The successful development of rituximab for the treatment of rheumatoid arthritis (RA) has spurred enthusiasm for targeting B cells in a variety of autoimmune diseases (1–6). Indeed, there are now ongoing randomized clinical trials of rituximab in multiple sclerosis, systemic lupus erythematosus (SLE), antineutrophil cytoplasmic antibody–associated vasculitis, and idiopathic inflammatory myositis, and a variety of new agents targeting B cells are in development. Given all of these clinical trials, it was inevitable that therapies targeting B cells would be investigated in primary Sjögren's syndrome (SS). Studies demonstrating unique changes in peripheral blood B cell subsets in primary SS have also promoted interest in therapies that target B cells (7, 8).

B cells in primary SS

  1. Top of page
  2. B cells in primary SS
  3. B cell depletion therapy in primary SS
  4. What is new in the study by Pers et al?
  5. Future directions in B cell–targeted therapies for primary SS
  6. Acknowledgements

Dry eyes and dry mouth are the hallmarks of primary SS, and sialadenitis with lymphocytic infiltration of the lacrimal and salivary glands is the characteristic pathology (9, 10). The pathogenesis of sialadenitis in primary SS can be viewed as a series of steps. In step 1, there is injury to epithelial cells, releasing autoantigens, chemokines, and cytokines (11). Step 2 involves the activation of endothelial cells and recruitment of inflammatory cells. In step 3, there is stimulation of T cells and B cells, with induction of autoantigen-specific T cells and autoantibodies, such as anti-Ro, anti-La, antifodrin, and anti–muscarinic receptor antibodies as well as rheumatoid factor (RF) (12). During step 4, the formation of autoantigen–autoantibody immune complexes stimulate further activation of inflammatory cells through complement and Fc receptors (FcR) and the production of interferon-α by infiltrating dendritic cells (13, 14). In step 5, there is hypofunction of the salivary and lacrimal glands and the development of sicca symptoms as a result of damage and/or dysfunction induced by infiltrating cells or as a result of anti–muscarinic receptor antibodies blocking parasympathetic stimulation of epithelial cells (15–17). And during step 6, BAFF and other factors that promote B cell activation and survival are produced by infiltrating T cells and macrophages and, possibly, by resident epithelial and mesenchymal cells. Ectopic germinal centers (GCs) with a follicular dendritic cell network are found in a subset of patients (18–20).

In this model of the pathogenesis of sialadenitis in primary SS, B cells are involved in numerous steps, but T cells and innate immunity are also involved. Whether B cells are critical for the occurrence of sialadenitis in primary SS remains to be determined and may be dependent on the stage of the disease; that is, B cells may be critical early in the process for breaking tolerance or for generating autoantibodies, but once autoimmune T cells and long-lived plasma cells have developed, B cells may no longer be needed.

Excessive B cell activation is responsible for a number of the extraglandular manifestations of primary SS, including hypergammaglobulinemia, cryoglobulinemia, hypocomplementemia, hypergammaglobulinemic purpura, arthritis, vasculitis, neuropathy, and glomerulonephritis. Moreover, patients with primary SS have a substantially increased risk of B cell malignancies, a risk shared with other chronic inflammatory diseases (e.g., RA, SLE, or chronic infection with hepatitis C virus [HCV] or Helicobacter pylori) (21–26). It has been hypothesized that the chronic inflammation associated with these diseases provides a microenvironment that allows B cells to evolve from a benign polyclonal population of autoantibody-producing cells, to an expanded monoclonal population, to malignancy (27). Interestingly, in both primary SS and in HCV infection, RF production may play an important role in this sequence of events, and both of these diseases are associated with cryoglobulinemia (28, 29). Patients with primary SS who are at low risk (type I primary SS) or high risk (type II primary SS) of developing B cell malignancies can be identified prospectively based on clinical and laboratory features that can be considered markers of excessive B cell stimulation (30, 31). Not unexpectedly, many of the severe extraglandular manifestations associated with excessive B cell stimulation are also more frequent in type II primary SS (32).

The characteristics of the microenvironment necessary to induce excessive B cell stimulation in primary SS have not been worked out, but increased levels of BAFF have been found and have been hypothesized to be important in this process (33–36). BAFF has been shown to rescue autoimmune B cells that would otherwise be deleted as they emerge from bone marrow precursors (37–39). Moreover, late in life, BAFF-transgenic mice develop sialadenitis, decreased production of saliva, and salivary gland destruction (33). Patients with primary SS have been found to have elevated serum levels of BAFF, and these primary SS patients have also been found to have BAFF in their salivary glands, primarily in infiltrating T cells and macrophages (33, 34, 40, 41). Thus, BAFF in the inflamed salivary glands of primary SS patients may promote the survival and development of immature B cells that produce autoantibodies and may promote the outgrowth of a subset of these B cells into monoclonal populations and malignancies. If this is true, then therapies targeting BAFF may effectively disrupt this progression.

Successful treatment of infection can lead to regression of lymphoproliferative disease associated with HCV or H pylori, presumably by reducing factors such as BAFF that promote B cell proliferation and survival (21). By analogy, any therapy that reduces salivary gland inflammation may have a similar beneficial effect on the excessive B cell stimulation seen in primary SS. However, even if salivary gland inflammation is not decreased, therapies that eliminate abnormal B cell populations may still be effective in preventing the evolution toward malignancy and in treating the severe extraglandular manifestations that are related to excessive B cell stimulation. In this regard, it is noteworthy that in a series of patients with HCV-associated cryoglobulinemia, rituximab was found to be effective in inducing a clinical response and in eliminating the monoclonal population in peripheral blood, but it did not improve the HCV infection (42–44).

B cell depletion therapy in primary SS

  1. Top of page
  2. B cells in primary SS
  3. B cell depletion therapy in primary SS
  4. What is new in the study by Pers et al?
  5. Future directions in B cell–targeted therapies for primary SS
  6. Acknowledgements

The literature on treating primary SS with rituximab is limited, and many studies initially published as abstracts have not yet been expanded (45–56). However, the results available so far are interesting. Several open series using rituximab in patients with primary SS are discussed below.

A study of a series of patients with primary SS treated with rituximab was recently published in Arthritis & Rheumatism (50). This was a small, but well done, study of patients with early primary SS (<4 years) and both IgM-RF and anti-SSA or anti-SSB antibodies compared with patients with primary SS and mucosa-associated lymphoid tissue (MALT)–type lymphoma originating in the parotid gland. The American–European Consensus Group criteria (57) were used to establish the diagnosis of primary SS. Patients were treated with the original dosage for lymphoma (i.e., an infusion of 375 mg/m2 of rituximab weekly for 4 weeks). Extensive clinical and laboratory data were collected to evaluate response, including all of the core criteria recommended by a recent workshop on outcome measures for Sjögren's syndrome (58). The study was completed by 14 patients; 1 patient dropped out because of a serum sickness–like reaction.

Over the 12 weeks of the study, there was a modest, but statistically significant, improvement in oral dryness and stimulated submandibular/sublingual salivary gland secretion in the 8 patients with early primary SS, but neither whole saliva production (unstimulated or stimulated) nor Schirmer's test results improved in either group. Submandibular/sublingual salivary flow in patients with early disease and in patients with better baseline saliva production was more likely to respond. Four of the 5 domains of the Multidimensional Fatigue Inventory showed significant improvement. Scores on the Short Form 36 health survey, used as a measure of quality of life, showed significant improvement in physical functioning, but social functioning did not improve. For the patients with primary SS and MALT-type lymphoma, rituximab treatment induced a complete remission in 3 and stabilized disease in another 3. Immunoglobulin levels did not change significantly with rituximab treatment, but 1 of the patients with primary SS and MALT-type lymphoma had a monoclonal IgGκ protein that disappeared. Thus, the effects of rituximab on sicca were measurable, but small, and there appeared to be responses in fatigue and quality of life.

This series did have significant treatment-related adverse events. Immediate infusion reactions were not a major problem (2 patients had mild infusion reactions), and infections were not severe (1 patient developed herpes zoster, which was treated with acyclovir, with full recovery). Human antichimeric antibodies (HACAs) developed in 4 of the 8 patients with early primary SS and in none of the 7 patients with MALT-type lymphoma/primary SS (P < 0.03). In 3 of the 4 patients with HACAs, a serum sickness–like illness (fever, arthritis, arthralgias, myalgias) developed 5–7 days after the second infusion of rituximab. One of the patients had HACAs at week 0, but the other 2 had no detectable HACAs until 24 weeks after the adverse event. Two of the patients had purpura; skin biopsy of a purpuric lesion showed mononuclear cells and nuclear debris, but no vasculitis.

A study of 6 patients with primary SS treated with rituximab was reported in 2005 (46). Data on these patients were collected retrospectively through the Club Rhumatismes et Inflammation. Two patients had MALT-type lymphoma, 2 had cryoglobulinemia and vasculitis, and 2 had parotid gland enlargement and either polysynovitis or polyarthralgias. Five of these 6 patients had at least a partial response of the manifestations for which they were treated. One patient with lymphoma experienced treatment failure. Subjective dryness improved in 3 of the 6 patients, but there was no improvement in objective measures in the 2 subjects tested.

An additional study of 12 patients with primary SS was presented at the American College of Rheumatology (ACR) Annual Scientific Meeting in 2005 (59). Indications for treatment with rituximab were lymphoma (n = 4), mixed cryoglobulinemia (n = 3), polysynovitis (n = 2), major lacrimal and salivary gland hyperplasia, immune-mediated thrombocytopenia, and mononeuritis multiplex not related to cryoglobulinemia. Rituximab was given at the dosage recommended for treatment of lymphoma. A response was seen in 9 patients. The 3 patients who failed to respond included 1 with lymphoma, 1 with polysynovitis, and the patient with mononeuritis multiplex. B cell depletion was achieved in all patients except the lymphoma patient, who did not respond. The mean daily prednisone dosage was decreased from 20 mg to 4.6 mg (P = 0.002). Self-reported dryness improved in only 3 patients. Treatment tolerance was good; 1 patient had a “benign” infusion reaction, and 2 patients had “mild” serum sickness reactions.

An update on this series, now with 16 patients, was presented at the ACR Annual Scientific Meeting in 2006 (60). After treatment with rituximab, there were dramatic decreases in RF (from 124 IU/ml to 7.5 IU/ml; P = 0.004) and IgG (from 10.8 gm/dl to 7.7 gm/dl; P = 0.003) levels, a significant decrease in β2-microglobulin levels, and cryoglobulinemia disappeared in 3 patients. BAFF levels increased early after treatment and decreased late, but these levels were not determined in all patients, and it is unclear whether these changes were significant. HACAs developed in 1 of the 8 patients tested, and this patient had a serum sickness reaction. Five patients relapsed clinically: 1 with lymphoma, 2 with polysynovitis, 1 with cryoglobulinemia, and 1 with cutaneous nodules. These 5 patients were re-treated, and 4 of them responded. However, 1 of the patients with cryoglobulinemia had to be treated twice. One of the patients who was re-treated developed a serum sickness reaction.

The use of rituximab plus the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 6 patients with primary SS and lymphoma has also been reported (56). This is a very interesting series because of the aggressive therapy used. Rituximab and CHOP were given for 8 cycles. All patients attained a complete response, which was sustained for a median of 23 months. Two-year survival was 100%, whereas historical controls with primary SS and lymphoma had a 2-year overall survival of <50% (P = 0.03 by Kaplan-Meier plot). Cutaneous vasculitis (n = 3) and neuropathy (n = 2) resolved in 3 of the patients. Sicca symptoms did not improve, and repeat minor salivary gland biopsy at 12 months posttreatment showed no significant histologic changes from biopsy tissues obtained pretreatment. Cryoglobulins disappeared completely (3 of 3 patients) and C4 levels normalized (3 of 3 patients). Antinuclear, anti-SSA, and anti-SSB antibodies did not change. Two patients had fever and shivers during rituximab infusion. CHOP treatment was complicated by alopecia (n = 6), neutropenia (<1,000/mm3) (n = 5), and neutropenic fever (n = 2). A trial using anti-CD22 to treat primary SS has recently been published (61). This open trial of 15 subjects showed ≥20% responses in 2 of 4 parameters in 47–67% of patients at 6–32 weeks after 4 infusions of epratuzumab. Thus, anti-CD22 antibodies for the treatment of SS also warrant further investigation.

To summarize the findings of previous clinical series using rituximab for the treatment of primary SS:

  • 1
    Sicca symptoms improved in some patients, and objective measures of salivary function improved in patients with early disease or those with better baseline salivary flow, although many patients had no improvement. Salivary gland enlargement may have been more responsive than sicca symptoms.
  • 2
    Extraglandular clinical manifestations of primary SS were reasonably responsive to rituximab (e.g., vasculitis, arthritis, and neuropathy). Laboratory abnormalities associated with B cell stimulation, such as cryoglobulinemia, hypergammaglobulinemia, RF, monoclonal gammopathies, and complement levels, also improved.
  • 3
    Nonspecific measures that included assessments of fatigue and quality of life responded to rituximab.
  • 4
    Lymphomas developing in patients with primary SS were responsive to rituximab, and combining rituximab with CHOP therapy may have improved responses. This combination was also remarkably effective in treating cryoglobulinemia, low C4 levels, neuropathy, and cutaneous vasculitis.
  • 5
    HACAs developed in a significant number of patients. Consistent with previous literature describing patients receiving rituximab treatment for lymphomas, patients with primary SS and lymphomas did not develop HACAs.
  • 6
    Serum sickness–like reactions occurred, and HACAs appeared to be associated with these reactions. However, HACAs were usually only detectable months after the reaction. It is not clear if these reactions really were serum sickness, and the exact mechanism and significance of these reactions still need to be determined.

What is new in the study by Pers et al?

  1. Top of page
  2. B cells in primary SS
  3. B cell depletion therapy in primary SS
  4. What is new in the study by Pers et al?
  5. Future directions in B cell–targeted therapies for primary SS
  6. Acknowledgements

The article by Pers et al, which is published in this issue of Arthritis & Rheumatism (62), is the fourth recent paper from Dr. Pierre Youinou's group at Brest University, France, characterizing B cells and/or BAFF in Sjögren's syndrome (63–65). The current article deals with B cell depletion and recovery after treatment with rituximab.

Recovery of B cell subsets after treatment with rituximab has recently been described in patients with RA and in patients with lymphoma (66–68). After an initial period of complete depletion, transitional B cells (type 1 [T1] and type 2 [T2] B cells) and plasmablasts reappear in about the same numbers as before depletion. Naive B cells recover more slowly, and memory B cells may remain lower, sometimes much lower, than baseline for years. Therefore, the proportions of different B cell subsets change dramatically, with T1 B cells and plasmablasts accounting for a relatively high proportion of early B cells, and then these cells are diluted out by recovery of naive B cells and, eventually, by recovery of memory B cells. Patients with a high proportion of transitional cells or a low proportion of memory cells at the time of initial reconstitution tended to do better clinically (66, 68). In a series of patients treated with rituximab for SLE, a high proportion of transitional cells at initial reconstitution predicted a low number of memory B cells on long-term followup, and these patients were long-term good responders clinically (69).

Pers et al (62) analyzed the recovery of B cell subsets after rituximab treatment in patients with primary SS and in a small group of patients with idiopathic thrombocytopenic purpura. Recovery was similar to the recovery described for patients treated with rituximab for RA or lymphoma; that is, a relatively high proportion of T1 B cells and plasmablasts initially was followed by dilution of these cells as the naive B cells recovered. The patients with primary SS may have had somewhat lower numbers of T1 B cells early in the process of repopulation, and the number of memory B cells was relatively low later. The paucity of memory B cells previously observed in untreated patients with primary SS was again seen, but similarly low numbers of memory B cells have also been seen in lymphoma patients and RA patients treated with rituximab (68, 69).

A novel finding by Pers and colleagues was the role of BAFF levels in B cell recovery. Pretreatment serum levels of BAFF had a strong correlation with time to reconstitution; that is, BAFF levels were inversely related to the time to recovery (r = –0.92, P < 0.0005). Unexpectedly, there was also a strong effect of BAFF levels on the serum levels of rituximab. Patients with undetectable levels of BAFF at baseline had markedly higher serum levels of rituximab after treatment than did patients with detectable levels of BAFF at baseline (24.3 ± 15.2 μg/ml versus 1.6 ± 0.5 μg/ml; P < 0.01). This dramatic effect of BAFF on rituximab levels may be critical in understanding the variability of response not only in primary SS patients, but also in patients with other autoimmune diseases or B cell malignancies. The persistence of high levels of BAFF may reflect a mixed effect of B cell depletion; that is, B cell depletion may affect inflammation and decreased BAFF production, but B cell depletion also decreases the consumption of BAFF.

One of the previous studies by Youinou's group (64) examined B cells in minor salivary glands from patients with primary SS. The predominant B cell subsets were memory B cells and transitional T2-like B cells. In 7 of 18 patients, ectopic GCs with follicular dendritic cell networks (CD21+,CD35+) and proliferating cells (Ki-67+) were found. The B cells in GCs from salivary glands differed from the B cells in tonsillar GCs. Salivary gland GC B cells were CD20+,CD38−,IgD+ and tonsillar GC B cells were CD20+,CD38++,IgD−. The T2-like B cells in the salivary glands could be distinguished from T1 B cells by IgD and CD21 staining (IgD++ versus IgD+/− and CD21++ versus CD21+/−). However, it is difficult to classify these T2-like salivary gland B cells as true T2 B cells, since they did not stain with CD38. True T2 B cells would also stain for CD24, but CD24 staining was not performed. Additional studies are clearly needed to understand these cells.

In the current study by Youinou's group (62), salivary gland B cells were examined during depletion and repopulation after rituximab treatment. At 4 months after treatment, salivary glands were completely devoid of B cells. This is an important observation, since information on B cell depletion by rituximab in target tissues has been limited. Limited data on B cells repopulating the salivary glands were presented, but what data there were suggested that repopulation was associated with changes in the types of B cells that were present. Of particular note, T2-like B cells were no longer detected. In addition, GCs could no longer be found (i.e., there was no staining for dendritic cells or proliferating cells). Thus, an important finding is that the atypical GCs previously seen in the salivary glands were no longer present after B cell recovery. This observation raises the possibility that B cell depletion therapy may alter the course of type II primary SS by disrupting ectopic GCs. Although the authors state that T cell numbers were modestly reduced, it is not clear from the data presented that this reduction was significant.

The inability of the investigators to confirm the effects of FcγRIIIa alleles on B cell depletion by rituximab treatment may be explained by how the data are presented. A previous study that analyzed this relationship at 2 months after a single infusion of rituximab presented the data as B cell levels versus serum levels of rituximab (70). In that study, rituximab levels accounted for 50% of the variance in B cell depletion, while FcγRIIIa alleles explained another 25% of the variance. In contrast, Pers presented the data as time to recovery versus BAFF levels rather than versus rituximab levels. However, both studies were quite small, so resolution of this issue will await the results of larger studies.

Future directions in B cell–targeted therapies for primary SS

  1. Top of page
  2. B cells in primary SS
  3. B cell depletion therapy in primary SS
  4. What is new in the study by Pers et al?
  5. Future directions in B cell–targeted therapies for primary SS
  6. Acknowledgements

Future studies of therapies targeting B cells in patients with primary SS should be focused on the following points:

  • 1
    Because of the results of pilot studies and the risk of morbidity and mortality without treatment, trials of B cell depletion therapy for extraglandular manifestations associated with excessive B cell activation in patients with type II primary SS should be given a relatively high priority. The benefit of B cell depletion therapy in type I primary SS is less clear.
  • 2
    Given the apparent importance of BAFF in the B cell abnormalities seen in primary SS, clinical trials and mechanistic studies with anti-BAFF therapies are of considerable interest. As with B cell depletion therapies, anti-BAFF therapies seem more likely to benefit patients with type II primary SS, but pilot studies in type I primary SS are probably reasonable, given the low toxicity reported so far with anti-BAFF agents.
  • 3
    The effect of BAFF on rituximab levels and the time to B cell repopulation in the study by Pers and colleagues suggests that combining B cell depletion with anti-BAFF therapy may have synergistic effects. Improved depletion of B cell subsets, including marginal zone B cells, with the combination of anti-CD20 and anti-BAFF therapy has been demonstrated in a mouse model (71).
  • 4
    The appeal of B cell–targeted therapies in primary SS should not exclude the pursuit of other possible therapies. Therapies targeting Toll-like receptors, including currently available antimalarial agents, selected immunosuppressive therapies, such as mycophenolate mofetil, anti-interferon agents, and anti–T cell agents, might be more effective for treating sialadenitis than therapies that specifically target B cells. If so, these therapies will be of particular benefit in patients with type I primary SS and might also benefit patients with type II primary SS by altering the salivary microenvironment and inhibiting the chronic activation of B cells.

In summary, while SS is too complex and diverse a disease to have a single answer, therapies targeting B cells in patients with primary SS are promising, especially for patients who have extraglandular manifestations associated with excessive B cell stimulation.


  1. Top of page
  2. B cells in primary SS
  3. B cell depletion therapy in primary SS
  4. What is new in the study by Pers et al?
  5. Future directions in B cell–targeted therapies for primary SS
  6. Acknowledgements
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