Sjögren's syndrome (SS) is a chronic lymphocytic inflammatory disorder characterized by xerostomia and keratoconjunctivitis sicca (1). Besides the glandular and extraglandular features of this disorder, the underlying lymphoproliferative process results in a 44-fold increase in the risk of developing lymphoma for patients with SS compared with the general population (2). The patient that we report here had severe SS for nearly 20 years characterized by profound parotid and salivary gland swelling, xeropthalmia, and xerostomia. His symptoms were refractory to supportive measures and hydroxychloroquine. He then developed marginal zone lymphoma that was treated with rituximab, a chimeric monoclonal antibody that reacts with the CD20 antigen, present on more than 90% of B cells, with complete resolution of his SS-related symptoms. This case suggests that SS may be, in part, B cell mediated and that therapy with rituximab may be useful in the management of SS.
The incidence of SS is estimated between 0.5% and 5% of the population, with an estimated worldwide prevalence of 500,000–2,000,000, yet SS is believed to be under diagnosed (3). Primary SS may involve extraglandular sites causing arthritis, pneumonitis, nephritis, nervous system manifestations, and vasculitis of skin and other organs. Secondary SS is defined by the occurrence of the syndrome in association with another known autoimmune disease. There are a number of objective tests and clinical features that are used to establish the diagnosis, including the Schirmer test, the tear break up time, corneal staining, the van Bijsterveld score, secretory sialography, salivary scintigraphy, whole mouth unstimulated collected salivary flow rate, and minor salivary gland biopsy. Serologic markers of autoimmune disease, including antinuclear antibodies (ANA), anti-SSA, anti-SSB, rheumatoid factor (RF), and cryoglobulins, are frequently present in SS.
Currently, there is no consensus treatment for SS. The treatment is generally aimed at alleviating the dryness symptoms and related morbidities. More recent approaches to therapy for SS have included therapies that increase glandular excretion using muscarinic (M3) receptor agonists. Systemic manifestations are treated with steroids, nonsteroidal antiinflammatory drugs (NSAIDs), hydroxychloroquine, or cytotoxic agents, but, in general, these therapies are marginally effective and have potentially serious side effects. Safer and more efficacious therapy directed at modifying the underlying disease process is needed. The present case report suggests that monoclonal antibody therapy targeting B lymphocytes may be a novel therapeutic approach to SS deserving further study.
A 46-year-old man with a long history of SS was referred for the management of marginal zone lymphoma. More than 10 years ago, he reported difficulty eating dry foods, and occasional ocular crust formation. Physical examination at that time showed mouth dryness with no sublingual salivary pool. A magnetic resonance image (MRI) showed enlarged multicystic parotid glands bilaterally. Laboratory studies were remarkable for ANA 1:80, speckled pattern, and positive SSB antibody. RF and human immunodeficiency virus test results were negative. Fine-needle biopsy of a parotid gland showed lymphoid cells consistent with reactive hyperplasia. The patient was treated for presumed suppurative parotitis and was thought to have SS. Nine years ago, he had a second episode of parotitis and soon afterwards, noted the onset of xeropthalmia with chronic redness of both eyes.
Five years ago, his Schirmer test with anesthesia showed an 8-mm right eye and an 8-mm left eye (normal), his tear break up time was 0.5 seconds (abnormal), and rose bengal/sodium fluorescein showed 2+ conjunctival and 3+ corneal staining (abnormal). The patient required 3 bilateral punctal plugs. His xerostomia had necessitated having a water bottle with him to maintain oral comfort. He was treated with artificial saliva, topical vitamin E, and a home humidifier with minimal improvement. Additionally, he reported constant fatigue and bilateral parotid discomfort. Physical examination at that time was remarkable for bilateral nontender parotid gland enlargement, a tongue depressor adhered to his buccal mucosa, he was only able to lick 1 envelope shut, and he could not expectorate any saliva over 5 minutes. His SSA antibody was 1.08 EU (normal < 0.17), SSB antibody was 1.01 EU (normal < 0.17), RF positive (1:80), ANA positive (1:320, speckled pattern), gamma globulin level was 1.8 gm/dl, and ß2 microglobulin level was 2.20 mg/liter.
Three years ago, his parotid enlargement and discomfort were worse. Punctal plugs had made his xeropthalmia somewhat tolerable. He was still fatigued. His salivary flow rate decreased to 0.036 cc/minute. His tear break up time was 1 second and his corneal staining exam showed 2+ conjunctival, and 2+ corneal staining, unimproved. He was started on hydroxychloroquine.
One year ago, his symptoms were stable. His salivary flow rate had increased to 0.1313 cc/minute. His RF was 180 IU/ml (normal < 30), β2 microglobulin level was 3.8 mg/liter (normal < 2.6), and gamma globulin level was 1.9 gm/dl. His anesthetized Schirmer test showed a 5-mm right eye and an 2.5-mm left eye. His tear break up time was 1 second and corneal staining showed 2+ conjunctival and 2+ corneal staining.
A few weeks prior to our initial evaluation at the cancer center, his parotids had enlarged bilaterally with the left gland larger than the right. On examination, there was right submandibular fullness and a 1-cm lymph node in the right anterior cervical region. MRI of the neck (Figure 1) showed bilateral parotid gland enlargement with multiple cysts bilaterally and multiple lobulated, homogenously enhancing masses within both parotid glands. There was also right submandibular gland enlargement with an associated multiloculated mass and an adjacent 1.8-cm lymph node present. Fine needle aspirations of the right submandibular gland and parotid were performed. Both sites showed a monotonous population of predominantly small lymphocytes with scattered larger lymphoid cells. Subsequently, the enlarged submandibular lymph node was excised and showed diffuse infiltration by small lymphocytes that expressed CD20, CD79a, and Bcl-2. Scattered small lymphocytes expressed CD3, CD5, and CD43. Cyclin D1 staining was negative. These results were consistent with marginal zone lymphoma. Followup fine needle aspirations of both parotid glands for flow cytometric analysis revealed a clonal B cell population with kappa light chain restriction and the following immunophenotype: CD19+, CD20+, CD5–, CD10–, subset dim CD23+, consistent with bilateral parotid gland involvement by marginal zone lymphoma. Bone marrow aspirate and biopsy showed no evidence of lymphoma. The serum lactate dehydrogenase level was 517 U/liter (normal), the β2 microglobulin level was 1.4 mg/liter (normal), and a Helicobacter pylori enzyme-linked immunosorbent assay result was negative. White blood cell count was 4.9 × 109/liter, hemoglobin was 15.5 gm/dl, platelet count was 220,000/μL. Computed tomography scans of the chest, abdomen, and pelvis showed subcentimeter mesenteric and retroperitoneal lymph nodes. Positron emission tomography (PET) scan showed 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake only in the parotid glands bilaterally. Thus the patient had clinical stage IIE marginal zone lymphoma with synchronous bilateral parotid gland involvement, and right submandibular salivary gland and lymph node involvement.
The patient was treated with rituximab (375 mg/m2) as an intravenous infusion weekly for 4 weeks without any complications. Hydroxychloroquine was discontinued. Within 1 month of treatment, the patient's parotid glands decreased significantly to the smallest size in 10 years (Figure 2), although there was still a diminutive parotid mass palpable on the left. The patient reported marked improvement in his ability to chew and swallow food, decreased mouth dryness, food rarely sticking to his teeth, decreased thirst, and decreased foreign body sensation in his eyes with tears frequently overflowing due to the punctal plugs. The patient also reported that his eye sensitivity to bright light and his eye fatigue had improved. These symptoms are retrospectively quantified over a 10-year period of disease as portrayed in Table 1. The figures portray significant progression of his disease over 10 years, and improvement following treatment with rituximab.
|Study||10 years ago||5 years ago||Before rituximab (taking plaquenil)||1–2 months following rituximab†|
|Food sticking to teeth||3||4||4||2|
|Xeropthalmia§||Eye foreign body sensation||3||5||5||1|
|Lack of tears||5||1||1||2|
|Sensitivity to light||4||5||5||3|
|Other SS symptoms¶||Mouth ache frequency||2||5||5||2|
|Face swelling degree||1||4||5||1|
|Opthalmologic||Anesthestized Schirmer||NA||Right 8 mm/Left 8 mm||Right 5 mm/Left 2.5 mm||Right 8 mm/Left 6 mm|
|Nonanesthestized Schirmer||—||—||—||Right 6 mm/Left 8 mm|
|Tear breakup time||NA||0.5 seconds||1.0 seconds||3 seconds|
|Salivary flow rate**||NA||None||0.1313 cc/minute||0.142 cc/minute|
|Buccal tongue depressor||NA||Positive||Positive||Negative|
|Rheumatoid factor||1:10 (nl<1:10)||1:80 (nl<1:20)||180 (high)||211 IU/ml|
|ANA||1:80 speckled||1:320 speckled||NA||1:1,280 speckled|
|SPEP||NA||1.8 gm/dl gamma globulin||1.6||—|
|β-2 microglobulin||NA||2.20 mg/dl||4||2.4 mg/liter|
Following treatment with rituximab, there was only minimal parotid enlargement on the left, tearing, moist oral mucous membranes, some pooling of salivary secretions, and no tongue depressor adherence to the buccal mucosa. Salivary flow rate at 5 minutes was 0.142 cc/minute. An anesthetized Schirmer test showed an 8-mm right eye and a 6-mm left eye, a nonanesthetized Schirmer test showed a 6-mm right eye and an 8-mm left eye, tear break up time was 3 seconds, and corneal staining was 1+ conjunctival and trace corneal staining (markedly improved). Laboratory studies approximately 4 weeks following rituximab were as follows: RF was 211 IU/ml, SSA antibody positive, SSB antibody positive, ANA positive at 1:1,280 speckled pattern, and β2 microglobulin level 2.4 mg/liter. Fine needle aspiration performed on the left parotid showed continued involvement by marginal zone lymphoma. Followup MRI (Figure 1) showed marked interval decrease in size in nearly all of the multiple mixed parotid masses/lesions. PET scan showed complete resolution of the previously noted areas of FDG uptake. At 6 months of followup, there was no worsening of his SS symptoms, his human antichimeric antibody test and human antimurine antibody test results were negative, and he received another 4-week course of rituximab for treatment of residual lymphoma, without adverse events. He is more than 1 year from initial therapy without recurrence of his Sjögren's symptoms.
The patient reported here had more than a decade of progressive xerophthalmia and xerostomia and developed lymphoma despite a variety of therapies for SS. Following treatment of his lymphoma with rituximab, a chimeric murine-human anti-CD20 monoclonal antibody that targets B lymphocytes (4), there was marked improvement in his SS. Objective measures of response included improvement in corneal staining, Schirmer's test, salivary flow rate, tear production, salivary pooling, and diminished parotid enlargement. In addition, the patient reports a marked improvement in quality of life related to symptomatic improvement in xerophthalmia and xerostomia. Of note, serologic markers of autoimmune disease did not improve. This later observation is not unexpected at this point in time because rituximab targets the CD20 antigen present only on B lymphocytes; most plasma cells, presumably the source of autoantibodies, do not express CD20.
Functional salivary and lacrimal glandular insufficiency in SS is associated with infiltration by a mixed population of B and T lymphocytes (5), often resembling germinal centers, and by numerous plasma cells that may produce rheumatoid factor, anti-Ro, and/or anti-La (6). Although B lymphocytes are present in this mixed cellular infiltrate, less than 50% of lymphocytes express CD20 (7), a lineage-specific marker for B cells, using immunohistochemical methods. Studies have demonstrated that antigen-driven clonal B cell proliferation accompanied by somatic hypermutation and antigen selection occurs in the salivary glands of Sjögren's patients (8). Clonal immunoglobulin heavy chain gene rearrangements have also been detected, suggesting that B cell lymphomas may arise in this setting of chronic antigenic stimulation (8). With all elements of a normal germinal center present, it is possible that the pathogenesis of SS involves an immune response similar to foreign antigenic stimulation, causing specific B cell proliferation and differentiation into plasma cells in a microenvironment that includes follicular dendritic cells, activated helper T cells, CD40–CD40 ligand interaction, and appropriate cytokines. Although evidence exists implicating genetic and environmental factors, as well as viral agents (9), in the development of SS, the stimulus for the observed immune response remains unknown.
Current therapies for SS are inadequate and no available therapy restores normal salivary or lacrimal gland secretion. Strategies aimed at relieving xeropthalmia and xerostomia have included topical agents for replacement of deficient secretions (artificial tears and saliva) and sialogogues including M3 receptor agonists, such as pilocarpine (10) and cevimeline. Additional therapies include topical fluorides, antibacterial mouthwash, and topical antiinflammatory agents for the eyes. Systemic therapies for more severe disease and for extraglandular complications include NSAIDs, corticosteroids, the antimalarial agent hydroxychloroquine (11), and cytotoxic therapy with methotrexate (12) or cyclophosphamide.
Investigational agents for SS include oral low-dose interferon alpha, anti-tumor necrosis factor α therapy, pyrimidine synthase inhibitors, and tyrosine kinase inhibitors (13). Because almost half of the secretory acinar cells remain histologically intact in patients with long-standing SS (14), with effective therapy aimed at the pathogenesis of the disease it is possible that the acinar cells could become active again. This is not the case in other autoimmune diseases that result in irreversible organ damage, for example, type I diabetes mellitus or lupus nephritis.
Rituximab has been approved by the Food and Drug Administration for treatment of relapsed and/or refractory low grade B cell non-Hodgkin's lymphomas. This monoclonal antibody binds to an epitope of the transmembrane CD20 protein that is expressed on most mature B lymphocytes, as well as B cell lymphoma cells, and causes cell death by induction of apoptosis, complement-mediated cell lysis, and antibody-dependent cell-mediated cytotoxicity (15). This patient with long-standing, severe primary SS had marked improvement in SS after a single 4-week course of rituximab. Clinical improvement continues more than 12 months following treatment. This single observation needs confirmation in clinical trials. It also suggests that selective depletion of B lymphocytes from salivary and lacrimal glands may reverse in part the pathophysiology of this disease and that the role of B cells in SS may not relate directly to production of autoantibodies. However, our patient also had infiltration of his salivary glands by malignant lymphoma, and the contribution of this process to his symptomatology is unclear. Further preclinical and clinical studies are indicated to elucidate the effect if B lymphocyte depletion in earlier stages of the disease and in SS uncomplicated by lymphoma.