Key clinical point: BCR/ABL transcript type B3a2_e14a2 is more common than B2a2_e13a2 in patients with chronic myeloid leukemia (CML) with B3a2_e14a2 being more common in women than men.

Major finding: The overall estimated prevalence was highest for B3a2_e14a2 transcript (54%), followed by B2a2_e13a2 (39%) and dual B2a2_e13a2/B3a2_e14a2 (1.11%) transcripts (all P less than .0001), with B3a2_e14a2 being more prevalent in women vs. men (60.6% vs. 51.1%; P less than .0001).

Study details: Findings are from a meta-analysis of 34 studies that evaluated the prevalence of main BCR/ABL transcript types in patients with CML.

Disclosures: No specific funding source was identified. The authors declared no conflicts of interest.

Source: Ghalesardi OK et al. Leuk Res. 2021 Jan 19. doi: 10.1016/j.leukres.2021.106512.

Key clinical point: BCR/ABL transcript type B3a2_e14a2 is more common than B2a2_e13a2 in patients with chronic myeloid leukemia (CML) with B3a2_e14a2 being more common in women than men.

Major finding: The overall estimated prevalence was highest for B3a2_e14a2 transcript (54%), followed by B2a2_e13a2 (39%) and dual B2a2_e13a2/B3a2_e14a2 (1.11%) transcripts (all P less than .0001), with B3a2_e14a2 being more prevalent in women vs. men (60.6% vs. 51.1%; P less than .0001).

Study details: Findings are from a meta-analysis of 34 studies that evaluated the prevalence of main BCR/ABL transcript types in patients with CML.

Disclosures: No specific funding source was identified. The authors declared no conflicts of interest.

Source: Ghalesardi OK et al. Leuk Res. 2021 Jan 19. doi: 10.1016/j.leukres.2021.106512.

Key clinical point: BCR/ABL transcript type B3a2_e14a2 is more common than B2a2_e13a2 in patients with chronic myeloid leukemia (CML) with B3a2_e14a2 being more common in women than men.

Major finding: The overall estimated prevalence was highest for B3a2_e14a2 transcript (54%), followed by B2a2_e13a2 (39%) and dual B2a2_e13a2/B3a2_e14a2 (1.11%) transcripts (all P less than .0001), with B3a2_e14a2 being more prevalent in women vs. men (60.6% vs. 51.1%; P less than .0001).

Study details: Findings are from a meta-analysis of 34 studies that evaluated the prevalence of main BCR/ABL transcript types in patients with CML.

Disclosures: No specific funding source was identified. The authors declared no conflicts of interest.

Source: Ghalesardi OK et al. Leuk Res. 2021 Jan 19. doi: 10.1016/j.leukres.2021.106512.

Key clinical point: Right ventricular systolic pressure (RVSP) increased significantly following dasatinib therapy in some patients with chronic-phase chronic myeloid leukemia (CML-CP), leading to dasatinib-induced pulmonary arterial hypertension (D-PAH) and consequent therapy discontinuation.

Major finding: During a median of 36.2 months of dasatinib therapy, mean RSVP increased significantly and gradually (P less than .001). Overall, 56 patients had RVSP over 40 mmHg, of which 51.8% of patients were diagnosed with D-PAH with clinical symptoms, all ultimately switching to other tyrosine kinase inhibitors.

Study details: Findings are from an analysis of a cohort of 451 patients with CML-CP who underwent 2D-echocardiography at least once at baseline and/or during dasatinib therapy (mean dose, 85 mg/day) as frontline (n=196) and subsequent line (n=255).

Disclosures: This study was funded by Korea Leukemia Bank. The authors declared no conflicts of interest.

Source: Lee SE et al. Cancer Med. 2021 Feb 15. doi: 10.1002/cam4.3588.

Key clinical point: Right ventricular systolic pressure (RVSP) increased significantly following dasatinib therapy in some patients with chronic-phase chronic myeloid leukemia (CML-CP), leading to dasatinib-induced pulmonary arterial hypertension (D-PAH) and consequent therapy discontinuation.

Major finding: During a median of 36.2 months of dasatinib therapy, mean RSVP increased significantly and gradually (P less than .001). Overall, 56 patients had RVSP over 40 mmHg, of which 51.8% of patients were diagnosed with D-PAH with clinical symptoms, all ultimately switching to other tyrosine kinase inhibitors.

Study details: Findings are from an analysis of a cohort of 451 patients with CML-CP who underwent 2D-echocardiography at least once at baseline and/or during dasatinib therapy (mean dose, 85 mg/day) as frontline (n=196) and subsequent line (n=255).

Disclosures: This study was funded by Korea Leukemia Bank. The authors declared no conflicts of interest.

Source: Lee SE et al. Cancer Med. 2021 Feb 15. doi: 10.1002/cam4.3588.

Key clinical point: Right ventricular systolic pressure (RVSP) increased significantly following dasatinib therapy in some patients with chronic-phase chronic myeloid leukemia (CML-CP), leading to dasatinib-induced pulmonary arterial hypertension (D-PAH) and consequent therapy discontinuation.

Major finding: During a median of 36.2 months of dasatinib therapy, mean RSVP increased significantly and gradually (P less than .001). Overall, 56 patients had RVSP over 40 mmHg, of which 51.8% of patients were diagnosed with D-PAH with clinical symptoms, all ultimately switching to other tyrosine kinase inhibitors.

Study details: Findings are from an analysis of a cohort of 451 patients with CML-CP who underwent 2D-echocardiography at least once at baseline and/or during dasatinib therapy (mean dose, 85 mg/day) as frontline (n=196) and subsequent line (n=255).

Disclosures: This study was funded by Korea Leukemia Bank. The authors declared no conflicts of interest.

Source: Lee SE et al. Cancer Med. 2021 Feb 15. doi: 10.1002/cam4.3588.

Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.

Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.

Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.

Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.

Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.

Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.

Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.

Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.

Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.

Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.

Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.

Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.

Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.

Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).

Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.

Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.

Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.

Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.

Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).

Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.

Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.

Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.

Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.

Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).

Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.

Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.

Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.

Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.

Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).

Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.

Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.

Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.

Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.

Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).

Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.

Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.

Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.

Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.

Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).

Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.

Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.

Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.

Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.

Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.

Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.

Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.

Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.

Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.

Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.

Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.

Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.

Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.

Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.

Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.

Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.

Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.

Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.

Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).

Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.

Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).

Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.

Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.

Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).

Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.

Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).

Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.

Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.

Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).

Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.

Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).

Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.

Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

[email protected]

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

[email protected]

Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.

“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.

This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.

Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.

Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.

This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
 

Delayed onset and resolution of rheumatologic immune-related adverse events

“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.

Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.

Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
 

Flares of preexisting rheumatic diseases

These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.

Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.

“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.

He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.

“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.

Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.

[email protected]

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

[email protected]

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

[email protected]

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

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