SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Objective

To evaluate the safety and efficacy of a maintenance regimen of infliximab in patients with active primary Sjögren's syndrome (SS) over a 1-year period.

Methods

This followup study included 10 of the 16 patients with primary SS who participated in a pilot study. Patients who continued to have symptoms received additional infusions of infliximab for 1 year.

Results

All patients completed the 1-year followup for evaluation of efficacy. After 1 year, a statistically significant decrease in global and local disease manifestations was observed in all 10 patients. Treatment was generally well tolerated, with the main side effect being a mild, self-limited infusion reaction.

Conclusion

Sustained improvement of active primary SS may be possible with infliximab treatment.

We recently reported that infliximab, an anti–tumor necrosis factor α antibody, seemed to be very effective in the treatment of active primary Sjögren's syndrome (SS) over a 3-month period (1). Sixteen patients with active primary SS according to both the European (2) and the American College of Rheumatology (3) classification criteria were initially enrolled in the study. Three infusions of infliximab (3 mg/kg) were given at weeks 0, 2, and 6. All patients completed the study, and no severe adverse events or lupus-like symptoms were observed. There was rapid and sustained improvement in all clinical and functional parameters, including global assessments (patient's global assessment, physician's global assessment, patient's assessment of pain and fatigue), erythrocyte sedimentation rate (ESR), salivary flow rate, the Schirmer I test, tender joint count, fatigue score, and dry eyes and dry mouth. Because of the successful results in the open study, we extended the protocol by administering additional infusions of infliximab for 1 year.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Clinical, ophthalmologic, and biologic evaluations and safety procedures were performed at weeks 28, 36, 48, and 50, using the same measurements as in the pilot study (1). Patients were allowed to continue using artificial tears, provided that the dosage and schedule regimen remained stable throughout the study.

Ten of the 16 patients with primary SS were enrolled in the 1-year extension study. All of them completed the 1-year followup for evaluation of efficacy. In 2 patients, the dosing regimen of infliximab was changed to 5 mg/kg, because of partial lack of efficacy of the lower dose. In addition, 3 patients who completed the 12-week open study were considered to be in complete remission over 1 year; they were symptom-free and did not receive additional infusions of infliximab. All 10 patients reported reexperiencing SS symptoms a median of 9 weeks (range 4–16 weeks) after receiving the third of the 3 initial infusions. A relapse was defined as a 30% increase in symptoms of dry eyes, dry mouth, or fatigue, and/or a 30% increase in the ESR.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Tables 1 and 2 summarize the results. Clear improvement was seen, particularly in dry mouth (questionnaire, visual analog scale, and unstimulated salivary flow). At week 50, a significant decrease (P < 0.05) for all variables was observed, which was comparable with the effect seen at week 14.

Table 1. Global assessments and clinical and laboratory findings in the 10 patients*
 BaselineWeek
1428364850
  • *

    Values are the median (range). VAS = visual analog scale; ESR = erythrocyte sedimentation rate; ND = not determined.

  • P < 0.01 versus baseline, by Wilcoxon's signed rank test.

  • P < 0.05 versus baseline, by Wilcoxon's signed rank test.

  • §

    P < 0.001 versus baseline, by Wilcoxon's signed rank test.

Global assessment, 0–100-mm VAS      
 Patient's71 (25–100)29.5 (0–94)44 (2–97)30 (17–89)54 (18–87)27 (2–91)
 Patient's assessment of pain78 (7–100)17.5 (2–91)41 (17–81)39 (2–97)32 (6–87)14 (2–84)
 Physician's assessment of pain46.5 (20–73)20 (6–45)§33 (4–64)30 (9–57)41 (11–54)21 (3–56)
Tender joint count (0–64 joints)5 (0–24)0 (0–16)2 (0–12)0 (0–4)0 (0–3)0 (0–4)
Fatigue      
 Global, 0–100-mm VAS85 (13–99)52.5 (4–98)61 (8–97)57 (28–82)47 (24–80)35 (6–76)
 Questionnaire, 0–3 scale3 (1–3)1 (0–3)§2 (0–3)1.5 (1–3)1 (1–3)1 (0–3)
Laboratory tests      
 ESR, mm/hour29 (4–57)18 (2–72)25 (5–61)11 (2–71)13 (17–81)10 (2–84)
 IgG, ×1,000 mg/liter1.3 (0.36–3.83)1.5 (0.57–4.28)1.6 (0.57–3.5)1.4 (0.61–3.5)ND1.7 (0.74–3.7)
 CD4+ cells/mm3565 (240–992)602 (223–1,445)ND505 (229–1,130)ND525 (200–1,250)
 CD8+ cells/mm3242 (67–630)267 (64–750)ND296 (133–625)ND295 (107–486)
Table 2. Local findings in the 10 patients*
 BaselineWeek
1428364850
  • *

    Values are the median (range). ND = not determined; USF = unstimulated salivary flow.

  • P < 0.01 versus baseline, by Wilcoxon's signed rank test.

  • P < 0.05 versus baseline, by Wilcoxon's signed rank test.

  • §

    P < 0.001 versus baseline, by Wilcoxon's signed rank test.

Dry eyes      
 Questionnaire, 0–2 scale2 (1–2)1 (0–2)2 (0–2)1 (0–2)1 (1–2)1 (0–2)
 Schirmer I test, mm/5 minutes8.5 (0–38)10 (0–40)NDNDND12 (0–36)
 Lissamine green staining, 0–9 scale3.5 (0–7)3 (0–7)3 (0–7)NDND3 (0–6)
Dry mouth      
 Questionnaire, 0–2 scale1.7 (1–2)1 (0–2)2 (0–2)1 (1–2)1 (1–2)1 (0–2)
 Speech test, “puttica”/2 minutes92.5 (63–126)132 (86–178)§126 (74–194)137 (77–162)119 (94–157)151 (98–187)
 USF, ml/minute0.09 (0–0.82)0.68 (0–10.4)§0.37 (0–1.12)0.32 (0–1.12)0.36 (0.01–1.12)0.62 (0.01–1.12)

No patients were withdrawn from the study because of adverse events. Infliximab infusions were well tolerated. Three patients described having mild, self-limiting, infusion-related adverse events after the fourth infusion. One patient developed a delayed infusion reaction 8 days after the fifth infusion, which was characterized by a full-body maculopapular rash, fever, and arthralgia. In addition, uncomplicated infections occurred in 2 patients (1 enteritis, which resolved after antibiotic treatment, and 1 tonsillitis) but did not result in withdrawal from the study. None of these infections required admission to the hospital. No malignancies were reported. During the 1-year followup, no anti– double-stranded DNA antibodies were detected, nor did any symptoms suggestive of lupus-like syndrome occur.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this study, we investigated the safety and efficacy of a maintenance regimen of infliximab (administered approximately every 12 weeks) in patients with active primary SS. The patients included in this extension study were initially treated with a loading dose of 3 infusions of infliximab, in a 14-week, open-label study (1). Based on results of the 1-year extension protocol, we can reach new conclusions. The data show that the improvement induced by a loading-dose regimen of 3 infusions of infliximab lasted 9 weeks before the first symptoms of SS reappeared; the most frequent of these symptoms was dry mouth. Three patients were completely symptom free for 1 year after the initial treatment; these 3 patients were younger (median 37.3 years) than the other patients and had a shorter disease duration (<3 years). We cannot, however, draw conclusions based on this small subgroup.

A statistically significant decrease in systemic and local disease manifestations was seen after 1 year of treatment in the 10 evaluated patients. Interestingly, retreatment induced an improvement that was comparable with the response seen at week 14 of the pilot study.

Treatment with infliximab in patients with primary SS was shown to be safe and was generally well tolerated. The main side effect was a mild, self-limited infusion reaction. The frequency of infusion reactions was similar to that reported in rheumatoid arthritis (4) and ankylosing spondylitis (5).

In conclusion, these data suggest that sustained improvement of active primary SS might be possible with infliximab treatment. The exact regimen of reinfusion should be defined in a controlled study.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES