Rituximab and Primary Sjögren Syndrome

Rituximab was greeted with high hopes as a treatment for the fatigue and dry eyes of primary Sjögren syndrome (pSS), a chronic autoimmune disorder. Typically, patients with fatigue or arthralgia are treated with hydroxychloroquine, and those with systemic involvement are treated with corticosteroids, methotrexate, or immunosuppressants. But recent research has been pointing toward B-cell depletion as a treatment, and the most widely studied target is the CD20 antigen.

In open-label studies, rituximab, an anti-CD20 antibody, had a good safety profile, induced rapid B-cell depletion in blood and salivary glands, and “seemed beneficial” in early active pSS and in pSS with active extraglandular involvement, say researchers who conducted the subsequent Tolerance and Efficacy of Rituximab in Primary Sjögren’s Syndrome (TEARS) trial.

Two small trials suggested an effect on fatigue and improvements in dryness symptoms. Those early promising findings led the TEARS trial researchers to conduct the multicenter (14 university hospitals in France), randomized, placebo-controlled trial to evaluate the efficacy and safety of rituximab in pSS. In the study, 120 patients with scores of 50 mm or greater on at least 2 of 4 visual analog scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (< 10 years) biologically active or systemic pSS were given rituximab 1 g at weeks 0 and 2 or placebo. The primary endpoint was improvement of at least 30 mm in 2 of 4 VASs by week 24.

Rituximab did not entirely fulfill its promise: It did not significantly increase the proportion of patients’ achieving the primary endpoint. However, it showed clinically significant improvements at week 6 (P = .036), suggesting transient efficacy of the study regimen that was not maintained throughout the 24-week period, the researchers say. Further, fatigue, the symptom that causes the most disability in patients with pSS, responded best—and quickly—to rituximab therapy. The VAS dryness score also improved, although by < 30 mm. Mean salivary flow rate was not improved.

Due to limitations of the study,  the researchers say they can’t recommend rituximab for patients with recent-onset or systemic pSS. But that doesn’t mean there couldn’t be better results. First, it would help to determine the best outcome measure for assessing treatment efficacy in pSS, which at the moment, they say, is “debatable.” They note that clinical trials of potentially disease-modifying treatments in pSS have used various outcome measures. For this study, they chose a large effect—improvement of at least 30 mm in at least 2 of 4 VAS scores evaluating different disease domains—which may have been insensitive to clinically important changes in symptoms.

They also point out that the best interval for assessing treatment efficacy in pSS is unclear. All previous studies on the biology of pSS evaluated the primary outcome between weeks 10 and 24; none of the studies suggested differences in treatment effects over time. For this study, the researchers chose 24 weeks, an interval that seemed consistent, they say, with the kinetics of effects of rituximab as established in patients with rheumatoid arthritis.

Finally, the study patients had low disease activity at baseline. The researchers say they cannot exclude a better effect of the treatment in more active pSS.

Thus, although rituximab didn’t produce sustained or substantial symptom relief, hope should not be abandoned—it still could prove its worth.

Source
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Ann Intern Med. 2014;160(4):233-242.
doi: 10.7326/M13-1085.

Rituximab was greeted with high hopes as a treatment for the fatigue and dry eyes of primary Sjögren syndrome (pSS), a chronic autoimmune disorder. Typically, patients with fatigue or arthralgia are treated with hydroxychloroquine, and those with systemic involvement are treated with corticosteroids, methotrexate, or immunosuppressants. But recent research has been pointing toward B-cell depletion as a treatment, and the most widely studied target is the CD20 antigen.

In open-label studies, rituximab, an anti-CD20 antibody, had a good safety profile, induced rapid B-cell depletion in blood and salivary glands, and “seemed beneficial” in early active pSS and in pSS with active extraglandular involvement, say researchers who conducted the subsequent Tolerance and Efficacy of Rituximab in Primary Sjögren’s Syndrome (TEARS) trial.

Two small trials suggested an effect on fatigue and improvements in dryness symptoms. Those early promising findings led the TEARS trial researchers to conduct the multicenter (14 university hospitals in France), randomized, placebo-controlled trial to evaluate the efficacy and safety of rituximab in pSS. In the study, 120 patients with scores of 50 mm or greater on at least 2 of 4 visual analog scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (< 10 years) biologically active or systemic pSS were given rituximab 1 g at weeks 0 and 2 or placebo. The primary endpoint was improvement of at least 30 mm in 2 of 4 VASs by week 24.

Rituximab did not entirely fulfill its promise: It did not significantly increase the proportion of patients’ achieving the primary endpoint. However, it showed clinically significant improvements at week 6 (P = .036), suggesting transient efficacy of the study regimen that was not maintained throughout the 24-week period, the researchers say. Further, fatigue, the symptom that causes the most disability in patients with pSS, responded best—and quickly—to rituximab therapy. The VAS dryness score also improved, although by < 30 mm. Mean salivary flow rate was not improved.

Due to limitations of the study,  the researchers say they can’t recommend rituximab for patients with recent-onset or systemic pSS. But that doesn’t mean there couldn’t be better results. First, it would help to determine the best outcome measure for assessing treatment efficacy in pSS, which at the moment, they say, is “debatable.” They note that clinical trials of potentially disease-modifying treatments in pSS have used various outcome measures. For this study, they chose a large effect—improvement of at least 30 mm in at least 2 of 4 VAS scores evaluating different disease domains—which may have been insensitive to clinically important changes in symptoms.

They also point out that the best interval for assessing treatment efficacy in pSS is unclear. All previous studies on the biology of pSS evaluated the primary outcome between weeks 10 and 24; none of the studies suggested differences in treatment effects over time. For this study, the researchers chose 24 weeks, an interval that seemed consistent, they say, with the kinetics of effects of rituximab as established in patients with rheumatoid arthritis.

Finally, the study patients had low disease activity at baseline. The researchers say they cannot exclude a better effect of the treatment in more active pSS.

Thus, although rituximab didn’t produce sustained or substantial symptom relief, hope should not be abandoned—it still could prove its worth.

Source
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Ann Intern Med. 2014;160(4):233-242.
doi: 10.7326/M13-1085.

Rituximab was greeted with high hopes as a treatment for the fatigue and dry eyes of primary Sjögren syndrome (pSS), a chronic autoimmune disorder. Typically, patients with fatigue or arthralgia are treated with hydroxychloroquine, and those with systemic involvement are treated with corticosteroids, methotrexate, or immunosuppressants. But recent research has been pointing toward B-cell depletion as a treatment, and the most widely studied target is the CD20 antigen.

In open-label studies, rituximab, an anti-CD20 antibody, had a good safety profile, induced rapid B-cell depletion in blood and salivary glands, and “seemed beneficial” in early active pSS and in pSS with active extraglandular involvement, say researchers who conducted the subsequent Tolerance and Efficacy of Rituximab in Primary Sjögren’s Syndrome (TEARS) trial.

Two small trials suggested an effect on fatigue and improvements in dryness symptoms. Those early promising findings led the TEARS trial researchers to conduct the multicenter (14 university hospitals in France), randomized, placebo-controlled trial to evaluate the efficacy and safety of rituximab in pSS. In the study, 120 patients with scores of 50 mm or greater on at least 2 of 4 visual analog scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (< 10 years) biologically active or systemic pSS were given rituximab 1 g at weeks 0 and 2 or placebo. The primary endpoint was improvement of at least 30 mm in 2 of 4 VASs by week 24.

Rituximab did not entirely fulfill its promise: It did not significantly increase the proportion of patients’ achieving the primary endpoint. However, it showed clinically significant improvements at week 6 (P = .036), suggesting transient efficacy of the study regimen that was not maintained throughout the 24-week period, the researchers say. Further, fatigue, the symptom that causes the most disability in patients with pSS, responded best—and quickly—to rituximab therapy. The VAS dryness score also improved, although by < 30 mm. Mean salivary flow rate was not improved.

Due to limitations of the study,  the researchers say they can’t recommend rituximab for patients with recent-onset or systemic pSS. But that doesn’t mean there couldn’t be better results. First, it would help to determine the best outcome measure for assessing treatment efficacy in pSS, which at the moment, they say, is “debatable.” They note that clinical trials of potentially disease-modifying treatments in pSS have used various outcome measures. For this study, they chose a large effect—improvement of at least 30 mm in at least 2 of 4 VAS scores evaluating different disease domains—which may have been insensitive to clinically important changes in symptoms.

They also point out that the best interval for assessing treatment efficacy in pSS is unclear. All previous studies on the biology of pSS evaluated the primary outcome between weeks 10 and 24; none of the studies suggested differences in treatment effects over time. For this study, the researchers chose 24 weeks, an interval that seemed consistent, they say, with the kinetics of effects of rituximab as established in patients with rheumatoid arthritis.

Finally, the study patients had low disease activity at baseline. The researchers say they cannot exclude a better effect of the treatment in more active pSS.

Thus, although rituximab didn’t produce sustained or substantial symptom relief, hope should not be abandoned—it still could prove its worth.

Source
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Ann Intern Med. 2014;160(4):233-242.
doi: 10.7326/M13-1085.