Key clinical point: Early rheumatoid arthritis (RA) strategies have different risk profiles. Moreover, the use of early steroid-based regimens did not emerge as more harmful.

Major finding: The risk for serious adverse events was higher with biologic monotherapy vs. methotrexate (MTX)+steroid therapy (rate ratio [RR], 3.22; 95% confidence interval [CI], 1.47-7.07) and with biological monotherapy vs. MTX monotherapy (RR, 1.39; 95% CI, 1.12-1.73) and MTX+biologic disease-modifying antirheumatic drugs (DMARD; RR, 1.26; 95% CI, 1.02-1.54).

Study details: Findings are from a network meta-analysis of 20 double-blind randomized clinical trials involving 9,202 adult patients with RA who were initiated on DMARD therapy.

Disclosures: This study received no external funding. The authors received speaker’s fees and honoraria from various pharmaceutical companies including AbbVie. None of the authors reported any conflict of interest.

Source: Adas MA et al. Rheumatology (Oxford). 2021 May 18. doi: 10.1093/rheumatology/keab429.

Key clinical point: Early rheumatoid arthritis (RA) strategies have different risk profiles. Moreover, the use of early steroid-based regimens did not emerge as more harmful.

Major finding: The risk for serious adverse events was higher with biologic monotherapy vs. methotrexate (MTX)+steroid therapy (rate ratio [RR], 3.22; 95% confidence interval [CI], 1.47-7.07) and with biological monotherapy vs. MTX monotherapy (RR, 1.39; 95% CI, 1.12-1.73) and MTX+biologic disease-modifying antirheumatic drugs (DMARD; RR, 1.26; 95% CI, 1.02-1.54).

Study details: Findings are from a network meta-analysis of 20 double-blind randomized clinical trials involving 9,202 adult patients with RA who were initiated on DMARD therapy.

Disclosures: This study received no external funding. The authors received speaker’s fees and honoraria from various pharmaceutical companies including AbbVie. None of the authors reported any conflict of interest.

Source: Adas MA et al. Rheumatology (Oxford). 2021 May 18. doi: 10.1093/rheumatology/keab429.

Key clinical point: Early rheumatoid arthritis (RA) strategies have different risk profiles. Moreover, the use of early steroid-based regimens did not emerge as more harmful.

Major finding: The risk for serious adverse events was higher with biologic monotherapy vs. methotrexate (MTX)+steroid therapy (rate ratio [RR], 3.22; 95% confidence interval [CI], 1.47-7.07) and with biological monotherapy vs. MTX monotherapy (RR, 1.39; 95% CI, 1.12-1.73) and MTX+biologic disease-modifying antirheumatic drugs (DMARD; RR, 1.26; 95% CI, 1.02-1.54).

Study details: Findings are from a network meta-analysis of 20 double-blind randomized clinical trials involving 9,202 adult patients with RA who were initiated on DMARD therapy.

Disclosures: This study received no external funding. The authors received speaker’s fees and honoraria from various pharmaceutical companies including AbbVie. None of the authors reported any conflict of interest.

Source: Adas MA et al. Rheumatology (Oxford). 2021 May 18. doi: 10.1093/rheumatology/keab429.

Key clinical point: Tocilizumab (TCZ) was associated with an increased risk for diverticulitis and gastrointestinal (GI) perforation related to diverticulitis compared with rituximab (RTX) and abatacept (ABA) in patients with rheumatoid arthritis (RA).

Major finding: TCZ vs. RTX or ABA was associated with an increased risk for diverticulitis (hazard ratio [HR], 3.1; P = .002) and GI perforation because of diverticulitis (HR, 2.9; P = .03).

Study details: Data come from an analysis of a real-life cohort of 4,501 patients with RA from 3 observational registries of the French Society of Rheumatology who received RTX (n=1,986), ABA (n=1,019), or TCZ (n=1,496).

Disclosures: The French Society of Rheumatology received unrestricted grants from Bristol Myers Squibb, Roche, and Roche-Chugai. Some of the authors including the lead author declared receiving grants and consulting/speaker/personal fees from various sources including Bristol Myers Squibb. C Rempenault, A Herrero, and I Pane declared no conflicts of interest.

Source: Rempenault C et al. Rheumatology (Oxford). 2021 May 16. doi: 10.1093/rheumatology/keab438.

Key clinical point: Tocilizumab (TCZ) was associated with an increased risk for diverticulitis and gastrointestinal (GI) perforation related to diverticulitis compared with rituximab (RTX) and abatacept (ABA) in patients with rheumatoid arthritis (RA).

Major finding: TCZ vs. RTX or ABA was associated with an increased risk for diverticulitis (hazard ratio [HR], 3.1; P = .002) and GI perforation because of diverticulitis (HR, 2.9; P = .03).

Study details: Data come from an analysis of a real-life cohort of 4,501 patients with RA from 3 observational registries of the French Society of Rheumatology who received RTX (n=1,986), ABA (n=1,019), or TCZ (n=1,496).

Disclosures: The French Society of Rheumatology received unrestricted grants from Bristol Myers Squibb, Roche, and Roche-Chugai. Some of the authors including the lead author declared receiving grants and consulting/speaker/personal fees from various sources including Bristol Myers Squibb. C Rempenault, A Herrero, and I Pane declared no conflicts of interest.

Source: Rempenault C et al. Rheumatology (Oxford). 2021 May 16. doi: 10.1093/rheumatology/keab438.

Key clinical point: Tocilizumab (TCZ) was associated with an increased risk for diverticulitis and gastrointestinal (GI) perforation related to diverticulitis compared with rituximab (RTX) and abatacept (ABA) in patients with rheumatoid arthritis (RA).

Major finding: TCZ vs. RTX or ABA was associated with an increased risk for diverticulitis (hazard ratio [HR], 3.1; P = .002) and GI perforation because of diverticulitis (HR, 2.9; P = .03).

Study details: Data come from an analysis of a real-life cohort of 4,501 patients with RA from 3 observational registries of the French Society of Rheumatology who received RTX (n=1,986), ABA (n=1,019), or TCZ (n=1,496).

Disclosures: The French Society of Rheumatology received unrestricted grants from Bristol Myers Squibb, Roche, and Roche-Chugai. Some of the authors including the lead author declared receiving grants and consulting/speaker/personal fees from various sources including Bristol Myers Squibb. C Rempenault, A Herrero, and I Pane declared no conflicts of interest.

Source: Rempenault C et al. Rheumatology (Oxford). 2021 May 16. doi: 10.1093/rheumatology/keab438.

Key clinical point: Use of methotrexate significantly reduced the risk for cardiovascular disease (CVD) events, particularly heart failure (HF)-related hospitalizations in patients with rheumatoid arthritis (RA).

Major finding: Use of methotrexate was associated with a significant 24% reduced risk for composite CVD events (hazard ratio [HR], 0.76; P = .04), including a 57% lower risk for HF hospitalizations (HR, 0.43; P = .005).

Study details: The data come from a prospective cohort study of 2,044 US veterans with RA.

Disclosures: The work was supported by Centre of Excellence for Suicide Prevention and Joint Department of Veterans Affairs and Department of Defense Mortality Data Repository—National Death Index. MD George reported receiving grant support from Bristol Myers Squibb for unrelated work.

Source: Johnson TM et al. Ann Rheum Dis. 2021 May 28. doi: 10.1136/annrheumdis-2021-220125.

Key clinical point: Use of methotrexate significantly reduced the risk for cardiovascular disease (CVD) events, particularly heart failure (HF)-related hospitalizations in patients with rheumatoid arthritis (RA).

Major finding: Use of methotrexate was associated with a significant 24% reduced risk for composite CVD events (hazard ratio [HR], 0.76; P = .04), including a 57% lower risk for HF hospitalizations (HR, 0.43; P = .005).

Study details: The data come from a prospective cohort study of 2,044 US veterans with RA.

Disclosures: The work was supported by Centre of Excellence for Suicide Prevention and Joint Department of Veterans Affairs and Department of Defense Mortality Data Repository—National Death Index. MD George reported receiving grant support from Bristol Myers Squibb for unrelated work.

Source: Johnson TM et al. Ann Rheum Dis. 2021 May 28. doi: 10.1136/annrheumdis-2021-220125.

Key clinical point: Use of methotrexate significantly reduced the risk for cardiovascular disease (CVD) events, particularly heart failure (HF)-related hospitalizations in patients with rheumatoid arthritis (RA).

Major finding: Use of methotrexate was associated with a significant 24% reduced risk for composite CVD events (hazard ratio [HR], 0.76; P = .04), including a 57% lower risk for HF hospitalizations (HR, 0.43; P = .005).

Study details: The data come from a prospective cohort study of 2,044 US veterans with RA.

Disclosures: The work was supported by Centre of Excellence for Suicide Prevention and Joint Department of Veterans Affairs and Department of Defense Mortality Data Repository—National Death Index. MD George reported receiving grant support from Bristol Myers Squibb for unrelated work.

Source: Johnson TM et al. Ann Rheum Dis. 2021 May 28. doi: 10.1136/annrheumdis-2021-220125.

Key clinical point: Patients with rheumatoid arthritis (RA) treated with rituximab or Janus kinase inhibitors (JAKi) at onset of COVID-19 were more likely to have poor COVID-19 outcomes compared with those treated with tumor necrosis factor inhibitors (TNFi).

Major finding: Odds of worse COVID-19 severity were 4.15 and 2.06 greater in patients on rituximab (odds ratio [OR], 4.15) and JAKi (OR, 2.06; both P less than .01) vs. those on TNFi. Patients on rituximab and JAKi therapy vs. TNFi were more susceptible to hospitalization (OR, 4.53 and 2.40, respectively; P less than .01) and death (OR, 4.57 and 2.04, respectively; P less than .01).

Study details: The data come from the analysis of 2,869 patients with RA and COVID-19 who were on abatacept (n=237), rituximab (n=364), interleukin 6 inhibitors (n=317), Janus kinase inhibitors (n=563), or TNFi (n=1,388) at the time of clinical COVID-19 onset.

Disclosures: The study received support from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. The authors reported receiving research support, grants, and speaker’s/consultancy/personal fees from various sources.

Source: Sparks JA et al. Ann Rheum Dis. 2021 May 28. doi: 10.1136/annrheumdis-2021-220418.

Key clinical point: Patients with rheumatoid arthritis (RA) treated with rituximab or Janus kinase inhibitors (JAKi) at onset of COVID-19 were more likely to have poor COVID-19 outcomes compared with those treated with tumor necrosis factor inhibitors (TNFi).

Major finding: Odds of worse COVID-19 severity were 4.15 and 2.06 greater in patients on rituximab (odds ratio [OR], 4.15) and JAKi (OR, 2.06; both P less than .01) vs. those on TNFi. Patients on rituximab and JAKi therapy vs. TNFi were more susceptible to hospitalization (OR, 4.53 and 2.40, respectively; P less than .01) and death (OR, 4.57 and 2.04, respectively; P less than .01).

Study details: The data come from the analysis of 2,869 patients with RA and COVID-19 who were on abatacept (n=237), rituximab (n=364), interleukin 6 inhibitors (n=317), Janus kinase inhibitors (n=563), or TNFi (n=1,388) at the time of clinical COVID-19 onset.

Disclosures: The study received support from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. The authors reported receiving research support, grants, and speaker’s/consultancy/personal fees from various sources.

Source: Sparks JA et al. Ann Rheum Dis. 2021 May 28. doi: 10.1136/annrheumdis-2021-220418.

Key clinical point: Patients with rheumatoid arthritis (RA) treated with rituximab or Janus kinase inhibitors (JAKi) at onset of COVID-19 were more likely to have poor COVID-19 outcomes compared with those treated with tumor necrosis factor inhibitors (TNFi).

Major finding: Odds of worse COVID-19 severity were 4.15 and 2.06 greater in patients on rituximab (odds ratio [OR], 4.15) and JAKi (OR, 2.06; both P less than .01) vs. those on TNFi. Patients on rituximab and JAKi therapy vs. TNFi were more susceptible to hospitalization (OR, 4.53 and 2.40, respectively; P less than .01) and death (OR, 4.57 and 2.04, respectively; P less than .01).

Study details: The data come from the analysis of 2,869 patients with RA and COVID-19 who were on abatacept (n=237), rituximab (n=364), interleukin 6 inhibitors (n=317), Janus kinase inhibitors (n=563), or TNFi (n=1,388) at the time of clinical COVID-19 onset.

Disclosures: The study received support from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. The authors reported receiving research support, grants, and speaker’s/consultancy/personal fees from various sources.

Source: Sparks JA et al. Ann Rheum Dis. 2021 May 28. doi: 10.1136/annrheumdis-2021-220418.

Key clinical point: ORAL Shift demonstrates safety and efficacy of tofacitinib modified-release 11 mg once daily (OD) plus methotrexate in a global population of patients with rheumatoid arthritis (RA).

Major finding: All efficacy outcomes improved from baseline to week 12 including Disease Activity Score in 28 joints, erythrocyte sedimentation rate (mean change [MC], −2.0), Clinical Disease Activity Index (CDAI; MC, −19.6), Simplified Disease Activity Index (MC, −20.3), and other patient-reported outcomes, which continued to improve through week 24. At week 24, 84.5% of patients achieved CDAI-defined low disease activity. Most adverse events were mild or moderate in severity and no deaths were reported.

Study details: ORAL Shift, a 48-week phase 3b/4 withdrawal study included patients with moderate to severe RA and an inadequate response to methotrexate who received open-label tofacitinib modified-release 11 mg OD and methotrexate.

Disclosures: This study was sponsored by Pfizer Inc. Some of the authors declared receiving research support and honoraria and serving as consultant or on speaker’s bureau for various sources including Pfizer. Seven of the authors declared being employees and shareholders at Pfizer Inc.

Source: Cohen SB et al. RMD Open. 2021 Jun 7. doi: 10.1136/rmdopen-2021-001673.

Key clinical point: ORAL Shift demonstrates safety and efficacy of tofacitinib modified-release 11 mg once daily (OD) plus methotrexate in a global population of patients with rheumatoid arthritis (RA).

Major finding: All efficacy outcomes improved from baseline to week 12 including Disease Activity Score in 28 joints, erythrocyte sedimentation rate (mean change [MC], −2.0), Clinical Disease Activity Index (CDAI; MC, −19.6), Simplified Disease Activity Index (MC, −20.3), and other patient-reported outcomes, which continued to improve through week 24. At week 24, 84.5% of patients achieved CDAI-defined low disease activity. Most adverse events were mild or moderate in severity and no deaths were reported.

Study details: ORAL Shift, a 48-week phase 3b/4 withdrawal study included patients with moderate to severe RA and an inadequate response to methotrexate who received open-label tofacitinib modified-release 11 mg OD and methotrexate.

Disclosures: This study was sponsored by Pfizer Inc. Some of the authors declared receiving research support and honoraria and serving as consultant or on speaker’s bureau for various sources including Pfizer. Seven of the authors declared being employees and shareholders at Pfizer Inc.

Source: Cohen SB et al. RMD Open. 2021 Jun 7. doi: 10.1136/rmdopen-2021-001673.

Key clinical point: ORAL Shift demonstrates safety and efficacy of tofacitinib modified-release 11 mg once daily (OD) plus methotrexate in a global population of patients with rheumatoid arthritis (RA).

Major finding: All efficacy outcomes improved from baseline to week 12 including Disease Activity Score in 28 joints, erythrocyte sedimentation rate (mean change [MC], −2.0), Clinical Disease Activity Index (CDAI; MC, −19.6), Simplified Disease Activity Index (MC, −20.3), and other patient-reported outcomes, which continued to improve through week 24. At week 24, 84.5% of patients achieved CDAI-defined low disease activity. Most adverse events were mild or moderate in severity and no deaths were reported.

Study details: ORAL Shift, a 48-week phase 3b/4 withdrawal study included patients with moderate to severe RA and an inadequate response to methotrexate who received open-label tofacitinib modified-release 11 mg OD and methotrexate.

Disclosures: This study was sponsored by Pfizer Inc. Some of the authors declared receiving research support and honoraria and serving as consultant or on speaker’s bureau for various sources including Pfizer. Seven of the authors declared being employees and shareholders at Pfizer Inc.

Source: Cohen SB et al. RMD Open. 2021 Jun 7. doi: 10.1136/rmdopen-2021-001673.

The American College of Gastroenterology has issued new guidelines on management of Clostridioides difficile infection that now include roles for fecal microbial transplant (FMT), combination testing, and bezlotoxumab.

The ACG’s previous guidelines on the diagnosis, management, and treatment of what was then still called Clostridium difficile were published in 2013. Since then, the organism’s name changed to Clostridioides difficile, and that’s just the beginning of the changes reflected in the scientific literature, wrote lead author Colleen R. Kelly, MD, of Brown University, Providence, R.I., and colleagues.

“Other developments include the increased recognition of diagnostic challenges in the era of nucleic acid amplification–based testing, new therapeutic options for treatment and prevention of recurrence, and increasing evidence to support fecal microbiota transplantation (FMT) in recurrent and severe infection,” the authors said.

The guidelines, published in the American Journal of Gastroenterology, include 23 graded recommendations addressing issues of prevention, diagnosis, treatment, prevention of recurrence, and guidance for special populations in the management of C. difficile infection (CDI).
 

New faces among familiar ones

In terms of diagnosis, the new guidelines recommend using both a highly sensitive testing modality and a highly specific one to help distinguish colonization from active infection. Specifically, the authors recommend that stool is first tested using a highly sensitive test, either nucleic acid amplification testing or glutamate dehydrogenase, followed by an enzyme immunoassays for its high specificity.

Changes to treatment recommendations include the initial use of oral vancomycin or oral fidaxomicin for cases of nonsevere CDI. Oral metronidazole may be considered for initial nonsevere CDI in low-risk patients, the authors noted. The evidence is strong for the continued recommendations of vancomycin (125 mg four times daily for 10 days) and fidaxomicin (200 mg twice daily for 10 days) for patients with severe CDI. For patients with fulminant CDI, the recommendations call for medical therapy including volume resuscitation and oral vancomycin, although combination therapy with parenteral metronidazole may be considered despite the very low quality of evidence.

A notable update to the guidelines is the recommendation of fecal microbiota transplant (FMT) for both severe and fulminant CDI cases that are resistant to antibiotics and to prevent recurrence in at-risk patients. Although the quality of evidence is ranked as low, the recommendation is strong, the authors wrote. “Beyond improved cure rates, FMT may result in decreased rates of CDI-related colectomy and sepsis and may offer survival benefit in this critically ill patient population.” However, most patients in studies of FMT required multiple treatments in combination with anti-CDI antibiotics.

Other recommendations to prevent recurrence include oral vancomycin prophylaxis during the subsequent use of systemic antibiotics in patients with a history of CDI. The guidelines also recommend bezlotoxumab for prevention of CDI recurrence in high-risk patients, and advise against discontinuing antisecretory therapy in CDI patients if there is an appropriate indication for use.

Based on the lack of quality evidence, the guidelines recommend against the use of probiotics for preventing CDI in patients being treated with antibiotics and for prevention of recurrent infection.
 

Special populations

For patients with inflammatory bowel disease, the guidelines recommend C. difficile testing when these individuals present with acute flares and diarrhea, and the use of vancomycin for treatment. In addition, the authors strongly recommended FMT for recurrent CDI in these patients. For pregnant, postpartum, and breastfeeding patients with CDI, the guidelines recommend vancomycin, and either vancomycin or fidaxomicin may be used for treating CDI in immunocompromised patients, the authors noted.

The updated guidelines are designed to complement those issued by the Infections Disease Society of America and Society of Healthcare Epidemiologists of America, the researchers noted.
 

Reflecting the research

The previous guidelines for C. difficile were issued in 2013, and much has changed since then in terms of epidemiology, diagnosis, treatment, and infection control, Sahil Khanna, MBBS, MS, of the Mayo Clinic, Rochester, Minn., said in an interview.

Notably, diagnostic testing has “made leaps and bounds” and new treatments have become available that were not included in earlier guidelines, said Dr. Khanna. In particular, the new guidelines are recommending a two-step diagnostic assay; “the diagnostic algorithm has changed, and hopefully that will help us change practice” to identify active infection more quickly and efficiently.

Another important update is the recommendation of fidaxomicin as an option for initial nonfulminant CDI as an alternative to vancomycin, Dr. Khanna said, noting that metronidazole remains an option for low-risk patients. An additional change is the advice to use a different treatment for a second recurrent infection rather than repeating the initial treatment.  

The recommendation of bezlotoxumab for prevention of CDI recurrence in patients who are at high risk of recurrence is the first time this drug has appeared in major guidelines, Dr. Khanna observed.

The recommendation in support of fecal microbiota transplant is a key update to the management of CDI, including the guidance that the procedure can be repeated if necessary, he said.

Looking ahead, “Additional research is needed to fully understand the best testing algorithms for CDI,” Dr. Khanna explained. “More studies also are needed to show how FMT fully fits into the picture, and some current studies are looking at its potential earlier in the course of infection.”

The guidelines were developed in collaboration with the Practice Parameters Committee of the American College of Gastroenterology and received no outside funding. Dr. Kelly disclosed serving as a site investigator of a clinical trial for Finch Therapeutics and is an unpaid clinical advisory board member for OpenBiome. Dr. Khanna has coauthored previous guidelines on C. difficile. He disclosed consulting relationships with Finch, GlaxoSmithKline, Jetson, ProbioTech, and Shire/Takeda, as well as research support from Rebiotix, Seres, and Vedanta.

The American College of Gastroenterology has issued new guidelines on management of Clostridioides difficile infection that now include roles for fecal microbial transplant (FMT), combination testing, and bezlotoxumab.

The ACG’s previous guidelines on the diagnosis, management, and treatment of what was then still called Clostridium difficile were published in 2013. Since then, the organism’s name changed to Clostridioides difficile, and that’s just the beginning of the changes reflected in the scientific literature, wrote lead author Colleen R. Kelly, MD, of Brown University, Providence, R.I., and colleagues.

“Other developments include the increased recognition of diagnostic challenges in the era of nucleic acid amplification–based testing, new therapeutic options for treatment and prevention of recurrence, and increasing evidence to support fecal microbiota transplantation (FMT) in recurrent and severe infection,” the authors said.

The guidelines, published in the American Journal of Gastroenterology, include 23 graded recommendations addressing issues of prevention, diagnosis, treatment, prevention of recurrence, and guidance for special populations in the management of C. difficile infection (CDI).
 

New faces among familiar ones

In terms of diagnosis, the new guidelines recommend using both a highly sensitive testing modality and a highly specific one to help distinguish colonization from active infection. Specifically, the authors recommend that stool is first tested using a highly sensitive test, either nucleic acid amplification testing or glutamate dehydrogenase, followed by an enzyme immunoassays for its high specificity.

Changes to treatment recommendations include the initial use of oral vancomycin or oral fidaxomicin for cases of nonsevere CDI. Oral metronidazole may be considered for initial nonsevere CDI in low-risk patients, the authors noted. The evidence is strong for the continued recommendations of vancomycin (125 mg four times daily for 10 days) and fidaxomicin (200 mg twice daily for 10 days) for patients with severe CDI. For patients with fulminant CDI, the recommendations call for medical therapy including volume resuscitation and oral vancomycin, although combination therapy with parenteral metronidazole may be considered despite the very low quality of evidence.

A notable update to the guidelines is the recommendation of fecal microbiota transplant (FMT) for both severe and fulminant CDI cases that are resistant to antibiotics and to prevent recurrence in at-risk patients. Although the quality of evidence is ranked as low, the recommendation is strong, the authors wrote. “Beyond improved cure rates, FMT may result in decreased rates of CDI-related colectomy and sepsis and may offer survival benefit in this critically ill patient population.” However, most patients in studies of FMT required multiple treatments in combination with anti-CDI antibiotics.

Other recommendations to prevent recurrence include oral vancomycin prophylaxis during the subsequent use of systemic antibiotics in patients with a history of CDI. The guidelines also recommend bezlotoxumab for prevention of CDI recurrence in high-risk patients, and advise against discontinuing antisecretory therapy in CDI patients if there is an appropriate indication for use.

Based on the lack of quality evidence, the guidelines recommend against the use of probiotics for preventing CDI in patients being treated with antibiotics and for prevention of recurrent infection.
 

Special populations

For patients with inflammatory bowel disease, the guidelines recommend C. difficile testing when these individuals present with acute flares and diarrhea, and the use of vancomycin for treatment. In addition, the authors strongly recommended FMT for recurrent CDI in these patients. For pregnant, postpartum, and breastfeeding patients with CDI, the guidelines recommend vancomycin, and either vancomycin or fidaxomicin may be used for treating CDI in immunocompromised patients, the authors noted.

The updated guidelines are designed to complement those issued by the Infections Disease Society of America and Society of Healthcare Epidemiologists of America, the researchers noted.
 

Reflecting the research

The previous guidelines for C. difficile were issued in 2013, and much has changed since then in terms of epidemiology, diagnosis, treatment, and infection control, Sahil Khanna, MBBS, MS, of the Mayo Clinic, Rochester, Minn., said in an interview.

Notably, diagnostic testing has “made leaps and bounds” and new treatments have become available that were not included in earlier guidelines, said Dr. Khanna. In particular, the new guidelines are recommending a two-step diagnostic assay; “the diagnostic algorithm has changed, and hopefully that will help us change practice” to identify active infection more quickly and efficiently.

Another important update is the recommendation of fidaxomicin as an option for initial nonfulminant CDI as an alternative to vancomycin, Dr. Khanna said, noting that metronidazole remains an option for low-risk patients. An additional change is the advice to use a different treatment for a second recurrent infection rather than repeating the initial treatment.  

The recommendation of bezlotoxumab for prevention of CDI recurrence in patients who are at high risk of recurrence is the first time this drug has appeared in major guidelines, Dr. Khanna observed.

The recommendation in support of fecal microbiota transplant is a key update to the management of CDI, including the guidance that the procedure can be repeated if necessary, he said.

Looking ahead, “Additional research is needed to fully understand the best testing algorithms for CDI,” Dr. Khanna explained. “More studies also are needed to show how FMT fully fits into the picture, and some current studies are looking at its potential earlier in the course of infection.”

The guidelines were developed in collaboration with the Practice Parameters Committee of the American College of Gastroenterology and received no outside funding. Dr. Kelly disclosed serving as a site investigator of a clinical trial for Finch Therapeutics and is an unpaid clinical advisory board member for OpenBiome. Dr. Khanna has coauthored previous guidelines on C. difficile. He disclosed consulting relationships with Finch, GlaxoSmithKline, Jetson, ProbioTech, and Shire/Takeda, as well as research support from Rebiotix, Seres, and Vedanta.

The American College of Gastroenterology has issued new guidelines on management of Clostridioides difficile infection that now include roles for fecal microbial transplant (FMT), combination testing, and bezlotoxumab.

The ACG’s previous guidelines on the diagnosis, management, and treatment of what was then still called Clostridium difficile were published in 2013. Since then, the organism’s name changed to Clostridioides difficile, and that’s just the beginning of the changes reflected in the scientific literature, wrote lead author Colleen R. Kelly, MD, of Brown University, Providence, R.I., and colleagues.

“Other developments include the increased recognition of diagnostic challenges in the era of nucleic acid amplification–based testing, new therapeutic options for treatment and prevention of recurrence, and increasing evidence to support fecal microbiota transplantation (FMT) in recurrent and severe infection,” the authors said.

The guidelines, published in the American Journal of Gastroenterology, include 23 graded recommendations addressing issues of prevention, diagnosis, treatment, prevention of recurrence, and guidance for special populations in the management of C. difficile infection (CDI).
 

New faces among familiar ones

In terms of diagnosis, the new guidelines recommend using both a highly sensitive testing modality and a highly specific one to help distinguish colonization from active infection. Specifically, the authors recommend that stool is first tested using a highly sensitive test, either nucleic acid amplification testing or glutamate dehydrogenase, followed by an enzyme immunoassays for its high specificity.

Changes to treatment recommendations include the initial use of oral vancomycin or oral fidaxomicin for cases of nonsevere CDI. Oral metronidazole may be considered for initial nonsevere CDI in low-risk patients, the authors noted. The evidence is strong for the continued recommendations of vancomycin (125 mg four times daily for 10 days) and fidaxomicin (200 mg twice daily for 10 days) for patients with severe CDI. For patients with fulminant CDI, the recommendations call for medical therapy including volume resuscitation and oral vancomycin, although combination therapy with parenteral metronidazole may be considered despite the very low quality of evidence.

A notable update to the guidelines is the recommendation of fecal microbiota transplant (FMT) for both severe and fulminant CDI cases that are resistant to antibiotics and to prevent recurrence in at-risk patients. Although the quality of evidence is ranked as low, the recommendation is strong, the authors wrote. “Beyond improved cure rates, FMT may result in decreased rates of CDI-related colectomy and sepsis and may offer survival benefit in this critically ill patient population.” However, most patients in studies of FMT required multiple treatments in combination with anti-CDI antibiotics.

Other recommendations to prevent recurrence include oral vancomycin prophylaxis during the subsequent use of systemic antibiotics in patients with a history of CDI. The guidelines also recommend bezlotoxumab for prevention of CDI recurrence in high-risk patients, and advise against discontinuing antisecretory therapy in CDI patients if there is an appropriate indication for use.

Based on the lack of quality evidence, the guidelines recommend against the use of probiotics for preventing CDI in patients being treated with antibiotics and for prevention of recurrent infection.
 

Special populations

For patients with inflammatory bowel disease, the guidelines recommend C. difficile testing when these individuals present with acute flares and diarrhea, and the use of vancomycin for treatment. In addition, the authors strongly recommended FMT for recurrent CDI in these patients. For pregnant, postpartum, and breastfeeding patients with CDI, the guidelines recommend vancomycin, and either vancomycin or fidaxomicin may be used for treating CDI in immunocompromised patients, the authors noted.

The updated guidelines are designed to complement those issued by the Infections Disease Society of America and Society of Healthcare Epidemiologists of America, the researchers noted.
 

Reflecting the research

The previous guidelines for C. difficile were issued in 2013, and much has changed since then in terms of epidemiology, diagnosis, treatment, and infection control, Sahil Khanna, MBBS, MS, of the Mayo Clinic, Rochester, Minn., said in an interview.

Notably, diagnostic testing has “made leaps and bounds” and new treatments have become available that were not included in earlier guidelines, said Dr. Khanna. In particular, the new guidelines are recommending a two-step diagnostic assay; “the diagnostic algorithm has changed, and hopefully that will help us change practice” to identify active infection more quickly and efficiently.

Another important update is the recommendation of fidaxomicin as an option for initial nonfulminant CDI as an alternative to vancomycin, Dr. Khanna said, noting that metronidazole remains an option for low-risk patients. An additional change is the advice to use a different treatment for a second recurrent infection rather than repeating the initial treatment.  

The recommendation of bezlotoxumab for prevention of CDI recurrence in patients who are at high risk of recurrence is the first time this drug has appeared in major guidelines, Dr. Khanna observed.

The recommendation in support of fecal microbiota transplant is a key update to the management of CDI, including the guidance that the procedure can be repeated if necessary, he said.

Looking ahead, “Additional research is needed to fully understand the best testing algorithms for CDI,” Dr. Khanna explained. “More studies also are needed to show how FMT fully fits into the picture, and some current studies are looking at its potential earlier in the course of infection.”

The guidelines were developed in collaboration with the Practice Parameters Committee of the American College of Gastroenterology and received no outside funding. Dr. Kelly disclosed serving as a site investigator of a clinical trial for Finch Therapeutics and is an unpaid clinical advisory board member for OpenBiome. Dr. Khanna has coauthored previous guidelines on C. difficile. He disclosed consulting relationships with Finch, GlaxoSmithKline, Jetson, ProbioTech, and Shire/Takeda, as well as research support from Rebiotix, Seres, and Vedanta.

Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.  

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.

2. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.

3. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.

4. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.

Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.  

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.

2. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.

3. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.

4. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.

Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.  

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.

2. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.

3. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.

4. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.

Psoriasis patients treated with biological disease-modifying antirheumatic drugs had a significantly lower incidence of psoriatic arthritis (PsA) compared with those treated with phototherapy, in a study of 464 adults.

Epidemiologic data show that PsA may be diagnosed as long as 5-10 years after a diagnosis of plaque psoriasis, but PsA ultimately occurs in up to 25% of cases, wrote the study investigators, Paolo Gisondi, MD, of the section of dermatology and venereology, department of medicine, at Università degli Studi di Verona, Italy, and colleagues.

“The delay between the onset of skin manifestations of psoriasis and joint disease may provide a therapeutic window of clinical opportunity for preventing the progression from psoriasis to PsA,” but the impact of continuous systemic treatment with biological disease-modifying antirheumatic drugs (DMARDs) has not been well studied, the researchers said.

In the retrospective, nonrandomized study published in Annals of the Rheumatic Diseases, the researchers reviewed data from adults with moderate to severe plaque psoriasis who received continuous treatment with biologic DMARDs, compared with those who received narrow-band ultraviolet light B (nb-UVB) phototherapy, between January 2012 and September 2020.

Patients with a past or present PsA diagnosis were excluded from the study. A total of 234 patients were treated with biologic DMARDs for at least 5 years and 230 were treated with at least three courses of nb-UVB phototherapy; all patients were followed for an average of 7 years.

PsA was determined based on the Classification for Psoriatic Arthritis criteria. Incidence was defined in terms of cases per 100 patients per year.

During the follow-up period, 51 patients (11%) developed incident PsA: 19 (8%) in the biologic DMARDs group and 32 (14%) in the nb-UVB phototherapy group. The annual incidence rate of PsA was 1.20 cases per 100 patients per year in the biologic DMARDs group compared with 2.17 cases per 100 patients per year in the phototherapy group (P = .006).

In a multivariate analysis, independent risk factors for PsA were older age (adjusted hazard ratio, 1.04; P < .001), nail psoriasis (aHR 3.15; P = .001), and psoriasis duration greater than 10 years (aHR, 2.02; P = .001). Most other baseline demographics, including smoking status, baseline Psoriasis Area and Severity Index (PASI) scores, and comorbidities, were similar in patients who did and did not develop PsA.

Of the patients taking biologic DMARDs, 39 (17%) were treated with infliximab, 17 (7%) with etanercept, 67 (29%) with adalimumab, 50 (21%) with ustekinumab, and 61 (26%) with secukinumab; 35 of these patients switched biologics during the study period.

The study findings were limited by several factors including the retrospective design and the resulting potential for biases, notably the potential confounding bias by indication because of the lack of randomization, the researchers noted. Another limitation was the inability to perform a subgroup analysis of biologic DMARD classes because of the small sample size, the authors said. However, they added, the findings were strengthened by the complete database and accurate PsA diagnoses supported by an expert rheumatologist.

Larger prospective and intervention studies are needed to validate the results, the researchers emphasized. However, data from the current study suggest that continued treatment with biologic DMARDs “may reduce the risk of incident PsA in patients with moderate to severe chronic plaque psoriasis,” they concluded.

The study was supported by the European Union’s Horizon 2020 Research and Innovation Program. Dr. Gisondi and several coauthors disclosed relationships with Abbvie, Almirall, Amgen, Janssen, Leo Pharma, Eli Lilly, Novartis, Pierre Fabre, Sandoz, Sanofi, and UCB. The study was supported by the European Union’s Horizon 2020 Research and Innovation Program.

Psoriasis patients treated with biological disease-modifying antirheumatic drugs had a significantly lower incidence of psoriatic arthritis (PsA) compared with those treated with phototherapy, in a study of 464 adults.

Epidemiologic data show that PsA may be diagnosed as long as 5-10 years after a diagnosis of plaque psoriasis, but PsA ultimately occurs in up to 25% of cases, wrote the study investigators, Paolo Gisondi, MD, of the section of dermatology and venereology, department of medicine, at Università degli Studi di Verona, Italy, and colleagues.

“The delay between the onset of skin manifestations of psoriasis and joint disease may provide a therapeutic window of clinical opportunity for preventing the progression from psoriasis to PsA,” but the impact of continuous systemic treatment with biological disease-modifying antirheumatic drugs (DMARDs) has not been well studied, the researchers said.

In the retrospective, nonrandomized study published in Annals of the Rheumatic Diseases, the researchers reviewed data from adults with moderate to severe plaque psoriasis who received continuous treatment with biologic DMARDs, compared with those who received narrow-band ultraviolet light B (nb-UVB) phototherapy, between January 2012 and September 2020.

Patients with a past or present PsA diagnosis were excluded from the study. A total of 234 patients were treated with biologic DMARDs for at least 5 years and 230 were treated with at least three courses of nb-UVB phototherapy; all patients were followed for an average of 7 years.

PsA was determined based on the Classification for Psoriatic Arthritis criteria. Incidence was defined in terms of cases per 100 patients per year.

During the follow-up period, 51 patients (11%) developed incident PsA: 19 (8%) in the biologic DMARDs group and 32 (14%) in the nb-UVB phototherapy group. The annual incidence rate of PsA was 1.20 cases per 100 patients per year in the biologic DMARDs group compared with 2.17 cases per 100 patients per year in the phototherapy group (P = .006).

In a multivariate analysis, independent risk factors for PsA were older age (adjusted hazard ratio, 1.04; P < .001), nail psoriasis (aHR 3.15; P = .001), and psoriasis duration greater than 10 years (aHR, 2.02; P = .001). Most other baseline demographics, including smoking status, baseline Psoriasis Area and Severity Index (PASI) scores, and comorbidities, were similar in patients who did and did not develop PsA.

Of the patients taking biologic DMARDs, 39 (17%) were treated with infliximab, 17 (7%) with etanercept, 67 (29%) with adalimumab, 50 (21%) with ustekinumab, and 61 (26%) with secukinumab; 35 of these patients switched biologics during the study period.

The study findings were limited by several factors including the retrospective design and the resulting potential for biases, notably the potential confounding bias by indication because of the lack of randomization, the researchers noted. Another limitation was the inability to perform a subgroup analysis of biologic DMARD classes because of the small sample size, the authors said. However, they added, the findings were strengthened by the complete database and accurate PsA diagnoses supported by an expert rheumatologist.

Larger prospective and intervention studies are needed to validate the results, the researchers emphasized. However, data from the current study suggest that continued treatment with biologic DMARDs “may reduce the risk of incident PsA in patients with moderate to severe chronic plaque psoriasis,” they concluded.

The study was supported by the European Union’s Horizon 2020 Research and Innovation Program. Dr. Gisondi and several coauthors disclosed relationships with Abbvie, Almirall, Amgen, Janssen, Leo Pharma, Eli Lilly, Novartis, Pierre Fabre, Sandoz, Sanofi, and UCB. The study was supported by the European Union’s Horizon 2020 Research and Innovation Program.

Psoriasis patients treated with biological disease-modifying antirheumatic drugs had a significantly lower incidence of psoriatic arthritis (PsA) compared with those treated with phototherapy, in a study of 464 adults.

Epidemiologic data show that PsA may be diagnosed as long as 5-10 years after a diagnosis of plaque psoriasis, but PsA ultimately occurs in up to 25% of cases, wrote the study investigators, Paolo Gisondi, MD, of the section of dermatology and venereology, department of medicine, at Università degli Studi di Verona, Italy, and colleagues.

“The delay between the onset of skin manifestations of psoriasis and joint disease may provide a therapeutic window of clinical opportunity for preventing the progression from psoriasis to PsA,” but the impact of continuous systemic treatment with biological disease-modifying antirheumatic drugs (DMARDs) has not been well studied, the researchers said.

In the retrospective, nonrandomized study published in Annals of the Rheumatic Diseases, the researchers reviewed data from adults with moderate to severe plaque psoriasis who received continuous treatment with biologic DMARDs, compared with those who received narrow-band ultraviolet light B (nb-UVB) phototherapy, between January 2012 and September 2020.

Patients with a past or present PsA diagnosis were excluded from the study. A total of 234 patients were treated with biologic DMARDs for at least 5 years and 230 were treated with at least three courses of nb-UVB phototherapy; all patients were followed for an average of 7 years.

PsA was determined based on the Classification for Psoriatic Arthritis criteria. Incidence was defined in terms of cases per 100 patients per year.

During the follow-up period, 51 patients (11%) developed incident PsA: 19 (8%) in the biologic DMARDs group and 32 (14%) in the nb-UVB phototherapy group. The annual incidence rate of PsA was 1.20 cases per 100 patients per year in the biologic DMARDs group compared with 2.17 cases per 100 patients per year in the phototherapy group (P = .006).

In a multivariate analysis, independent risk factors for PsA were older age (adjusted hazard ratio, 1.04; P < .001), nail psoriasis (aHR 3.15; P = .001), and psoriasis duration greater than 10 years (aHR, 2.02; P = .001). Most other baseline demographics, including smoking status, baseline Psoriasis Area and Severity Index (PASI) scores, and comorbidities, were similar in patients who did and did not develop PsA.

Of the patients taking biologic DMARDs, 39 (17%) were treated with infliximab, 17 (7%) with etanercept, 67 (29%) with adalimumab, 50 (21%) with ustekinumab, and 61 (26%) with secukinumab; 35 of these patients switched biologics during the study period.

The study findings were limited by several factors including the retrospective design and the resulting potential for biases, notably the potential confounding bias by indication because of the lack of randomization, the researchers noted. Another limitation was the inability to perform a subgroup analysis of biologic DMARD classes because of the small sample size, the authors said. However, they added, the findings were strengthened by the complete database and accurate PsA diagnoses supported by an expert rheumatologist.

Larger prospective and intervention studies are needed to validate the results, the researchers emphasized. However, data from the current study suggest that continued treatment with biologic DMARDs “may reduce the risk of incident PsA in patients with moderate to severe chronic plaque psoriasis,” they concluded.

The study was supported by the European Union’s Horizon 2020 Research and Innovation Program. Dr. Gisondi and several coauthors disclosed relationships with Abbvie, Almirall, Amgen, Janssen, Leo Pharma, Eli Lilly, Novartis, Pierre Fabre, Sandoz, Sanofi, and UCB. The study was supported by the European Union’s Horizon 2020 Research and Innovation Program.

Key clinical point: Antibiotic resistance increased with longer hospital stays; vancomycin resistance increased among enterococci, and ceftriaxone and carbapenem resistance among Enterobacterales.

Major finding: A total of 183 community-associated coinfections were identified in COVID-19 patients who met criteria for infection (6%); hospital-acquired infections occurred in 350 patients (12%). Of the hospital-acquired infections, 57% were caused by gram-negative bacteria and 19% were caused by fungi.  

Study details: The data come from 3,028 adults with COVID-19 diagnosed between March 2, 2020, and May 31, 2020, who were hospitalized for at least 24 hours; 516 patients of 899 with positive cultures met criteria for infection.

Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Centers for Disease Control and Prevention. The researchers had no financial conflicts to disclose.

Source: Kubin CJ et al. Open Forum Infect Dis. 2021 May 5. doi: 10.1093/ofid/ofab201.

Key clinical point: Antibiotic resistance increased with longer hospital stays; vancomycin resistance increased among enterococci, and ceftriaxone and carbapenem resistance among Enterobacterales.

Major finding: A total of 183 community-associated coinfections were identified in COVID-19 patients who met criteria for infection (6%); hospital-acquired infections occurred in 350 patients (12%). Of the hospital-acquired infections, 57% were caused by gram-negative bacteria and 19% were caused by fungi.  

Study details: The data come from 3,028 adults with COVID-19 diagnosed between March 2, 2020, and May 31, 2020, who were hospitalized for at least 24 hours; 516 patients of 899 with positive cultures met criteria for infection.

Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Centers for Disease Control and Prevention. The researchers had no financial conflicts to disclose.

Source: Kubin CJ et al. Open Forum Infect Dis. 2021 May 5. doi: 10.1093/ofid/ofab201.

Key clinical point: Antibiotic resistance increased with longer hospital stays; vancomycin resistance increased among enterococci, and ceftriaxone and carbapenem resistance among Enterobacterales.

Major finding: A total of 183 community-associated coinfections were identified in COVID-19 patients who met criteria for infection (6%); hospital-acquired infections occurred in 350 patients (12%). Of the hospital-acquired infections, 57% were caused by gram-negative bacteria and 19% were caused by fungi.  

Study details: The data come from 3,028 adults with COVID-19 diagnosed between March 2, 2020, and May 31, 2020, who were hospitalized for at least 24 hours; 516 patients of 899 with positive cultures met criteria for infection.

Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Centers for Disease Control and Prevention. The researchers had no financial conflicts to disclose.

Source: Kubin CJ et al. Open Forum Infect Dis. 2021 May 5. doi: 10.1093/ofid/ofab201.

Key clinical point: More than half of hospitalized COVID-19 patients developed at least one superinfection, including 75 cases of ventilator-associated pneumonia and 57 systemic infections. Overall, bacterial infections, age, and the highest Sequential Organ Failure Assessment score were independently associated with ICU mortality or 28-day mortality.

Major finding: The most common pathogens behind cases of ventilator-associated pneumonia were Pseudomonas aeruginosa (34.7%) and Stenotrophomonas maltophilia (18.7%). Bloodstream infections occurred in 16 cases, and fungal infections occurred in 41 cases.

Study details: The data come from a retrospective analysis of prospectively collected data from 92 adults with COVID-19 who were admitted to a single ICU between February 21, 2020, and May 6, 2020.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Signorini L et al. Crit Care Explor. 2021 Jun 11. doi: 10.1097/CCE.0000000000000430.

Key clinical point: More than half of hospitalized COVID-19 patients developed at least one superinfection, including 75 cases of ventilator-associated pneumonia and 57 systemic infections. Overall, bacterial infections, age, and the highest Sequential Organ Failure Assessment score were independently associated with ICU mortality or 28-day mortality.

Major finding: The most common pathogens behind cases of ventilator-associated pneumonia were Pseudomonas aeruginosa (34.7%) and Stenotrophomonas maltophilia (18.7%). Bloodstream infections occurred in 16 cases, and fungal infections occurred in 41 cases.

Study details: The data come from a retrospective analysis of prospectively collected data from 92 adults with COVID-19 who were admitted to a single ICU between February 21, 2020, and May 6, 2020.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Signorini L et al. Crit Care Explor. 2021 Jun 11. doi: 10.1097/CCE.0000000000000430.

Key clinical point: More than half of hospitalized COVID-19 patients developed at least one superinfection, including 75 cases of ventilator-associated pneumonia and 57 systemic infections. Overall, bacterial infections, age, and the highest Sequential Organ Failure Assessment score were independently associated with ICU mortality or 28-day mortality.

Major finding: The most common pathogens behind cases of ventilator-associated pneumonia were Pseudomonas aeruginosa (34.7%) and Stenotrophomonas maltophilia (18.7%). Bloodstream infections occurred in 16 cases, and fungal infections occurred in 41 cases.

Study details: The data come from a retrospective analysis of prospectively collected data from 92 adults with COVID-19 who were admitted to a single ICU between February 21, 2020, and May 6, 2020.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Signorini L et al. Crit Care Explor. 2021 Jun 11. doi: 10.1097/CCE.0000000000000430.