.2% (95% CI 58.1%-94.6%) and 54.4% (95% CI 44.8%-64.1%) to 70.6% (95% CI 38.4%-81.9%) and 90.4% (95% CI 83.9%-95.6%), respectively. Overall, 45 of the 46 patients were cleared of preliminary diagnosis-based PsA suspicion after musculoskeletal ultrasound.

Study details: This was a prospective study including 140 patients with psoriasis who presented to dermatologists with arthralgia, of which 19 patients were diagnosed with PsA by a rheumatologist.

Disclosures: This study was supported by Novartis Pharma. The authors declared no conflicts of interest.

Source: Grobelski J et al. Prospective double-blind study on the value of musculoskeletal ultrasound by dermatologists as a screening instrument for psoriatic arthritis. Rheumatology (Oxford). 2022 (Dec 22). Doi: 10.1093/rheumatology/keac702

Key clinical point: Ustekinumab and tumor necrosis factor inhibitors (TNFi) demonstrated similar efficacy and persistence and were well tolerated as first-line to third-line biologic treatment for psoriatic arthritis (PsA).

Major finding: Over 3 years, treatment with ustekinumab vs TNFi resulted in comparable odds of attaining clinical Disease Activity Index for PsA low disease activity (adjusted odds ratio [aOR] 0.89; 95% CI 0.63-1.26) and remission (aOR 0.72; 95% CI 0.50-1.05), similar risk for stopping/switching treatment (adjusted hazard ratio 0.87; 95% CI 0.68-1.11), and no clinically relevant difference in serious adverse event rates (6.3% vs 7.2%).

Study details: The data come from an analysis of 895 patients with PsA from PsABio, a prospective observational study, who were prescribed first-line to third-line ustekinumab or a TNFi.

Disclosures: This study was sponsored by Janssen. Two authors declared being current or former employees of or owning stocks in Johnson & Johnson or Janssen. Several authors reported receiving personal fees, consulting fees, grants, payments, or honoraria from Janssen and various other sources.

Source: Gossec L et al. Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: Final 3-year results from the PsABio real-world study. Ann Rheum Dis. 2022 (Dec 13). Doi: 10.1136/ard-2022-222879

Key clinical point: Ustekinumab and tumor necrosis factor inhibitors (TNFi) demonstrated similar efficacy and persistence and were well tolerated as first-line to third-line biologic treatment for psoriatic arthritis (PsA).

Major finding: Over 3 years, treatment with ustekinumab vs TNFi resulted in comparable odds of attaining clinical Disease Activity Index for PsA low disease activity (adjusted odds ratio [aOR] 0.89; 95% CI 0.63-1.26) and remission (aOR 0.72; 95% CI 0.50-1.05), similar risk for stopping/switching treatment (adjusted hazard ratio 0.87; 95% CI 0.68-1.11), and no clinically relevant difference in serious adverse event rates (6.3% vs 7.2%).

Study details: The data come from an analysis of 895 patients with PsA from PsABio, a prospective observational study, who were prescribed first-line to third-line ustekinumab or a TNFi.

Disclosures: This study was sponsored by Janssen. Two authors declared being current or former employees of or owning stocks in Johnson & Johnson or Janssen. Several authors reported receiving personal fees, consulting fees, grants, payments, or honoraria from Janssen and various other sources.

Source: Gossec L et al. Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: Final 3-year results from the PsABio real-world study. Ann Rheum Dis. 2022 (Dec 13). Doi: 10.1136/ard-2022-222879

Key clinical point: Ustekinumab and tumor necrosis factor inhibitors (TNFi) demonstrated similar efficacy and persistence and were well tolerated as first-line to third-line biologic treatment for psoriatic arthritis (PsA).

Major finding: Over 3 years, treatment with ustekinumab vs TNFi resulted in comparable odds of attaining clinical Disease Activity Index for PsA low disease activity (adjusted odds ratio [aOR] 0.89; 95% CI 0.63-1.26) and remission (aOR 0.72; 95% CI 0.50-1.05), similar risk for stopping/switching treatment (adjusted hazard ratio 0.87; 95% CI 0.68-1.11), and no clinically relevant difference in serious adverse event rates (6.3% vs 7.2%).

Study details: The data come from an analysis of 895 patients with PsA from PsABio, a prospective observational study, who were prescribed first-line to third-line ustekinumab or a TNFi.

Disclosures: This study was sponsored by Janssen. Two authors declared being current or former employees of or owning stocks in Johnson & Johnson or Janssen. Several authors reported receiving personal fees, consulting fees, grants, payments, or honoraria from Janssen and various other sources.

Source: Gossec L et al. Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: Final 3-year results from the PsABio real-world study. Ann Rheum Dis. 2022 (Dec 13). Doi: 10.1136/ard-2022-222879

Key clinical point: Fluorescence-optical imaging (FOI) successfully detected the early signs of musculoskeletal inflammation in hands and predicted transition from psoriasis to psoriatic arthritis (PsA) at initial stages in patients with psoriasis at risk for PsA.

Major finding: PsA diagnosis was confirmed by clinical evaluations (CE) in 50% of patients with psoriasis at risk for PsA and an additional 30% of patients who were positive on FOI. Compared with previously published annual incidence rates, the incidence rate of PsA was higher among patients positive on FOI but negative on CE (11.8%).

Study details: This was an investigator-initiated prospective two-part observational cohort study including 389 patients with plaque psoriasis who were at risk for PsA.

Disclosures: This study was sponsored by Fraunhofer ITMP and supported by a research grant from Pfizer Germany. Five authors declared being supported by Fraunhofer ITMP. Several authors reported ties with various sources, including Pfizer. GR Burmester reported being on the editorial board of RMD Open.

Source: Koehm M et al. Fluorescence-optical imaging as a promising easy-to-use imaging biomarker to increase early psoriatic arthritis detection in patients with psoriasis: A cross-sectional cohort study with follow-up. RMD Open. 2022;8(2):e002682 (Dec 6). Doi: 10.1136/rmdopen-2022-002682

Key clinical point: Fluorescence-optical imaging (FOI) successfully detected the early signs of musculoskeletal inflammation in hands and predicted transition from psoriasis to psoriatic arthritis (PsA) at initial stages in patients with psoriasis at risk for PsA.

Major finding: PsA diagnosis was confirmed by clinical evaluations (CE) in 50% of patients with psoriasis at risk for PsA and an additional 30% of patients who were positive on FOI. Compared with previously published annual incidence rates, the incidence rate of PsA was higher among patients positive on FOI but negative on CE (11.8%).

Study details: This was an investigator-initiated prospective two-part observational cohort study including 389 patients with plaque psoriasis who were at risk for PsA.

Disclosures: This study was sponsored by Fraunhofer ITMP and supported by a research grant from Pfizer Germany. Five authors declared being supported by Fraunhofer ITMP. Several authors reported ties with various sources, including Pfizer. GR Burmester reported being on the editorial board of RMD Open.

Source: Koehm M et al. Fluorescence-optical imaging as a promising easy-to-use imaging biomarker to increase early psoriatic arthritis detection in patients with psoriasis: A cross-sectional cohort study with follow-up. RMD Open. 2022;8(2):e002682 (Dec 6). Doi: 10.1136/rmdopen-2022-002682

Key clinical point: Fluorescence-optical imaging (FOI) successfully detected the early signs of musculoskeletal inflammation in hands and predicted transition from psoriasis to psoriatic arthritis (PsA) at initial stages in patients with psoriasis at risk for PsA.

Major finding: PsA diagnosis was confirmed by clinical evaluations (CE) in 50% of patients with psoriasis at risk for PsA and an additional 30% of patients who were positive on FOI. Compared with previously published annual incidence rates, the incidence rate of PsA was higher among patients positive on FOI but negative on CE (11.8%).

Study details: This was an investigator-initiated prospective two-part observational cohort study including 389 patients with plaque psoriasis who were at risk for PsA.

Disclosures: This study was sponsored by Fraunhofer ITMP and supported by a research grant from Pfizer Germany. Five authors declared being supported by Fraunhofer ITMP. Several authors reported ties with various sources, including Pfizer. GR Burmester reported being on the editorial board of RMD Open.

Source: Koehm M et al. Fluorescence-optical imaging as a promising easy-to-use imaging biomarker to increase early psoriatic arthritis detection in patients with psoriasis: A cross-sectional cohort study with follow-up. RMD Open. 2022;8(2):e002682 (Dec 6). Doi: 10.1136/rmdopen-2022-002682

Key clinical point: Patient-reported flares occurred more frequently than physician-reported flares and demonstrated moderate agreement with worsening of disease activity in psoriatic arthritis (DAPSA), with patients with psoriatic arthritis (PsA) who reported flares having a significantly more active disease.

Major finding: Overall, 27.0% and 17.6% of patients had patient-reported and physician-reported flares, respectively, with patient-reported flare demonstrating 69.8% crude agreement with DAPSA (prevalence adjusted bias adjusted kappa  =  0.40) and patients reporting vs not reporting disease flare indicating a significantly more active disease for all outcomes (P < .001) except skin lesions (P  =  .01).

Study details: This was a longitudinal observational study including 222 patients with PsA.

Disclosures: This study was supported by unrestricted investigator-initiated research grant from Pfizer. Three authors declared receiving funds, research grants, or support from the US National Institutes of Health and other sources.

Source: Sousa M et al. Patient-defined flares and disease activity worsening in 222 patients with psoriatic arthritis from 14 countries. Joint Bone Spine. 2022;90(3):105511 (Dec 15). Doi: 10.1016/j.jbspin.2022.105511

Key clinical point: Patient-reported flares occurred more frequently than physician-reported flares and demonstrated moderate agreement with worsening of disease activity in psoriatic arthritis (DAPSA), with patients with psoriatic arthritis (PsA) who reported flares having a significantly more active disease.

Major finding: Overall, 27.0% and 17.6% of patients had patient-reported and physician-reported flares, respectively, with patient-reported flare demonstrating 69.8% crude agreement with DAPSA (prevalence adjusted bias adjusted kappa  =  0.40) and patients reporting vs not reporting disease flare indicating a significantly more active disease for all outcomes (P < .001) except skin lesions (P  =  .01).

Study details: This was a longitudinal observational study including 222 patients with PsA.

Disclosures: This study was supported by unrestricted investigator-initiated research grant from Pfizer. Three authors declared receiving funds, research grants, or support from the US National Institutes of Health and other sources.

Source: Sousa M et al. Patient-defined flares and disease activity worsening in 222 patients with psoriatic arthritis from 14 countries. Joint Bone Spine. 2022;90(3):105511 (Dec 15). Doi: 10.1016/j.jbspin.2022.105511

Key clinical point: Patient-reported flares occurred more frequently than physician-reported flares and demonstrated moderate agreement with worsening of disease activity in psoriatic arthritis (DAPSA), with patients with psoriatic arthritis (PsA) who reported flares having a significantly more active disease.

Major finding: Overall, 27.0% and 17.6% of patients had patient-reported and physician-reported flares, respectively, with patient-reported flare demonstrating 69.8% crude agreement with DAPSA (prevalence adjusted bias adjusted kappa  =  0.40) and patients reporting vs not reporting disease flare indicating a significantly more active disease for all outcomes (P < .001) except skin lesions (P  =  .01).

Study details: This was a longitudinal observational study including 222 patients with PsA.

Disclosures: This study was supported by unrestricted investigator-initiated research grant from Pfizer. Three authors declared receiving funds, research grants, or support from the US National Institutes of Health and other sources.

Source: Sousa M et al. Patient-defined flares and disease activity worsening in 222 patients with psoriatic arthritis from 14 countries. Joint Bone Spine. 2022;90(3):105511 (Dec 15). Doi: 10.1016/j.jbspin.2022.105511

Key clinical point: Ultrasound-detected residual inflammation in peripheral articular structures may be present even in patients with psoriatic arthritis (PsA) who have achieved stable minimal disease activity (MDA), with residual inflammation being more prevalent in patients with shorter duration of MDA.

Major finding: Despite stable MDA, 54.2% of patients had ≥1 positive Power Doppler (PD) signal in examined tissues, with 19.4% and 23.6% of patients showing ≥1 joint and enthesis with a positive PD signal, respectively. A higher proportion of patients with ≤12 vs >12 months of sustained MDA had ≥1 ultrasound detected PD lesion (55% vs 41%; P  =  .024).

Study details: This cross-sectional study included 72 patients with PsA who were on biologic or conventional synthetic disease-modifying antirheumatic drugs for ≥12 months and in continuous MDA for ≥6 months.

Disclosures: This study did not declare the source of funding. The authors declared no conflicts of interest.

Source: Macchioni P et al. Residual inflammation in psoriatic arthritis patients in stable minimal disease activity. Front Med. 2022;9:1096547 (Dec 20). Doi: 10.3389/fmed.2022.1096547

Key clinical point: Ultrasound-detected residual inflammation in peripheral articular structures may be present even in patients with psoriatic arthritis (PsA) who have achieved stable minimal disease activity (MDA), with residual inflammation being more prevalent in patients with shorter duration of MDA.

Major finding: Despite stable MDA, 54.2% of patients had ≥1 positive Power Doppler (PD) signal in examined tissues, with 19.4% and 23.6% of patients showing ≥1 joint and enthesis with a positive PD signal, respectively. A higher proportion of patients with ≤12 vs >12 months of sustained MDA had ≥1 ultrasound detected PD lesion (55% vs 41%; P  =  .024).

Study details: This cross-sectional study included 72 patients with PsA who were on biologic or conventional synthetic disease-modifying antirheumatic drugs for ≥12 months and in continuous MDA for ≥6 months.

Disclosures: This study did not declare the source of funding. The authors declared no conflicts of interest.

Source: Macchioni P et al. Residual inflammation in psoriatic arthritis patients in stable minimal disease activity. Front Med. 2022;9:1096547 (Dec 20). Doi: 10.3389/fmed.2022.1096547

Key clinical point: Ultrasound-detected residual inflammation in peripheral articular structures may be present even in patients with psoriatic arthritis (PsA) who have achieved stable minimal disease activity (MDA), with residual inflammation being more prevalent in patients with shorter duration of MDA.

Major finding: Despite stable MDA, 54.2% of patients had ≥1 positive Power Doppler (PD) signal in examined tissues, with 19.4% and 23.6% of patients showing ≥1 joint and enthesis with a positive PD signal, respectively. A higher proportion of patients with ≤12 vs >12 months of sustained MDA had ≥1 ultrasound detected PD lesion (55% vs 41%; P  =  .024).

Study details: This cross-sectional study included 72 patients with PsA who were on biologic or conventional synthetic disease-modifying antirheumatic drugs for ≥12 months and in continuous MDA for ≥6 months.

Disclosures: This study did not declare the source of funding. The authors declared no conflicts of interest.

Source: Macchioni P et al. Residual inflammation in psoriatic arthritis patients in stable minimal disease activity. Front Med. 2022;9:1096547 (Dec 20). Doi: 10.3389/fmed.2022.1096547

Key clinical point: The overall incidence of hematologic malignancies was not higher among patients with psoriatic arthritis (PsA) receiving treatment with tumor necrosis factor inhibitors (TNFi) compared with those who were biological disease-modifying antirheumatic drug (bDMARD) naive or individuals from the general population.

Major finding: Overall, the incidence rate of hematologic malignancies was similar among patients treated with TNFi vs those who were bDMARD naive (incidence rate ratio [IRR] 0.96; 95% CI 0.68-1.35) or individuals in the general population (IRR 1.35; 95% CI 0.98-1.86).

Study details: Findings are from a cohort study including patients with PsA who either initiated first TNFi (n = 10,621) or were bDMARD-naive (n = 18,387) and matched comparators from the general population.

Disclosures: This study was supported by NordForsk and FOREUM. B Delcoigne declared being partly employed by ARTIS/Swedish Biologics Register. Several authors reported receiving grants or research support or serving as consultants for or on speaker’s bureaus of various sources.

Source: Cordtz RL et al. Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: A Nordic cohort study. RMD Open. 2022;8(2):e002776 (Dec 23). Doi: 10.1136/rmdopen-2022-002776

Key clinical point: The overall incidence of hematologic malignancies was not higher among patients with psoriatic arthritis (PsA) receiving treatment with tumor necrosis factor inhibitors (TNFi) compared with those who were biological disease-modifying antirheumatic drug (bDMARD) naive or individuals from the general population.

Major finding: Overall, the incidence rate of hematologic malignancies was similar among patients treated with TNFi vs those who were bDMARD naive (incidence rate ratio [IRR] 0.96; 95% CI 0.68-1.35) or individuals in the general population (IRR 1.35; 95% CI 0.98-1.86).

Study details: Findings are from a cohort study including patients with PsA who either initiated first TNFi (n = 10,621) or were bDMARD-naive (n = 18,387) and matched comparators from the general population.

Disclosures: This study was supported by NordForsk and FOREUM. B Delcoigne declared being partly employed by ARTIS/Swedish Biologics Register. Several authors reported receiving grants or research support or serving as consultants for or on speaker’s bureaus of various sources.

Source: Cordtz RL et al. Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: A Nordic cohort study. RMD Open. 2022;8(2):e002776 (Dec 23). Doi: 10.1136/rmdopen-2022-002776

Key clinical point: The overall incidence of hematologic malignancies was not higher among patients with psoriatic arthritis (PsA) receiving treatment with tumor necrosis factor inhibitors (TNFi) compared with those who were biological disease-modifying antirheumatic drug (bDMARD) naive or individuals from the general population.

Major finding: Overall, the incidence rate of hematologic malignancies was similar among patients treated with TNFi vs those who were bDMARD naive (incidence rate ratio [IRR] 0.96; 95% CI 0.68-1.35) or individuals in the general population (IRR 1.35; 95% CI 0.98-1.86).

Study details: Findings are from a cohort study including patients with PsA who either initiated first TNFi (n = 10,621) or were bDMARD-naive (n = 18,387) and matched comparators from the general population.

Disclosures: This study was supported by NordForsk and FOREUM. B Delcoigne declared being partly employed by ARTIS/Swedish Biologics Register. Several authors reported receiving grants or research support or serving as consultants for or on speaker’s bureaus of various sources.

Source: Cordtz RL et al. Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: A Nordic cohort study. RMD Open. 2022;8(2):e002776 (Dec 23). Doi: 10.1136/rmdopen-2022-002776

Key clinical point: The failure to achieve minimal disease activity (MDA) in the first year after the diagnosis of psoriatic arthritis (PsA) was associated with worse health-related quality of life and health status, functional impairment, fatigue, pain, and higher anxiety and depression.

Major finding: Compared with patients who achieved sustained MDA in the first year after diagnosis, those who did not achieve MDA had higher scores for pain (estimated mean difference [β] 35.38), fatigue (β 17.88), and functional ability (β 0.81; all P < .001) and higher anxiety and depression (both P < .001) during follow-up, which persisted despite treatment intensification.

Study details: This prospective cohort study included 240 patients with newly diagnosed PsA with oligoarthritis or polyarthritis  who were disease-modifying antirheumatic drug naive.

Disclosures: This study was sponsored by UCB Pharma. S Welby and AR Prickett declared being stockholders of UCB.

Source: Snoeck Henkemans SVJ et al. Importance of quick attainment of minimal disease activity for a positive impact on lives of patients with psoriatic arthritis. RMD Open. 2022;8(2):e002706 (Dec 7). Doi: 10.1136/rmdopen-2022-002706

Key clinical point: The failure to achieve minimal disease activity (MDA) in the first year after the diagnosis of psoriatic arthritis (PsA) was associated with worse health-related quality of life and health status, functional impairment, fatigue, pain, and higher anxiety and depression.

Major finding: Compared with patients who achieved sustained MDA in the first year after diagnosis, those who did not achieve MDA had higher scores for pain (estimated mean difference [β] 35.38), fatigue (β 17.88), and functional ability (β 0.81; all P < .001) and higher anxiety and depression (both P < .001) during follow-up, which persisted despite treatment intensification.

Study details: This prospective cohort study included 240 patients with newly diagnosed PsA with oligoarthritis or polyarthritis  who were disease-modifying antirheumatic drug naive.

Disclosures: This study was sponsored by UCB Pharma. S Welby and AR Prickett declared being stockholders of UCB.

Source: Snoeck Henkemans SVJ et al. Importance of quick attainment of minimal disease activity for a positive impact on lives of patients with psoriatic arthritis. RMD Open. 2022;8(2):e002706 (Dec 7). Doi: 10.1136/rmdopen-2022-002706

Key clinical point: The failure to achieve minimal disease activity (MDA) in the first year after the diagnosis of psoriatic arthritis (PsA) was associated with worse health-related quality of life and health status, functional impairment, fatigue, pain, and higher anxiety and depression.

Major finding: Compared with patients who achieved sustained MDA in the first year after diagnosis, those who did not achieve MDA had higher scores for pain (estimated mean difference [β] 35.38), fatigue (β 17.88), and functional ability (β 0.81; all P < .001) and higher anxiety and depression (both P < .001) during follow-up, which persisted despite treatment intensification.

Study details: This prospective cohort study included 240 patients with newly diagnosed PsA with oligoarthritis or polyarthritis  who were disease-modifying antirheumatic drug naive.

Disclosures: This study was sponsored by UCB Pharma. S Welby and AR Prickett declared being stockholders of UCB.

Source: Snoeck Henkemans SVJ et al. Importance of quick attainment of minimal disease activity for a positive impact on lives of patients with psoriatic arthritis. RMD Open. 2022;8(2):e002706 (Dec 7). Doi: 10.1136/rmdopen-2022-002706