Sirolimus may be an effective rescue treatment option for children with refractory inflammatory bowel disease, according to Dr. Mohamed Mutalib and his associates.

In a retrospective analysis of 11 ulcerative colitis (UC) and 3 Crohn’s disease patients treated with sirolimus, 5 of the UC patients and all of the Crohn’s disease patients achieved clinical remission. An additional 2 UC patients achieved clinical response. The remaining 4 UC patients did not respond to sirolimus treatment.

Mucosal healing was achieved in 5 of 11 UC patients and 2 of 3 Crohn’s patients. Clinical response to treatment occurred at least 2 weeks after treatment was started. The only significant side effect reported was minor gastrointestinal distress.

“Our data provide compelling evidence that sirolimus is effective as rescue therapy in a subgroup of children with severe [inflammatory bowel disease] refractory to conventional therapies by inducing both clinical remission and mucosal healing. However, randomized placebo-controlled studies are warranted to extend our encouraging initial findings,” the investigators concluded.

Find the full study in the Journal of Crohn’s and Colitis (doi: 10.1016/j.crohns.2014.08.014).

[email protected]

Sirolimus may be an effective rescue treatment option for children with refractory inflammatory bowel disease, according to Dr. Mohamed Mutalib and his associates.

In a retrospective analysis of 11 ulcerative colitis (UC) and 3 Crohn’s disease patients treated with sirolimus, 5 of the UC patients and all of the Crohn’s disease patients achieved clinical remission. An additional 2 UC patients achieved clinical response. The remaining 4 UC patients did not respond to sirolimus treatment.

Mucosal healing was achieved in 5 of 11 UC patients and 2 of 3 Crohn’s patients. Clinical response to treatment occurred at least 2 weeks after treatment was started. The only significant side effect reported was minor gastrointestinal distress.

“Our data provide compelling evidence that sirolimus is effective as rescue therapy in a subgroup of children with severe [inflammatory bowel disease] refractory to conventional therapies by inducing both clinical remission and mucosal healing. However, randomized placebo-controlled studies are warranted to extend our encouraging initial findings,” the investigators concluded.

Find the full study in the Journal of Crohn’s and Colitis (doi: 10.1016/j.crohns.2014.08.014).

[email protected]

Sirolimus may be an effective rescue treatment option for children with refractory inflammatory bowel disease, according to Dr. Mohamed Mutalib and his associates.

In a retrospective analysis of 11 ulcerative colitis (UC) and 3 Crohn’s disease patients treated with sirolimus, 5 of the UC patients and all of the Crohn’s disease patients achieved clinical remission. An additional 2 UC patients achieved clinical response. The remaining 4 UC patients did not respond to sirolimus treatment.

Mucosal healing was achieved in 5 of 11 UC patients and 2 of 3 Crohn’s patients. Clinical response to treatment occurred at least 2 weeks after treatment was started. The only significant side effect reported was minor gastrointestinal distress.

“Our data provide compelling evidence that sirolimus is effective as rescue therapy in a subgroup of children with severe [inflammatory bowel disease] refractory to conventional therapies by inducing both clinical remission and mucosal healing. However, randomized placebo-controlled studies are warranted to extend our encouraging initial findings,” the investigators concluded.

Find the full study in the Journal of Crohn’s and Colitis (doi: 10.1016/j.crohns.2014.08.014).

[email protected]

Photo courtesy of UBC

A tiny magnetic implant could provide a new method of drug delivery, according to research published in Advanced Functional Materials.

The device is a silicone sponge with magnetic carbonyl iron particles wrapped in a round polymer layer. It measures 6 mm in diameter.

A drug is injected into the device, which is surgically implanted in the area being treated.

Passing a magnet over the implant activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue through a tiny opening.

“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths,” said study author Ali Shademani, a PhD student at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada.

“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” added John K. Jackson, also of UBC.

The researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. The device was able to deliver the drug on demand even after repeated use.

The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, suggesting that drugs stored in the device stay effective.

The researchers are now working on refining the device and narrowing down the conditions for its use.

“This could one day be used for administering painkillers, hormones, chemotherapy drugs, and other treatments for a wide range of health conditions,” said Mu Chiao, PhD, of UBC. “In the next few years, we hope to be able to test it for long-term use and for viability in living models.”

Photo courtesy of UBC

A tiny magnetic implant could provide a new method of drug delivery, according to research published in Advanced Functional Materials.

The device is a silicone sponge with magnetic carbonyl iron particles wrapped in a round polymer layer. It measures 6 mm in diameter.

A drug is injected into the device, which is surgically implanted in the area being treated.

Passing a magnet over the implant activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue through a tiny opening.

“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths,” said study author Ali Shademani, a PhD student at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada.

“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” added John K. Jackson, also of UBC.

The researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. The device was able to deliver the drug on demand even after repeated use.

The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, suggesting that drugs stored in the device stay effective.

The researchers are now working on refining the device and narrowing down the conditions for its use.

“This could one day be used for administering painkillers, hormones, chemotherapy drugs, and other treatments for a wide range of health conditions,” said Mu Chiao, PhD, of UBC. “In the next few years, we hope to be able to test it for long-term use and for viability in living models.”

Photo courtesy of UBC

A tiny magnetic implant could provide a new method of drug delivery, according to research published in Advanced Functional Materials.

The device is a silicone sponge with magnetic carbonyl iron particles wrapped in a round polymer layer. It measures 6 mm in diameter.

A drug is injected into the device, which is surgically implanted in the area being treated.

Passing a magnet over the implant activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue through a tiny opening.

“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths,” said study author Ali Shademani, a PhD student at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada.

“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” added John K. Jackson, also of UBC.

The researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. The device was able to deliver the drug on demand even after repeated use.

The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, suggesting that drugs stored in the device stay effective.

The researchers are now working on refining the device and narrowing down the conditions for its use.

“This could one day be used for administering painkillers, hormones, chemotherapy drugs, and other treatments for a wide range of health conditions,” said Mu Chiao, PhD, of UBC. “In the next few years, we hope to be able to test it for long-term use and for viability in living models.”

Wind turbines in Styria, Austria. Styrene is used in the manufacture of wind turbines.

A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.

The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.

On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).

The research was published in Epidemiology.

“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.

“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”

In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.

For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.

There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.

As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.

For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.

The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.

For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.

The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.

The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.

The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.

There were no such associations for other cancer sites.

Wind turbines in Styria, Austria. Styrene is used in the manufacture of wind turbines.

A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.

The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.

On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).

The research was published in Epidemiology.

“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.

“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”

In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.

For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.

There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.

As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.

For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.

The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.

For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.

The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.

The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.

The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.

There were no such associations for other cancer sites.

Wind turbines in Styria, Austria. Styrene is used in the manufacture of wind turbines.

A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.

The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.

On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).

The research was published in Epidemiology.

“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.

“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”

In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.

For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.

There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.

As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.

For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.

The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.

For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.

The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.

The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.

The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.

There were no such associations for other cancer sites.

and Margaret Shear

A novel vaccination approach can offer 100% protection against malaria, according to research published in Nature.

The approach involved direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated Plasmodium falciparum sporozoites (PfSPZ) in healthy adults taking chloroquine for antimalarial chemoprophylaxis (PfSPZ-CVac).

At the optimal dose and schedule, PfSPZ-CVac prevented infection in 9 of 9 volunteers, and this protection lasted 10 weeks after the last dose.

In addition, researchers said PfSPZ-CVac was well-tolerated.

PfSPZ was provided by Sanaria. This research was supported by federal funding and the Bill and Melinda Gates Foundation.

Treatment and challenge

The researchers tested PfSPZ-CVac in healthy adults, ages 18 to 45, who were malaria-naive. They received different doses of PfSPZ at different intervals and different doses/schedules of chloroquine.

In the first part of the study, test subjects received 3 doses of PfSPZ at 3.2 × 10³ (n=9), 1.28 × 10⁴ (n=9), or 5.12 × 10⁴ (n=9), and controls (n=13) received 3 doses of normal saline.

Doses were given at 28-day intervals, and controlled human malaria infection (CHMI) was performed at 8 to 10 weeks after immunization.

In the second part of the study, test subjects received 3 doses of PfSPZ at 5.12 × 10⁴ at 14-day intervals (n=9) or 5-day intervals (n=9), and controls (n=6) received 3 doses of normal saline.

CHMI was performed at 10 weeks post-immunization.

Most subjects received chloroquine at a base loading dose of 10 mg kg^-1 or 620 mg two days before the first dose of PfSPZ, whichever dose was less, followed by weekly doses of 5 mg kg^-1 or 310 mg through 5 days after the last dose of PfSPZ. Subjects who were immunized on days 0, 5, and 10 received chloroquine on days 0, 5, 10, and 15.

Results

All controls, who received normal saline plus chloroquine, developed parasitemia.

However, 3 doses of PfSPZ at 5.12 × 10⁴, given at 28-day intervals, prevented infection in 9 of 9 subjects (100%).

The 3.2 × 10³ dose of PfSPZ (also given at 28-day intervals) protected 3 of 9 subjects (33%), and the 1.28 × 10⁴ dose protected 6 of 9 subjects (67%).

Three doses of PfSPZ at 5.12 × 10⁴, given at 5-day intervals, protected 5 of 8 subjects (63%). And 3 doses of PfSPZ at 5.12 × 10⁴, given at 14-day intervals, protected 6 of 9 subjects (67%).

“By vaccinating with a live, fully active pathogen, it seems clear that we were able to set off a very strong immune response,” said study author Benjamin Mordmüller, of the University of Tübingen in Germany.

“Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection.”

“That protection was probably caused by specific T lymphocytes and antibody responses to the parasites in the liver,” added Peter Kremsner, also of the University of Tübingen.

The researchers said there were no serious adverse events, and the frequencies of grade 1-3 events were similar in subjects who received PfSPZ-CVac and controls.

Chloroquine was considered well-tolerated, although 2 subjects discontinued the trial after the loading dose because they experienced nausea and vomiting.

and Margaret Shear

A novel vaccination approach can offer 100% protection against malaria, according to research published in Nature.

The approach involved direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated Plasmodium falciparum sporozoites (PfSPZ) in healthy adults taking chloroquine for antimalarial chemoprophylaxis (PfSPZ-CVac).

At the optimal dose and schedule, PfSPZ-CVac prevented infection in 9 of 9 volunteers, and this protection lasted 10 weeks after the last dose.

In addition, researchers said PfSPZ-CVac was well-tolerated.

PfSPZ was provided by Sanaria. This research was supported by federal funding and the Bill and Melinda Gates Foundation.

Treatment and challenge

The researchers tested PfSPZ-CVac in healthy adults, ages 18 to 45, who were malaria-naive. They received different doses of PfSPZ at different intervals and different doses/schedules of chloroquine.

In the first part of the study, test subjects received 3 doses of PfSPZ at 3.2 × 10³ (n=9), 1.28 × 10⁴ (n=9), or 5.12 × 10⁴ (n=9), and controls (n=13) received 3 doses of normal saline.

Doses were given at 28-day intervals, and controlled human malaria infection (CHMI) was performed at 8 to 10 weeks after immunization.

In the second part of the study, test subjects received 3 doses of PfSPZ at 5.12 × 10⁴ at 14-day intervals (n=9) or 5-day intervals (n=9), and controls (n=6) received 3 doses of normal saline.

CHMI was performed at 10 weeks post-immunization.

Most subjects received chloroquine at a base loading dose of 10 mg kg^-1 or 620 mg two days before the first dose of PfSPZ, whichever dose was less, followed by weekly doses of 5 mg kg^-1 or 310 mg through 5 days after the last dose of PfSPZ. Subjects who were immunized on days 0, 5, and 10 received chloroquine on days 0, 5, 10, and 15.

Results

All controls, who received normal saline plus chloroquine, developed parasitemia.

However, 3 doses of PfSPZ at 5.12 × 10⁴, given at 28-day intervals, prevented infection in 9 of 9 subjects (100%).

The 3.2 × 10³ dose of PfSPZ (also given at 28-day intervals) protected 3 of 9 subjects (33%), and the 1.28 × 10⁴ dose protected 6 of 9 subjects (67%).

Three doses of PfSPZ at 5.12 × 10⁴, given at 5-day intervals, protected 5 of 8 subjects (63%). And 3 doses of PfSPZ at 5.12 × 10⁴, given at 14-day intervals, protected 6 of 9 subjects (67%).

“By vaccinating with a live, fully active pathogen, it seems clear that we were able to set off a very strong immune response,” said study author Benjamin Mordmüller, of the University of Tübingen in Germany.

“Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection.”

“That protection was probably caused by specific T lymphocytes and antibody responses to the parasites in the liver,” added Peter Kremsner, also of the University of Tübingen.

The researchers said there were no serious adverse events, and the frequencies of grade 1-3 events were similar in subjects who received PfSPZ-CVac and controls.

Chloroquine was considered well-tolerated, although 2 subjects discontinued the trial after the loading dose because they experienced nausea and vomiting.

and Margaret Shear

A novel vaccination approach can offer 100% protection against malaria, according to research published in Nature.

The approach involved direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated Plasmodium falciparum sporozoites (PfSPZ) in healthy adults taking chloroquine for antimalarial chemoprophylaxis (PfSPZ-CVac).

At the optimal dose and schedule, PfSPZ-CVac prevented infection in 9 of 9 volunteers, and this protection lasted 10 weeks after the last dose.

In addition, researchers said PfSPZ-CVac was well-tolerated.

PfSPZ was provided by Sanaria. This research was supported by federal funding and the Bill and Melinda Gates Foundation.

Treatment and challenge

The researchers tested PfSPZ-CVac in healthy adults, ages 18 to 45, who were malaria-naive. They received different doses of PfSPZ at different intervals and different doses/schedules of chloroquine.

In the first part of the study, test subjects received 3 doses of PfSPZ at 3.2 × 10³ (n=9), 1.28 × 10⁴ (n=9), or 5.12 × 10⁴ (n=9), and controls (n=13) received 3 doses of normal saline.

Doses were given at 28-day intervals, and controlled human malaria infection (CHMI) was performed at 8 to 10 weeks after immunization.

In the second part of the study, test subjects received 3 doses of PfSPZ at 5.12 × 10⁴ at 14-day intervals (n=9) or 5-day intervals (n=9), and controls (n=6) received 3 doses of normal saline.

CHMI was performed at 10 weeks post-immunization.

Most subjects received chloroquine at a base loading dose of 10 mg kg^-1 or 620 mg two days before the first dose of PfSPZ, whichever dose was less, followed by weekly doses of 5 mg kg^-1 or 310 mg through 5 days after the last dose of PfSPZ. Subjects who were immunized on days 0, 5, and 10 received chloroquine on days 0, 5, 10, and 15.

Results

All controls, who received normal saline plus chloroquine, developed parasitemia.

However, 3 doses of PfSPZ at 5.12 × 10⁴, given at 28-day intervals, prevented infection in 9 of 9 subjects (100%).

The 3.2 × 10³ dose of PfSPZ (also given at 28-day intervals) protected 3 of 9 subjects (33%), and the 1.28 × 10⁴ dose protected 6 of 9 subjects (67%).

Three doses of PfSPZ at 5.12 × 10⁴, given at 5-day intervals, protected 5 of 8 subjects (63%). And 3 doses of PfSPZ at 5.12 × 10⁴, given at 14-day intervals, protected 6 of 9 subjects (67%).

“By vaccinating with a live, fully active pathogen, it seems clear that we were able to set off a very strong immune response,” said study author Benjamin Mordmüller, of the University of Tübingen in Germany.

“Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection.”

“That protection was probably caused by specific T lymphocytes and antibody responses to the parasites in the liver,” added Peter Kremsner, also of the University of Tübingen.

The researchers said there were no serious adverse events, and the frequencies of grade 1-3 events were similar in subjects who received PfSPZ-CVac and controls.

Chloroquine was considered well-tolerated, although 2 subjects discontinued the trial after the loading dose because they experienced nausea and vomiting.

The field of transgender health is growing. What began as a lone German physician in 1918 defying the norms of treating gender identity as a disease now has burgeoned into a field that includes 1,079 PubMed articles,two medical guidelines^1,2, and a multitude of books. As we learn more about the complexity of gender and gender identity, we also are discovering potential problems that occur when providing care to our transgender patients. One is eating disorders.

A systematic review by Jones et al. showed only a handful of studies on eating disorders in transgender individuals, most of them restricted to case studies.³ In some situations, the issue of gender identity arises during treatment for an eating disorder, as the individual realizes that body dissatisfaction is due to the gender identity instead of a fear of gaining weight. In other cases, a transgender person in the process of transitioning to the affirmed gender develops an eating disorder.

References

1. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

2. Adv Urol. 2012;2012:581712.

3. Int Rev Psychiatry. 2016;28(1):81-94.

4. J Adolesc Health. 2015 Aug;57(2):144-9.

5. J Adolesc Health. 2016. doi: 10.1016/j.jadohealth.2016.08.027.

6. Feeding and Eating Disorders. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (Washington: American Psychiatric Association, 2013).

7. Gender Dysphoria. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (Washington: American Psychiatric Association, 2013).

8. Psychol Bull. 2003 Sep;129(5):674-97.

9. Int J Law Psychiatry. 2003 Sep-Oct;26(5):533-48.

10. Arch Gen Psychiatry. 2011 Jul;68(7):724-31.

11. Clin Endocrinol (Oxf). 2010 Feb;72(2):214-31.

12. CNS drugs. 2006;20(8):655-63.

13. Int J Eat Disord. 2015 Nov;48(7):942-5.

14. Eat Disord. 2012;20(4):300-11.

The field of transgender health is growing. What began as a lone German physician in 1918 defying the norms of treating gender identity as a disease now has burgeoned into a field that includes 1,079 PubMed articles,two medical guidelines^1,2, and a multitude of books. As we learn more about the complexity of gender and gender identity, we also are discovering potential problems that occur when providing care to our transgender patients. One is eating disorders.

A systematic review by Jones et al. showed only a handful of studies on eating disorders in transgender individuals, most of them restricted to case studies.³ In some situations, the issue of gender identity arises during treatment for an eating disorder, as the individual realizes that body dissatisfaction is due to the gender identity instead of a fear of gaining weight. In other cases, a transgender person in the process of transitioning to the affirmed gender develops an eating disorder.

References

1. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

2. Adv Urol. 2012;2012:581712.

3. Int Rev Psychiatry. 2016;28(1):81-94.

4. J Adolesc Health. 2015 Aug;57(2):144-9.

5. J Adolesc Health. 2016. doi: 10.1016/j.jadohealth.2016.08.027.

6. Feeding and Eating Disorders. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (Washington: American Psychiatric Association, 2013).

7. Gender Dysphoria. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (Washington: American Psychiatric Association, 2013).

8. Psychol Bull. 2003 Sep;129(5):674-97.

9. Int J Law Psychiatry. 2003 Sep-Oct;26(5):533-48.

10. Arch Gen Psychiatry. 2011 Jul;68(7):724-31.

11. Clin Endocrinol (Oxf). 2010 Feb;72(2):214-31.

12. CNS drugs. 2006;20(8):655-63.

13. Int J Eat Disord. 2015 Nov;48(7):942-5.

14. Eat Disord. 2012;20(4):300-11.

The field of transgender health is growing. What began as a lone German physician in 1918 defying the norms of treating gender identity as a disease now has burgeoned into a field that includes 1,079 PubMed articles,two medical guidelines^1,2, and a multitude of books. As we learn more about the complexity of gender and gender identity, we also are discovering potential problems that occur when providing care to our transgender patients. One is eating disorders.

A systematic review by Jones et al. showed only a handful of studies on eating disorders in transgender individuals, most of them restricted to case studies.³ In some situations, the issue of gender identity arises during treatment for an eating disorder, as the individual realizes that body dissatisfaction is due to the gender identity instead of a fear of gaining weight. In other cases, a transgender person in the process of transitioning to the affirmed gender develops an eating disorder.

References

1. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

2. Adv Urol. 2012;2012:581712.

3. Int Rev Psychiatry. 2016;28(1):81-94.

4. J Adolesc Health. 2015 Aug;57(2):144-9.

5. J Adolesc Health. 2016. doi: 10.1016/j.jadohealth.2016.08.027.

6. Feeding and Eating Disorders. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (Washington: American Psychiatric Association, 2013).

7. Gender Dysphoria. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (Washington: American Psychiatric Association, 2013).

8. Psychol Bull. 2003 Sep;129(5):674-97.

9. Int J Law Psychiatry. 2003 Sep-Oct;26(5):533-48.

10. Arch Gen Psychiatry. 2011 Jul;68(7):724-31.

11. Clin Endocrinol (Oxf). 2010 Feb;72(2):214-31.

12. CNS drugs. 2006;20(8):655-63.

13. Int J Eat Disord. 2015 Nov;48(7):942-5.

14. Eat Disord. 2012;20(4):300-11.

Raising children is a lot like drinking out of a fire hose. Feeding, cleaning, dressing, transporting, teaching, entertaining, protecting, comforting, and managing one child is demanding, but is increased exponentially by multiple children, a spouse, and a job.

In our dataset of more than 74,900 parents of 0- to 3-year-olds completing a routine previsit questionnaire about the “best” and “hardest” parts of parenting their child, the most frequent spontaneous comment for the hardest part was “time-life balance.” The goal of asking these questions is to broaden the agenda for the pediatric visit to address stresses that are highly relevant to the child’s life in the family, and their current well-being and future outcome. The hardest part also rather succinctly captures the stress I hear every day from parents coming to me not only for health supervision, but especially for child behavior problems.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. Email her at [email protected].

Raising children is a lot like drinking out of a fire hose. Feeding, cleaning, dressing, transporting, teaching, entertaining, protecting, comforting, and managing one child is demanding, but is increased exponentially by multiple children, a spouse, and a job.

In our dataset of more than 74,900 parents of 0- to 3-year-olds completing a routine previsit questionnaire about the “best” and “hardest” parts of parenting their child, the most frequent spontaneous comment for the hardest part was “time-life balance.” The goal of asking these questions is to broaden the agenda for the pediatric visit to address stresses that are highly relevant to the child’s life in the family, and their current well-being and future outcome. The hardest part also rather succinctly captures the stress I hear every day from parents coming to me not only for health supervision, but especially for child behavior problems.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. Email her at [email protected].

Raising children is a lot like drinking out of a fire hose. Feeding, cleaning, dressing, transporting, teaching, entertaining, protecting, comforting, and managing one child is demanding, but is increased exponentially by multiple children, a spouse, and a job.

In our dataset of more than 74,900 parents of 0- to 3-year-olds completing a routine previsit questionnaire about the “best” and “hardest” parts of parenting their child, the most frequent spontaneous comment for the hardest part was “time-life balance.” The goal of asking these questions is to broaden the agenda for the pediatric visit to address stresses that are highly relevant to the child’s life in the family, and their current well-being and future outcome. The hardest part also rather succinctly captures the stress I hear every day from parents coming to me not only for health supervision, but especially for child behavior problems.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. Email her at [email protected].

The Food and Drug Administration has approved brodalumab, an interleukin-17 receptor A-antagonist, for treating adults with moderate to severe plaque psoriasis, with a Risk Evaluation and Mitigation Strategy (REMS) that addresses the “observed risk of suicidal ideation and behavior” in clinical trials, the agency announced on Feb. 16.

In the three pivotal phase III studies of 4,373 adults with moderate to severe plaque psoriasis who were candidates for systemic therapy or phototherapy, 83%-86% of those treated with brodalumab achieved Psoriasis Area and Severity Index (PASI 75) scores at 12 weeks of treatment, compared with 3%-8% of those on placebo. In addition, 37%-44% of those on brodalumab achieved PASI 100 scores, compared with 1% or fewer of those on placebo. In the psoriasis clinical trials, suicidal ideation and behavior, which included four completed suicides, occurred in patients treated with brodalumab, according to the prescribing information

[email protected]

The Food and Drug Administration has approved brodalumab, an interleukin-17 receptor A-antagonist, for treating adults with moderate to severe plaque psoriasis, with a Risk Evaluation and Mitigation Strategy (REMS) that addresses the “observed risk of suicidal ideation and behavior” in clinical trials, the agency announced on Feb. 16.

In the three pivotal phase III studies of 4,373 adults with moderate to severe plaque psoriasis who were candidates for systemic therapy or phototherapy, 83%-86% of those treated with brodalumab achieved Psoriasis Area and Severity Index (PASI 75) scores at 12 weeks of treatment, compared with 3%-8% of those on placebo. In addition, 37%-44% of those on brodalumab achieved PASI 100 scores, compared with 1% or fewer of those on placebo. In the psoriasis clinical trials, suicidal ideation and behavior, which included four completed suicides, occurred in patients treated with brodalumab, according to the prescribing information

[email protected]

The Food and Drug Administration has approved brodalumab, an interleukin-17 receptor A-antagonist, for treating adults with moderate to severe plaque psoriasis, with a Risk Evaluation and Mitigation Strategy (REMS) that addresses the “observed risk of suicidal ideation and behavior” in clinical trials, the agency announced on Feb. 16.

In the three pivotal phase III studies of 4,373 adults with moderate to severe plaque psoriasis who were candidates for systemic therapy or phototherapy, 83%-86% of those treated with brodalumab achieved Psoriasis Area and Severity Index (PASI 75) scores at 12 weeks of treatment, compared with 3%-8% of those on placebo. In addition, 37%-44% of those on brodalumab achieved PASI 100 scores, compared with 1% or fewer of those on placebo. In the psoriasis clinical trials, suicidal ideation and behavior, which included four completed suicides, occurred in patients treated with brodalumab, according to the prescribing information

[email protected]

Administering doses of a vitamin D supplement to patients can significantly mitigate their risk of developing acute respiratory tract infections, according to a recent study published by the BMJ.

“[Existing] epidemiological and in vitro data have prompted numerous randomized controlled trials to determine whether vitamin D supplementation can decrease the risk of acute respiratory tract infection,” wrote the authors of the study, led by Adrian R. Martineau, PhD, of Queen Mary University of London. “A total of five aggregate data meta-analyses incorporating data from up to 15 primary trials have been conducted to date [but] all but one of these aggregate data meta-analyses reported statistically significant heterogeneity of effect between primary trials.”

Kaspri/Fotolia

[email protected]

Administering doses of a vitamin D supplement to patients can significantly mitigate their risk of developing acute respiratory tract infections, according to a recent study published by the BMJ.

“[Existing] epidemiological and in vitro data have prompted numerous randomized controlled trials to determine whether vitamin D supplementation can decrease the risk of acute respiratory tract infection,” wrote the authors of the study, led by Adrian R. Martineau, PhD, of Queen Mary University of London. “A total of five aggregate data meta-analyses incorporating data from up to 15 primary trials have been conducted to date [but] all but one of these aggregate data meta-analyses reported statistically significant heterogeneity of effect between primary trials.”

Kaspri/Fotolia

[email protected]

Administering doses of a vitamin D supplement to patients can significantly mitigate their risk of developing acute respiratory tract infections, according to a recent study published by the BMJ.

“[Existing] epidemiological and in vitro data have prompted numerous randomized controlled trials to determine whether vitamin D supplementation can decrease the risk of acute respiratory tract infection,” wrote the authors of the study, led by Adrian R. Martineau, PhD, of Queen Mary University of London. “A total of five aggregate data meta-analyses incorporating data from up to 15 primary trials have been conducted to date [but] all but one of these aggregate data meta-analyses reported statistically significant heterogeneity of effect between primary trials.”

Kaspri/Fotolia

[email protected]

SNOWMASS, COLO. – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.

He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.

Enhancing effectiveness of biologics

One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.

“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.

He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.

“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.

He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.

Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.

The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well (Ann Rheum Dis. 2015 Jun;74[6]:1037-44).

“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.

With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.

“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.

Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.

The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy (Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307).

An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.

“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.

Side effects of methotrexate

“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.

Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.

“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.

Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk (Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66).

“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.

The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.

“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.

He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.

[email protected]

SNOWMASS, COLO. – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.

He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.

Enhancing effectiveness of biologics

One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.

“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.

He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.

“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.

He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.

Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.

The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well (Ann Rheum Dis. 2015 Jun;74[6]:1037-44).

“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.

With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.

“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.

Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.

The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy (Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307).

An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.

“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.

Side effects of methotrexate

“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.

Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.

“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.

Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk (Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66).

“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.

The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.

“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.

He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.

[email protected]

SNOWMASS, COLO. – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.

He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.

Enhancing effectiveness of biologics

One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.

“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.

He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.

“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.

He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.

Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.

The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well (Ann Rheum Dis. 2015 Jun;74[6]:1037-44).

“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.

With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.

“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.

Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.

The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy (Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307).

An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.

“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.

Side effects of methotrexate

“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.

Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.

“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.

Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk (Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66).

“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.

The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.

“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.

He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.

[email protected]