Presented in part at the 68th Annual Scientific Meeting of the American College of Rheumatology, San Antonio, TX, October 2004.
Rituximab treatment in patients with primary Sjögren's syndrome: An open-label phase II study†
Article first published online: 2 SEP 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 9, pages 2740–2750, September 2005
How to Cite
Pijpe, J., van Imhoff, G. W., Spijkervet, F. K. L., Roodenburg, J. L. N., Wolbink, G. J., Mansour, K., Vissink, A., Kallenberg, C. G. M. and Bootsma, H. (2005), Rituximab treatment in patients with primary Sjögren's syndrome: An open-label phase II study. Arthritis & Rheumatism, 52: 2740–2750. doi: 10.1002/art.21260
- Issue published online: 2 SEP 2005
- Article first published online: 2 SEP 2005
- Manuscript Accepted: 3 JUN 2005
- Manuscript Received: 10 FEB 2005
- Innovation Fund of the University Medical Center Groningen
To investigate the safety and efficacy of B cell depletion treatment of patients with active primary Sjögren's syndrome of short duration (early primary SS) and patients with primary SS and mucosa-associated lymphoid tissue (MALT)–type lymphoma (MALT/primary SS).
Fifteen patients with primary SS were included in this phase II trial. Inclusion criteria for the early primary SS group were B cell hyperactivity (IgG >15 gm/liter), presence of autoantibodies (IgM rheumatoid factor, anti-SSA/SSB), and short disease duration (<4 years). Inclusion criteria for the MALT/primary SS group were primary SS and an associated MALT-type lymphoma (Ann Arbor stage IE) localized in the parotid gland. Patients were treated with 4 infusions of rituximab (375 mg/m2) given weekly after pretreatment with prednisone (25 mg) and clemastine. Patients were evaluated, using immunologic, salivary/lacrimal function, and subjective parameters, at baseline and at 5 and 12 weeks after the first infusion.
Significant improvement of subjective symptoms and an increase in salivary gland function was observed in patients with residual salivary gland function. Immunologic analysis showed a rapid decrease of peripheral B cells and stable levels of IgG. Human antichimeric antibodies (HACAs) developed in 4 of 15 patients (27%), all with early primary SS. Three of these patients developed a serum sickness–like disorder. Of the 7 patients with MALT/primary SS, complete remission was achieved in 3, and disease was stable in 3 and progressive in 1.
Findings of this phase II study suggest that rituximab is effective in the treatment of primary SS. The high incidence of HACAs and associated side effects observed in this study needs further evaluation.
Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of salivary and lacrimal glands, frequently accompanied by systemic symptoms. The presence of various autoantibodies such as rheumatoid factor (RF) and anti-SSA/SSB antibodies, as well as hypergammaglobulinemia, is considered to reflect B cell hyperactivity. Five percent of patients with SS develop malignant B cell lymphoma, usually of the mucosa-associated lymphoid tissue (MALT) type and most frequently located in the major salivary glands (1).
Currently, there is no evidence-based intervention therapy for SS. Corticosteroids and disease-modifying antirheumatic drugs (DMARDs) have no major effect on the disease course (2, 3). Rituximab, a chimeric murine/human anti-CD20 monoclonal antibody that binds to the B cell surface antigen CD20, is currently used in the treatment of B cell lymphomas (4–6). It is also considered a promising agent for treatment of various autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (7–9). It has been hypothesized that because B cells appear to be involved in the pathogenesis of SS, B cell depletion may lead to a decrease of disease activity. Progressive loss of salivary gland function occurs mainly in early SS (i.e., the first 4 years after disease onset), and salivary gland function stays relatively stable during the subsequent course (10). Patients with residual exocrine gland function, i.e., those with early SS, may benefit most from systemic therapy. Based on these considerations, this phase II study was undertaken to investigate the safety and efficacy of rituximab in the treatment of patients with early, active primary SS and patients with primary SS with associated MALT-type lymphoma.
PATIENTS AND METHODS
This was a prospective, single-center, open-label phase II study. The study protocol was approved by the ethics committee of University Medical Center Groningen. All patients provided written informed consent.
All patients were at least 18 years old, and all fulfilled the American-European consensus criteria for primary SS, including histopathologic criteria (11). Patients had either primary SS with active disease and short duration (early primary SS group) or primary SS with associated MALT-type lymphoma (MALT/primary SS group). Inclusion criteria for the early primary SS group were increased B cell activity (IgG >15 gm/liter) in combination with the presence of both IgM-RF and anti-SSA or anti-SSB antibodies, short disease duration (maximum 4 years from the onset of oral symptoms), and absence of MALT-type lymphoma. Inclusion criteria for the MALT/primary SS group were primary SS and associated MALT-type lymphoma, localized in the parotid gland and confirmed by incision biopsy (Ann Arbor stage IE). Patients who had another known autoimmune disease or had been previously treated with monoclonal antibodies were excluded. Treatment with DMARDS (e.g., hydroxychloroquine, methotrexate, cyclosporine) and corticosteroids was not allowed during the study and had to be discontinued at least 6 months before baseline, except in patients with severe extraglandular manifestations necessitating continuation of their previous treatment (with no change in dosage allowed) (patients 10, 13, and 14). The use of any type of systemic drug for the relief of dryness-related symptoms (xerostomia, dry eyes) was not permitted during the study.
Patients were treated with 4 infusions of 375 mg/m2 rituximab (Roche, Woerden, The Netherlands), given once weekly. To minimize infusion reactions, patients were pretreated with prednisone (25 mg intravenously), clemastine (2 mg intravenously), and acetaminophen (1 gm orally) before each infusion. Prednisone at this dose has been used as premedication in conjunction with rituximab treatment of patients with lymphoma (12).
Patients were assessed for adverse events and disease activity at baseline and at 5 weeks and 12 weeks after initiation of rituximab treatment. Immunologic, salivary/lacrimal function, and subjective parameters were the response criteria. MALT-type lymphoma was restaged 12 weeks after treatment initiation in the MALT/primary SS group.
Laboratory assessments (including complete blood cell counts and serum biochemical analyses) were performed at baseline and at weeks 5 and 12. Levels of immunoglobulins (IgG, IgA, and IgM) and IgM-RF were measured by nephelometry. Numbers of CD19+ B cells and CD3+, CD4+, CD8+, CD4+,CD25+, and CD8+,HLA–DR+ T cells were measured by fluorescence-activated cell sorting. Rituximab-specific IgG (human antichimeric antibodies [HACAs]) was measured by an antigen binding test, essentially according to the procedure described by Aalberse et al (13). Briefly, serum (1 μl/test) was preincubated with agarose-immobilized protein A (1 mg/test; Pharmacia, Uppsala, Sweden). Nonbound serum components were removed by washing, after which 1 ng of 125I-labeled pepsin-treated rituximab was added. After overnight incubation, nonbound radiolabel was washed away and agarose-bound radioactivity was measured. Highly reactive samples were retested at appropriate dilutions (Central Laboratory of The Netherlands Red Cross Blood Transfusion Service). Samples obtained from the patients before treatment with rituximab were used as controls.
Whole and glandular saliva were collected in a standardized manner at baseline and at the 5-week and 12-week followup visits. Whole saliva was collected as recommended in the revised American-European criteria (11). Unstimulated salivary secretions were collected during a 15-minute period, followed by collection of stimulated secretions (2% citric acid solution applied to the lateral border of the tongue every 30 seconds) during a period of 10 minutes. Flow rates were calculated, and sialochemical analysis was performed. Glandular saliva specimens obtained simultaneously from both individual parotid glands and the submandibular/sublingual glands were collected with Lashley cups (placed on the orifices of the Stensen duct) and by syringe aspiration (from the orifices of the Wharton duct located anteriorly in the floor of the mouth), respectively (14). Sialochemical analysis focused on the concentration of sodium in parotid saliva, because an increase in sodium is indicative of chronic sialadenitis (15).
Parameters included in the revised American-European criteria (11) were evaluated by the same ophthalmologist at baseline and during the 5-week and 12-week followup visits. Schirmer's test was carried out with a filter paper strip, which was placed in the lower fornix of the conjunctiva of the nonanesthetized eye. The amount of wetting was measured after 5 minutes. The rose bengal test was performed by instillation of a 1% rose bengal solution in both eyes. After 1 or 2 full blinks, the intensity of staining of both medial and lateral bulbar conjunctiva and the cornea was scored (up to 3 points for each section [1 = sparsely scattered; 2 = densely scattered; 3 = confluent]), such that a maximum of 9 points could be obtained (16). To determine the tear break-up time (interval between a complete blink and the appearance of the first randomly distributed dry spots), a 1% fluorescein solution was instilled in the inferior fornix of both eyes. The patient was asked to blink a few times, after which the interval in seconds between the last blink and the first break in the tear film was measured (17).
At baseline and at weeks 5 and 12, patients rated oral dryness during the day, oral dryness during the night, difficulty in swallowing dry food without any additional liquids, and dryness of eyes, on a 100-mm visual analog scale. Patients also completed the Multidimensional Fatigue Inventory (MFI) (18) and the Short Form 36 (SF-36) (19). The MFI is a 20-item self-report scale, which has been validated for SS (20) and is designed to objectively measure fatigue, including the following dimensions: 1) general fatigue, 2) physical fatigue, 3) mental fatigue, 4) reduced motivation, and 5) reduced activity. A higher score (possible range 4–20) indicates a higher level of fatigue. The SF-36 questionnaire, which has been used for measuring subjective well-being, has also been validated for SS (21). A higher score indicates a higher level of well-being.
MALT-type lymphoma staging.
Prior to treatment, all patients with MALT-type lymphoma underwent staging procedures including history, physical examination, complete blood cell counts, chemistry profile, computed tomography of the chest, abdomen, and pelvis, magnetic resonance imaging of the head and neck, and bone marrow biopsy. The effect of rituximab treatment on MALT-type lymphoma was evaluated by complete clinical restaging 12 weeks after treatment initiation. Restaging included repeat administration of all staging tests for which results were previously abnormal. Tumor responses were classified as complete response, partial response, stable disease, or relapsing/progressive disease, according to the standardized response criteria for non-Hodgkin's lymphoma (22).
Data are presented as the mean or median and range, and were analyzed on an intent-to-treat basis. The statistical significance of the change from baseline was measured by Wilcoxon's signed rank test. The Mann-Whitney U test (in SPSS version 10.0) was used to analyze the differences between patient groups. P values less than 0.05 were considered significant.
Characteristics of the patients.
Baseline characteristics of the individual patients are summarized in Table 1. Between July 2003 and September 2004, 15 consecutive patients with early primary SS (n = 8) or MALT/primary SS (n = 7) were prospectively enrolled in the study and treated with rituximab. The group of patients with early primary SS differed significantly (P < 0.05) at baseline from the group with MALT/primary SS with regard to disease duration, flow rate of stimulated whole saliva, stimulated parotid flow, level of IgG, level of CD4+ T cells, and physical functioning (Tables 1 and 2). In particular, the MALT/primary SS group was characterized by longer disease duration, and the majority of patients in this group had very low stimulated salivary secretion levels. Of the 7 patients with MALT/primary SS, 3 (patients 10, 13, and 14) had longstanding primary SS (time since diagnosis of primary SS 13, 9, and 4 years, respectively) complicated by recent persistent parotid gland swelling, prompting performance of a parotid gland biopsy which showed MALT-type lymphoma. The other 4 patients in the MALT/primary SS group (patients 9, 11, 12, and 15) had been referred for evaluation for possible SS, and routine diagnostic parotid gland biopsy revealed SS and concomitant MALT-type lymphoma. Of the latter patients, patients 11 and 12 also had swelling of the right parotid gland.
|Patient||Age/sex||Disease duration, months||Anti-SSA/SSB positivity||IgG, gm/liter||IgM-RF, KIU/liter||Monoclonal protein||Parotid gland swelling||Extraglandular manifestations|
|Early primary SS|
|1†||41/F||36||SSA/SSB||18.2||125||—||No||Raynaud's phenomenon, fatigue, arthralgia|
|2||56/F||30||SSA/SSB||21.4||168||—||Yes||Raynaud's phenomenon, fatigue, arthralgia|
|3||50/F||18||SSA/SSB||18.9||741||—||No||Raynaud's phenomenon, fatigue|
|4||65/F||48||SSA/SSB||15.8||108||—||Yes||Raynaud's phenomenon, fatigue, arthralgia|
|5†||39/F||24||SSA/SSB||15.4||16||—||No||Raynaud's phenomenon, fatigue, arthralgia|
|7||43/F||18||SSA||15.2||647||—||No||Raynaud's phenomenon, fatigue, arthralgia, myalgia|
|8†||27/F||36||SSA||30.2||569||—||Yes||Arthralgia, pulmonary involvement|
|10‡||52/F||120||SSA||6.8||101||—||Yes||Fatigue, pulmonary, hepatic, and renal involvement, vasculitis|
|13‡||49/F||12||SSA/SSB||5.9||342||—||Yes||Raynaud's phenomenon, fatigue, arthritis, vasculitis and esophageal involvement|
|14‡||40/F||120||SSA/SSB||14.7||124||+ (IgGκ)||Yes||Raynaud's phenomenon, fatigue, arthralgia|
|Early primary SS group||MALT/primary SS group|
|Week 0||Week 5||Week 12||Week 0||Week 5||Week 12|
|WBCs, 109/liter||4.8 (3.2–8.7)||4.2 (2.9–7.4)||4.6 (2.7–8.7)||4.5 (2.4–10.7)||4.9 (2.3–10.7)||6.0 (2.6–10.7)|
|β2-microglobulin, gm/liter||2.5 (2–4.7)||2.8 (1.8–3.3)||2.4 (2.2–3.2)||2.5 (1.8–3.7)||2.8 (1.7–24)||2.4 (1.9–3.5)|
|CD19+ cells, 109/liter||0.17 (0.11–0.32)||0 (0–0)†||0 (0–0.11)†||0.10 (0.01–0.18)||0 (0–0)†||0 (0–0)†|
|CD4+ cells, 109/liter||0.53 (0.25–1.12)‡||0.58 (0.29–1.03)||0.57 (0.27–1.25)†||0.33 (0.21–0.61)||0.33 (0.24–0.67)||0.30 (0.09–0.73)|
|CD8+ cells, 109/liter||0.20 (0.13–0.66)||0.20 (0.13–0.83)||0.21 (0.14–0.89)||0.23 (0.07–0.39)||0.25 (0.09–0.59)||0.21 (0.05–0.55)|
|CD4+, CD25+ cells, 109/liter||0.04 (0.02–0.06)||0.03 (0.02–0.05)||0.04 (0.02–0.07)||0.03 (0.01–0.13)||0.03 (0–0.19)||0.02 (0.01–0.55)|
|CD8+, HLA–DR+ cells, 109/liter||0.02 (0.01–0.06)||0.02 (0.01–0.06)||0.02 (0.01–0.08)||0.03 (0–0.26)||0.12 (0–0.55)||0.02 (0.01–0.56)|
|UWS, ml/minute||0.04 (0–0.19)||0.07 (0.02–0.15)||0.08 (0.02–0.34)||0 (0–0.5)||0.01 (0–0.09)||0.01 (0–0.14)|
|SWS, ml/minute||0.38 (0.2–1.38)‡||0.62 (0.27–0.80)||0.58 (0.14–1.21)||0.01 (0–0.47)||0.01 (0–0.48)||0.02 (0.01–0.35)|
|Parotid stimulated secretion, ml/minute||0.15 (0.01–0.5)‡||0.21 (0.05–0.25)||0.21 (0.02–0.38)||0 (0–0.07)||0 (0.09)||0.01 (0–0.4)|
|Na in parotid saliva, mmoles/liter||19 (4–63)||11 (3–30)||8 (3–43)†||4 (4–4)||5 (5–5)||4 (3–4)|
|Schirmer's, mm/5 minutes||5 (1–33)||9 (2–30)||10 (2–34)||2 (0–5)||3 (1–6)||3 (2–4)|
|Rose bengal score||6 (1–9)||5 (0–7)†||4 (0–6)†||7 (5–8)||6 (3–7)§||5 (4–7)†|
|Tear break-up time, seconds||2 (0–9)||7 (1–10)§||7 (1–10)†||4 (0–6)||3 (0–8)||3 (0–5)|
|General fatigue||18 (11–20)||14 (8–18)||9 (4–20)†||17 (15–20)||16 (9–19)||14 (8–20)|
|Physical fatigue||15 (6–18)||13 (9–19)||8 (6–19)†||17 (12–19)||16 (8–19)||17 (4–20)|
|Reduced activity||13 (7–16)||12 (6–16)||6 (4–16)†||14 (9–20)||13 (7–17)||15 (5–20)|
|Reduced motivation||11 (6–16)||12 (6–19)||6 (4–16)†||11 (6–16)||8 (7–19)||11 (5–17)|
|Mental fatigue||14 (4–19)||9 (5–20)||12 (4–17)||12 (8–20)||12 (4–18)||12 (8–20)|
|Physical functioning||1 (1–90)‡||72 (55–90)†||85 (40–100)†||55 (15–75)||50 (20–90)||50 (20–95)|
|Social functioning||63 (13–100)||63 (50–75)||75 (13–100)||25 (0–75)||50 (0–88)§||63 (13–100)|
|Role physical||13 (0–100)||25 (0–100)||11 (0–100)§||0 (0–50)||0 (0–100)||0 (0–100)|
|Role emotional||100 (100–100)||100 (33–100)||100 (0–100)||66 (0–100)||0 (0–100)§||1 (0–100)|
|Mental health||80 (40–88)||80 (60–92)||84 (40–100)||64 (36–80)||64 (16–72)||72 (12–84)|
|Vitality||38 (20–80)||45 (25–80)||65 (20–80)†||30 (10–50)||45 (20–50)||40 (15–70)|
|Bodily pain||56 (32–100)||58 (45–100)||78 (67–90)§||45 (20–100)||78 (33–100)§||45 (33–100)|
|General health perception||43 (15–70)||50 (25–65)||60 (10–65)||30 (0–70)||40 (20–75)§||35 (15–75)|
|Health change||25 (0–100)||50 (0–100)§||75 (0–100)†||0 (0–50)||50 (0–75)||50 (0–100)|
Three patients with early primary SS (patients 1, 5, and 8) did not complete the treatment protocol because of a serious adverse event. Each of these 3 patients received only 2 infusions of rituximab. All but 1 of them (patient 1) completed the study assessments. The latter patient refused further followup. There were no serious adverse events in the MALT/primary SS group, and all 7 patients with MALT/primary SS completed the study. Analysis of efficacy could therefore be performed in 14 patients. Treatment with rituximab resulted in improvement in various measures of primary SS disease activity in the patients with early primary SS. Of the 7 patients with MALT/primary SS, complete clinical remission was achieved in 3 (patients 11, 12, and 14), and disease remained stable in 3 (patients 9, 10, and 15) and progressed in 1 (patient 13). After an initial improvement of the extraglandular manifestations, patient 10 had an exacerbation at 24 weeks after her SS had become active, necessitating additional immunosuppressive treatment.
Laboratory assessments in the 14 patients who completed the study.
Rapid decrease of peripheral B cells, lasting for 12 weeks, occurred in all but 2 patients (patients 5 and 8). The latter patients had received only 2 infusions of rituximab. B cell depletion was accompanied by a significant decrease in IgM-RF levels at week 5 in patients with MALT/primary SS (Figure 1). In the 7 patients with early primary SS, a small but significant increase in the number of CD4+ T cells was seen at week 12 (P < 0.05) (Table 2). No changes in T cell subsets were observed in patients with MALT/primary SS. Levels of IgG, IgA, IgM, and β2-microglobulin did not change in either group of patients. Monoclonal protein disappeared following treatment in the only patient who was positive for this protein at baseline (patient 14).
Functional assessments in the 14 patients who completed the study.
Although no significant changes were seen in whole saliva, stimulated submandibular/sublingual salivary secretion increased significantly in patients whose stimulated salivary flow was >0.10 ml/minute at baseline (all patients with early primary SS and 2 with MALT/primary SS). No change was seen in patients who had a stimulated salivary flow of <0.10 ml/minute at baseline (5 patients with MALT/primary SS) (Figures 2A and B). Furthermore, a significant decrease in sodium levels in parotid saliva from baseline to week 12 was observed in the patients with an increase in salivary function (Table 2).
Results of the Schirmer's test did not change significantly, but significant improvements in the rose bengal score in the group with early primary SS and the group with MALT/primary SS, and in tear break-up time in the group with early primary SS, were observed (Table 2).
Subjective assessments in the 14 patients who completed the study.
Significant improvement was observed in patients' assessment of mouth dryness (Figure 3), arthralgia, physical functioning, vitality, and most domains of the MFI in the group with early primary SS. In patients with MALT/primary SS, these features remained stable or showed a tendency toward slight improvement (Table 2).
Long-term followup data were available on 7 patients. Peripheral blood B cell counts returned to normal after 6–9 months, followed by an increase in IgM-RF levels and a concomitant increase in fatigue. In 3 of 4 patients with an initial increase in salivary gland function (3 with early primary SS and 1 with MALT/primary SS), this increase persisted up to 48 weeks after treatment. In 2 patients with MALT/primary SS (patients 10 and 13), increases in IgM-RF levels preceded exacerbation of disease activity (vasculitis and respiratory insufficiency at week 24 [patient 10]) or progression of MALT-type lymphoma (suggested by parotid gland swelling and confirmed by parotid gland biopsy at week 12 [patient 13]). In 1 of these patients (patient 13), peripheral blood B cells were not yet detectable at the time of increase in the IgM-RF level.
Two patients with primary SS (patients 2 and 7) had a mild infusion reaction, i.e., fever and headache, after the first infusion. No additional treatment for the reaction was necessary. In patient 3, herpes zoster developed 10 days after the last infusion. She was treated by her general practitioner with acyclovir, which led to full recovery.
HACAs developed in 4 of the 8 patients with early primary SS (50%) (patients 1, 2, 5, and 8), and in none of the patients with MALT/primary SS. In 3 of the patients in whom HACAs developed (patients 1, 5, and 8), rituximab treatment was discontinued after 2 infusions, because of a serious side effect. These patients presented 5–7 days after the second infusion of rituximab with fever (38–39°C), arthritis, serious arthralgia, and myalgia. Two of them also presented with purpura on the extremities (Figure 4A). Skin biopsy of a purpuric lesion revealed moderate perivascular lymphocytic infiltration in the dermis and subcutis, with nuclear debris but without leukocytoclastic vasculitis (Figure 4B). Direct immunofluorescence showed deposition of IgA, IgM, and complement in the subepidermal vessel walls, but no deposition of IgG. There were no signs of viral or bacterial infections. Laboratory investigations revealed increases in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level in all 3 patients, and elevated complement C3d levels in patients 5 and 8. A decreased level of complement C4 was observed in patient 5 (Table 3). Proteinuria was not detectable in any of the 3 patients. No significant changes in the ESR or in levels of leukocytes, thrombocytes, or CRP were observed in the remaining 12 patients who did not have serious clinical side effects.
|Patient 1||Patient 5||Patient 8|
|Week 0||During SAE||2–4 weeks after SAE||48 weeks after SAE||Week 0||During SAE||2–4 weeks after SAE||24 weeks after SAE||Week 0||During SAE||2–4 weeks after SAE||24 weeks after SAE|
|B cells, 109/liter||0.15||NA||NA||NA||0.16||NA||0.10||NA||0.32||NA||0||NA|
|HACA response, % of agarose-bound radioactivity||<1||NA||<1||1.16||1.05||1.32||1.73||7.54||<1||<1||<1||9.35|
Two of the 3 patients were treated with methylprednisolone (500 mg and 1,000 mg intravenously, respectively) and a nonsteroidal antiinflammatory drug (NSAID); the third patient was treated with an NSAID only, because her symptoms had begun to resolve spontaneously. Treatment resulted in complete resolution of all clinical side effects, and laboratory results returned to normal (Table 3). It was of interest that HACAs and serum sickness–like symptoms occurred in patients with early primary SS only, and in none of those with MALT/primary SS.
In this phase II study, selective depletion of B cells led to improvement of subjective and objective parameters of disease activity, including salivary and lacrimal gland function, in patients with early primary SS as well as patients with MALT/primary SS with residual gland function. In parallel, B cell depletion occurred quickly and B cells remained undetectable at 12 weeks in all patients except the 2 who received only 2 infusions of rituximab due to the occurrence of a serious adverse event. Rituximab, with or without additional chemotherapy, seems to be effective in the treatment of MALT-type lymphoma (5). This was confirmed in our study, in which complete remission was achieved in 3 of the 7 patients with MALT/primary SS, and disease remained stable in 3.
Anti–B cell monoclonal antibody treatment is a promising therapeutic modality in autoimmune disorders. Initial data have shown rituximab to be efficacious and relatively safe in the treatment of systemic diseases such as RA, Wegener's granulomatosis, and SLE (7, 9, 23). Although SS is considered to be a T cell–mediated disease, its systemic complications are associated with increased B cell activity. A positive effect of rituximab on clinical parameters of both SS and MALT-type lymphoma in SS patients has been described in case-reports (24–26), as well as in a report of a case series of 4 patients with aggressive lymphoma and SS treated with rituximab combined with chemotherapy (cyclophosphamide/doxorubicin/vincristine/prednisone) (27). Recently, Gottenberg et al reported on 6 patients with primary SS treated with rituximab (23). Extraglandular symptoms and cryoglobulinemia-related vasculitis responded to rituximab in all but 1 patient, but data on the subjective and objective parameters of mouth and eye dryness were not recorded for all patients, so no conclusion could be drawn regarding the effect of rituximab on salivary/lacrimal gland function in the patients in that study.
The objective of this open-label phase II study was to evaluate the efficacy and safety of rituximab in patients with primary SS with active disease and short disease duration and in patients with primary SS with localized MALT-type lymphoma. Since there are no validated disease activity criteria for SS, active disease was arbitrarily defined as the presence of hypergammaglobulinemia (>15 gm/liter), and most components of the outcome criteria for clinical trials in SS as proposed by Pillemer et al (28) were used. Both patient groups had increased levels of IgM-RF. Levels of circulating IgM-RF correlate positively with the number of extraglandular disease manifestations (29). Most myoepithelial sialadenitis–associated B cell clones, and subsequently, lymphomas, express RF (30). Moreover, serious systemic complications of primary SS, such as vasculitis and nephritis, occur mainly in patients with elevated IgM-RF levels (29). We observed a slight decrease in IgM-RF levels after treatment in 12 of 15 patients. A rise in IgM-RF levels soon after treatment was seen in 2 patients with MALT/primary SS, preceding an exacerbation of their disease (patients 10 and 13; Figure 1). IgM-RF is probably produced by short-lived plasma cells and might be a good surrogate marker for SS activity (31), e.g., an increase in the IgM-RF level might indicate the need for retreatment.
In patients with primary SS, progressive reduction of salivary gland function is observed early in the course of the disease, with the submandibular and sublingual glands being the first to be affected. This is usually accompanied by a change in the composition of parotid and submandibular/sublingual saliva (10, 14, 32). These parameters were the first to improve in our patients with early primary SS. Systemic therapy is probably most beneficial in patients who manifest substantial residual exocrine gland function. This is supported by the finding in this study that patients with longstanding primary SS (most of those with MALT-type lymphoma), who had no salivary secretion at baseline, did not exhibit any improvement in salivary secretion (Figure 2B), while patients with MALT/primary SS who had some residual salivary gland function did show improvement.
Analysis of parotid saliva revealed a decrease in sodium concentration, indicating normalization of sodium readsorption by the salivary gland ductal system. This was especially prominent in patients with early SS, who had high concentrations of sodium at baseline (Table 2). In healthy subjects, most of the sodium is reabsorbed from primary saliva during its transport through the ductal system (15). The increase in salivary secretion and the normalization of sodium concentration might indicate recovery or regeneration of salivary gland tissue. This regeneration probably occurs only in patients with residual salivary gland tissue (24). Furthermore, high concentrations of salivary sodium are related to more severe disease manifestations (33). This highlights the need for early and aggressive treatment of primary SS of short duration, which is often characterized by residual salivary gland function and high levels of salivary sodium. Physical functioning in these patients is frequently severely impaired, and B cell depletion may lead to improved quality of life as well as preservation of lacrimal and salivary gland function.
An unexpected finding was the high incidence of serious adverse events in patients with early primary SS without MALT-type lymphoma. Three patients developed serum sickness–like symptoms, with HACAs. Only 6 cases of serum sickness after rituximab treatment have been reported to date in the literature (23, 34–36), including 1 case in a patient with primary SS and associated MALT-type lymphoma (23). Most of the toxicities associated with rituximab are infusion related, presumably due to cytokine release (37). To our knowledge, serum sickness or a similar adverse event has never been reported to occur in association with rituximab treatment of lymphoma patients without autoimmune disease. Our patients had a clinical presentation compatible with serum sickness. An acute-phase response was observed in all 3 patients, accompanied by an increase in the level of C3d, which is indicative of complement consumption, in 2 (Table 3). The presence of HACAs makes a type III hypersensitivity reaction very likely. Surprisingly, skin biopsy did not reveal the classic findings of leukocytoclastic vasculitis (Figure 4B). Recent reports on rituximab treatment of SLE and RA do not mention similar adverse events (9, 38, 39). However, patients in the latter studies also received cyclophosphamide, methotrexate, or high-dose corticosteroids, which may account for the lack of these events.
Because prednisone can influence salivary flow in selected patients (40), we decided to use a relatively low, single dose of prednisone as premedication in our study, based on safety data from a large trial of rituximab treatment in patients with relapses of low-grade lymphoma (6). In addition to the premedication, 3 of the 7 patients with MALT/primary SS continued to receive prednisone 7.5–15 mg/day in combination with methotrexate or azathioprine, which might have contributed to the lack of serious adverse events in this group.
HACAs have been reported to occur at a higher rate in patients with autoimmune disease than in patients with lymphoma (27% in our study of patients with SS, 4.3% in patients with RA, 35% in SLE patients, and 0.6% in patients with lymphoma) (6, 9, 41). In patients with RA, SLE, or lymphoma, HACAs have not been reported to result in clinical manifestations. It seems that monoclonal antibodies are more immunogenic in active autoimmune disease, independent of the type of disease. It is not known why HACAs did not lead to infusion reactions in the RA and SLE patients in the above studies, but the additional use of immunosuppressive medication in those studies might be explanatory. This is supported by the findings of Gottenberg et al (23). Although no information about HACA formation is available in their report, they present data on tolerability and short-term efficacy of rituximab in 43 patients with systemic autoimmune disease, including 6 with primary SS. Two patients with SLE and 1 patient with primary SS had serum sickness–like reactions. In total, 15 of their 43 patients received rituximab alone, without other immunosuppressive agents. Of the 6 patients with primary SS, all but the 1 who developed a serum sickness–like reaction were receiving concomitant prednisone or other immunosuppressive treatment. This patient had the highest level of IgM-RF (499 IU/liter) (23).
Steinfeld et al treated 16 patients with primary SS with infliximab, another chimeric monoclonal antibody (42). Infliximab was well tolerated, and all patients completed the study. There were no serious adverse events. These SS patients also had an increased ESR and/or hypergammaglobulinemia, comparable with our findings. Use of DMARDs and corticosteroids was not allowed during the study. No details on development of HACAs among Steinfeld and colleagues' patients are available, and no serious adverse events were reported. The only difference between their patients and ours, apart from the type of antibody treatment, was the proportion of patients who were positive for IgM-RF (50% in their study versus 100% in ours). Although we cannot exclude a possible role of an intrinsic factor related to SS, we hypothesize that the combination of high B cell activity (as reflected by high levels of IgM-RF) and lack of concomitant immunosuppressive therapy might be responsible for the development of serum–sickness like reactions after treatment with rituximab in our SS patients.
In conclusion, the findings of this open-label phase II study in 15 patients with primary SS suggest that rituximab is efficacious in the treatment of SS with or without MALT-type lymphoma. Early initiation of therapy may lead to a decrease in disease activity and may prevent irreversible chronic damage of the salivary glands. The occurrence of serum sickness, a previously rarely observed side effect of rituximab, in 3 of 8 patients with early primary SS with high disease activity but without MALT-type lymphoma warrants further study. Based on our preliminary results, we would recommend that concomitant corticosteroid treatment be given at a higher dosage and/or for a longer period of time in order to prevent development of serum sickness–like disorders in rituximab-treated patients with SS.
We are grateful to Philip M. Kluin, Jacqueline E. van der Wal, and Caroline Roozendaal for their support and meaningful discussions.
- 1Members of the European Concerted Action on Sjögren's syndrome. Malignant lymphoma in primary Sjögren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren's Syndrome. Arthritis Rheum 1999; 42: 1765–72., , , , and the
- 13IgG4 as a blocking antibody. In: HalpernGM, editor. Clinical reviews in allergy. vol. I. New York: Elsevier Biomedical; 1983. p. 289–302., , , , , .
- 28Outcome measures for Sjogren's syndrome, April 10-11, 2003, Bethesda, Maryland, USA. J Rheumatol 2005; 32: 143–9., , , .