Introduction 1 2 3 5 6 7 8 9 1 10 11 Recent insights in the cellular mechanisms of T and B lymphocyte activity in the pathogenesis of SS and the current availability of various biological agents have resulted in new strategies for therapeutic intervention. The use of these biological agents in the treatment of SS will be discussed in this review. Biological Agents 12 13 Anti-TNF-α Monoclonal Antibodies There are three main biological agents targeting TNF-α: the chimeric monoclonal IgG1 antibody infliximab, the receptor fusion protein etanercept, and the fully humanized monoclonal antibody adalimumab. 14 15 2 16 17 In conclusion, TNF-targeting treatment could not be proven to be of benefit in reducing the complaints of pSS patients. IFN-α 6 6 7 18 7 In conclusion, no clinical evidence for the efficacy of IFN-á treatment in pSS patients has been shown yet; however, an improvement of unstimulated whole saliva was observed. Further research is needed to objectify the effect of IFN-á on salivary gland tissue. Anti-CD20 Monoclonal Antibodies 19 20 21 23 24 2 8 Five of the eight pSS patients without a MALT lymphoma received a second course of rituximab (after 9–11 months) due to recurrence of symptoms. Retreatment resulted in the same significant improvement of the salivary flow rate and subjective symptoms compared to the results of the first treatment, together with a decrease in B cells and IgM-RF levels. Six of the seven MALT/pSS patients were initially effectively treated with rituximab. The remaining MALT/pSS patient had progressive MALT disease and severe extraglandular SS disease within 3 months after the start of rituximab treatment. Cyclophosphamide was added, which led to stable disease of both MALT and SS. One of the six patients initially responding had a recurrence of MALT lymphoma after 9 months and was successfully retreated with rituximab. The other patients are still in remission (unpublished data). 2 25 8 25 2 26 27 In conclusion, in phase II trials, it has been shown that rituximab seems to be effective for at least 6–9 months in pSS patients with active disease, improving both subjective and objective complaints. Retreatment with rituximab resulted in a similar good clinical response. In pSS patients with longer disease duration, without residual salivary gland function, rituximab treatment seems to be effective for systemic features. To confirm these promising results, randomized placebo-controlled clinical trials are needed. Anti-CD22 Monoclonal Antibodies 28 2 29 Anti-BAFF 30 11 31 32 33 Safety and Tolerability of Biological Agents 1 Table 1 Adverse events after treatment with biological agents in SS   Agent/dose Number of patients in trial (number treated with the agent) Premedication/concomitant immunosuppressive therapy Infusion reaction Infections Serum sickness HACA/HAHA formation Other Anti-TNF-α monoclonal antibodies 14 Infliximab intravenous, 3 mg/kg 16 (16) n.r./no 1 (6%) 2 (13%) (respiratory tract) – n.r. – 15 Infliximab intravenous, 3 mg/kg 10 (10) n.r./no 4 (40%) 2 (20%) (enteritis, tonsillitis) – n.r. – 2 Infliximab intravenous, 5 mg/kg 103 (54) n.r./continuation of hydroxychloroquine and corticosteroids (≤15 mg/day) 2 (4%) 2 (4%) (1 cutaneous, 1 respiratory tract) – n.r. a 16 Etanercept subcutaneously, 25 mg 15 (15) n.r./pilocarpine at a constant dose – 1 (7%) (parotitis) – n.r. – 17 Etanercept subcutaneously, 25 mg 28 (14) n.r./allowed to use long-term medication 1 (7%) b – n.r. – IFN-α 18 IFN-α oromucosal, 150 IU, 450 IU 109 (87) n.r./no n.a. – – n.r. c 7 IFN-α oromucosal, 450 IU 497 (300) n.r./no n.a. – – – d Anti-CD20 8 2 15 (15) n 2 (13%) 1 (7%) (zoster) e 4 (27%) – 25 2 16 (16) n.r./no – – 1 (6%) n.r. – 26 2 6 (6) n n 1 (17%) – 1 (17%) n.r. – 27 2 12 (12) n n n 1 (8%) – 2 (17%) n.r. – Anti-CD22 29 2 16 (16) 0.5–1 g acetominophen, 25–50 mg antihistamine./no 2 (13%) 2 (13%) (sinusitis, dental abscess) – 3 (19%) 6 (38%) (TIA, osteoporotic fracture, diarrhea, dyspepsia, palpitations, paresthesia) n.a. n.r. HACA HAHA a b c d e 8 Future Perspectives Biological agents are promising therapies for SS. Randomized studies failed to show a clinical effect of anti-TNF-α and IFN-α in the treatment of SS. Notwithstanding the unfortunate results of anti-TNF-α and IFN-α, B cell depletion (both anti-CD20 and anti-CD22) seems very promising. Again, this promising effect, as was previously also assumed for anti-TNF-α and IFN-α, must be confirmed in larger randomized controlled clinical trials. 34 35