Round 27: Sjögren’s Syndrome: Clinical picture, adverse outcome and B-cell neoplasia

Athanasios G. Tzioufas, MD
Department of Pathophysiology, Medical School
National University of Athens, Greece

Dr. Tzioufas has no significant financial interest or relationships to disclose.

Release Date: March 31, 2010
Expiration Date: January 1, 2011

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Objective

To discuss the clinical picture and the adverse outcome in B-cell neoplasia in Sjögren’s Syndrome.

Background

Sjögren’s is:

  • A female disease;
  • A common disease; it affects 0.2% – 1.0% of all adult females; and
  • Usually found in the fourth and fifth decades of life.

Sjögren’s disease has a very important characteristic that makes it different from other systemic autoimmune disease; the disease progresses very slowly—not like lupus or rheumatoid arthritis (RA), which have robust clinical pictures.

Figure 1

Here you see with the black line–the peak of patients at the onset–and the dotted red line–the peak of patients at diagnosis. There is around 8 years elapsed time from the onset of disease until disease diagnosis. This is particularly important because many patients are struggling without having the right diagnosis.

Sjögren’s is also a center of autoimmune disorder.  Since it can be found alone we call it primary Sjögren’s Syndrome or in association with other autoimmune diseases, called secondary Sjögren’s Syndrome.  It has a wide clinical spectrum extending from organ-specific disease to systemic disease, and finally neoplasia. It is also a prototype immune disease since both humoral and cellular arms of the adoptive and native immunity are contributing equally to the development of the pathologenesis of the disorder.

Association of Sjögren’s syndrome with other autoimmune rheumatic diseases:

  • RA—around 20% may also have Sjögren’s syndrome. Sjögren’s patients with RA is expressed a little bit different in clinical terms since these patients may usually present with dry eyes rather than dry mouth or major glandular enlargement.
  • Systemic lupus erythematosus
  • Scleroderma
  • Mixed connective tissue disease
  • Primary biliary cirrhosis
  • Myositis
  • Vasculitis
  • Thyroiditis—Thyroiditis Hashimoto has a high prevalence of secondary Sjögren’s Syndrome.
  • Chronic active hepatitis
  • Mixed cryoglobulinemia

Figure 2

The characteristic tongue of patients with Sjögren’s Syndrome (right). The tongue papillae have completely disappeared and sometimes in some neglected patients you see also food sticking to the dry oral mucosa.

Figure 3

The eyes are equally affected.  (Left) shows the most specific tests for dry eye, which are the Schirmer’s test and the Rose-Bengal staining of cornea.  Rose-Bengal staining is the most specific test to see corneal inflammation.  Here in the States ophthalmologists usually do not do Rose-Bengal staining, instead they have staining of cornea by flushing and staining of conjunctiva by lissamine green. In Europe the Rose-Bengal staining is used. The red dye is called Rose-Bengal and allows one to see inflammation.

The American-European Consensus Group classification criteria

When diagnosis is made according to the American-European classification criteria, there are six criteria:

  1. Subjective
    (Positive = a positive response to at least one of the three following questions)
    I. Ocular symptoms:
    Have you had daily, persistent, troublesome dry eyes for more than 3 months?
    Do you have a recurrent sensation of sand or gravel in the eyes?
    Do you use tear substitutes more than three times a day?
    II. Oral symptoms:
    Have you had a daily feeling of dry mouth for more than 3 months?
    Have you had recurrently or persistently swollen salivary gland as an adult?
    Do you frequently drink liquids to aid in swallowing dry food?
  2. Objective
    III. Ocular signs (positive result in at least one of the following tests)
    Schirmer’s test
    Rose-Bengal score or another ocular dye score
    IV. Histopathology
    Focus score ≥1
    V.  Salivary gland involvement (positive result in at least one of the following tests)
    Unstimulated salivary flow
    Parotid sialography
    Salivary scintigraphy
    VI. Autoantibodies:
    The presence of Ro(SSA) and/or La(SSB)—the specific markers for Sjögren’s Syndrome

In order to define if a patient has primary Sjögren’s Syndrome, they must have the presence of any four of the six criteria or they must have three objective criteria and should not have any of the potentially associated diseases such as RA.  Secondary Sjögren’s Syndrome is defined if the patient has one subjective criterion, two objective criteria and an associated disease.

Exclusion criteria:

  • Prior head and neck irradiation
  • Pre-existing lymphoma
  • Acquired immunodeficiency disease (AIDS)
  • Hepatitis C infection
  • Sarcoidosis
  • Graft‑versus‑host disease
  • Sialoadenosis
  • Drugs (neuroleptic, anti‑depressant, anti‑hypertensive, parasympatholytic)

Autoimmunity Hallmarks

Figure 4

The autoimmunity hallmarks are two; first is the lymphocytic infiltrates with destruction of epithelial tissues, shown below, and second is B-lymphocytic hyperactivity.

The most common autoantigens in primary Sjögren’s are rheumatoid factors found in 8 out of 10 patients.  Some of these patients, around 30%, may also have monoclonal rheumatoid factors, which are found in the form of cryoglobulins.  Fifty percent to eighty percent may have antibodies to Ro/SSA and La/SSB, depending on the method that is used for the detection. The best method appears to be radioimmunoprecipitation assay after de novo in vitro transcription and translation of the autoantigen.  There is still a lot of work to be done to classify the prevalence of anti-fodrin.  Initial enthusiastic reports in Japan claimed anti-fodrin antibodies in around 95% of primary Sjögren’s patients. However, several European and U.S. reports claim the prevalence of anti-fodrin antibodies is around 30-40% and there is also high prevalence of this antibodies in systemic lupus erythematosus and RA.

Antibodies to Ro/SSA and La/SSB are particularly important in Sjögren’s Syndrome. They are usually associated with longer disease duration. They are associated with extraglandular manifestations, in particular vasculitis. They are associated with higher intensity of salivary gland infiltrates, but direct pathogenic effect has not been yet demonstrated.

Systemic/Extraglandular manifestations

Arthralgias/arthritis are observed in more than 50% of patients. Arthritis with Sjögren’s looks very much like lupus arthritis. It is not an erosive arthritis and a delayed sequela of arthritis in primary Sjögren’s is Jaccoud’s arthropathy. This happens in patients with systemic lupus erythematosus. Raynaud’s phenomenon is found in around one-third of patients and is quite often the primary sign of the disease. From these patients, around 60% may present a distinct clinical picture that is associated with anticentromere antibodies. Purpura, mainly in the form of vasculitis, is found in 15% of patients.  Peripheral neuropathy due to vasculitis is also noted in around 2% of patients; lung involvement in 10% of patients; kidney involvement in 8% of patients; liver involvement in 5% and muscle involvement (including polymyositis and inclusion body myositis) in 1% of patients.

Lung involvement.  Below is a chest x-ray of a patient with Sjögren’s and what we call a dirty chest x-ray.

Figure 5

However if a high resolution CT of the lungs is taken, we see that there is a peribronchial thickening.

Figure 6

The pulmonary function tests usually reveal small airway disease without effecting DLCO and bronchial biopsy in these patients usually show peribronchial infiltrates. So, initially in the old reports, we thought that this is an interstitial pattern, but actually this is not an interstitial pattern, this is an obstructive pattern associated with small airway disease.

Kidney involvement. This is found in 8% of patients, and the most common form of kidney involvement is interstitial nephritis, affecting 25% of patients with primary Sjögren’s. It can be proximal or distal tubular acidosis and at the end these patients may produce nephrocalcinosis.  Glomerulonephritis is found only in 2.5% of patients.  It can be membronoproliferative form, the membranous form or the messangioproliferative form.
Strict clinical differences between interstitial nephritis and glomerulonephritis

Systemic manifestations

IN
(n=10)

GMN
(n=10)

Statistical
significance

Age (mean SD)

37 ± 12

46 ± 7

P=0.063

Years after disease onset

2 ± 3

8 ± 6

P=0.001

Cryoglobulins

20

80

P=0.023

Interstitial nephritis is found in younger patients.  Interstitial nephritis usually develops right from the disease onset together with dry mouth and dry eyes while glomerulonephritis comes later. Finally, glomerulonephritis is highly associated with immune complexes in the form of cryoglobulins. Almost all patients have cryoglobulinemia and low complement levels.

Liver involvement. This is found in around 5% of patients.

Number of patients 300
Clinical symptoms & signs of liver involvement 2%
Elevated liver enzymes 5%
Antimitochondrial antibodies (AMA) 7%

Results of 300 patient cohort

Differences between antimitochondrial positive and antimitrochondrial negative patients

Patients (%)

Antimitochodrial positive,
n = 20

Antimitochodrial negative,
n = 250

Clinical symptoms & signs of liver involvement

20

0.3

Elevated liver enzymes

- AST

41

15

- ALT

50

15

- ALP

64

0

Liver histology

- Primary billiary chirrosis

82

0

- Chronic active hepatitis

0

0.3

- Viral hepatitis

0

1

These patients had increased liver enzymes and the liver histology in the majority of these patients shows pericholangitis, reminiscent of stage 1 of primary biliary cirrhosis.

To summarize the pathologic picture of primary Sjögren’s, one realizes that the target tissue is the epithelial cell.

  • Labial salivary gland biopsy: periductal infiltrates
  • Kidney: peritubular infiltrates and interstitial nephritis
  • Lung: peribronchial infiltrates around the small bronchi
  • Liver: pericholangeal infiltrates.

In other words, it appears that the target organ is the epithelial cell. In the autoimmune lesion of the Sjögren’s Syndrome are the activated infiltrating cells, but there is also equally activated epithelium.

Activated infiltrating cells

  • B cells
  • T cells
  • helper/memory
  • LFA.1/HLA-DR+
  • Dendritic cells in advanced lesions

Activated epithelium

  • HLA-DR
  • c-myc
  • proinflammatory cytokines
  • lymphoid chemokines
  • co-stimulatory/adhesion molecules
  • autoantigens

Systemic manifestations

The clinical, laboratory and basic observations suggest that the systemic manifestation of Sjögren’s can be reclassified as periepithelial systemic manifestations or tissue-specific manifestations (including liver, lung and kidney) Extraepithelial manifestations are really systemic manifestations such as vasculitis, peripheral neuropathy, kidney glomerulonephritis and myositis.  Additionally, a small number of patients may develop B-cell neoplasia.

Figure 7

The figure above represents the dominated thinking about the evolution of Sjögren’s Syndrome for the past 25 years.  It reads that Sjögren’s starts with glandular manifestations, evolves in around 50% of patients through extraglandular manifestations and terminates (in some patients) to lymphoma. The question is: Is this true? Is this what really happens?

Case presentation

A 64-year-old woman presented in 1988 with dry mouth, dry eyes, conjunctivitis sicca with bilateral parotid gland enlargement, Raynaud’s phenomenon and skin purpura. At presentation she had anemia, leukopenia, high titer of antinuclear antibodies and the classic antibodies of Sjögren’s: Ro/SSA and La/SSB. She also had serum cryoglobulins and low C4 levels.

Figure 8

Above is the apparent parotid gland enlargement and skin purpura at presentation.

The cryoglobulins were shown to be monoclonal cryoglobulins containing an IgM kappa monoclonal rheumatoid factor. At that time, the patient had positive minor salivary gland biopsy.  She received high doses of prednisone for a short time, which resulted in the remission of skin vasculitis.

In 2000, during a follow-up exam, the patient presented with easy fatigue, low-grade fever and axillary and inguinal lymphadenopathy. Lymph node biopsy revealed high-grade non-Hodgkin’s lymphoma. This case had certain clinical and laboratory parameters that were present at least 12 years before the development of lymphoma. This observation, along with the presence of Sjögren’s, indicates an ideal model to start the predictors of adverse outcome. This experiment may provide us a long observation time per patient. There are well-defined end points, such as the B-cell lymphoproliferation, and universally accepted diagnostic criteria.

Adverse outcome in Sjögren’s Syndrome

  1. Predictor markers for poor outcome
  2. Lymphoproliferation
  3. Treatment of lymphoma

A predictor marker should be present in the majority of patients who develop a given disease before the appearance of the disease and should be absent in the majority of patients who did not develop the disease.  A study in 2000 (Skopouli et al., Semin Arthritis Rheum 2000; 29: 296) was the first study to show the evolution, and impact of the evolution, in overall survival in patients with primary Sjögren’s Syndrome. More than 250 patients with primary Sjögren’s Syndrome were studied with a mean follow-up of 3.6 years after diagnosis. The study aimed to identify the evolution of the clinical picture and laboratory profile, the incidence and predictors of systemic disease and the impact of Sjögren’s and overall survival. The time interval from the first symptoms to diagnosis had a mean of 6 years, the follow-up from the time of diagnosis was 3.6 years and the total reported duration of symptoms was 9.5 years.

Manifestations referred as first symptoms and at diagnosis (261 patients)

Patients (%)

first symptoms

at diagnosis

Dry eyes

46.5

95

Dry mouth

41.5

90

Parotid gland enlargement

16.2

49

Arthralgia/arthritis

33.8

70

Raynaud’s phenomenon

19.2

41

Dry cough

3

30

Dyspareunia

3.9

29

Purpura

1

10

The clinical symptoms from the time of diagnosis and during follow-up

Patients (%)

Diagnosis

At end of follow-up

Arthralgia/arthritis

70

75

Raynaud’s phenomenon

41

48

Purpura

10

11

Pulmonary involvement
(small airway disease)

19

23

Primary biliary cirrhosis

4

4

Renal involvement

interstitial

7

9

glomerulonephritis

0.4

2

Peripheral Neuropathy

1

2

Lymphoproliferative disorders

2

4

The laboratory profile of the patients didn’t change. Rheumatoid factor was the same, and antinuclear antibodies were the same. Ro/SSA and La/SSB antibodies were the same. There was an increase of monoclonal cryoglobulins.

The study indicates that certain systemic manifestations such as arthritis, Raynaud’s phenomena, pulmonary involvement, interstitial nephritis and liver involvement (periepithelial manifestations), and serologic profile do not change during follow-up on patients. Other systemic manifestations, such as glomerulonephritis, peripheral neuropathy and lymphoma, are observed more during follow-up—during the late sequela of the disease.

Consecration analysis

Outcome Predictor P-value Relative Risk
Glomerulonephritis Low C4 levels 0.015 8.6
Monoclonal cryoglobulins 0.03 6.5
Palpable purpura 0.0024 16.3
Lymphoproliferative Low C4 levels 0.016 7.5
disease Monoclonal cryoglobulins 0.0012 7.9
Palpable purpura 0.015 5.0
Death low C4 levels 0.014 4.9

This initial observation prompted a larger study to determine the incidence of predictors of adverse long-term outcomes in Sjögren’s. The study used 723 consecutive patients with primary Sjögren’s syndrome, covered more than 4,000 people per year and sought to determine the mortality and lymphroliferative disease rate.  The study also aimed to develop a rational predicted classification for the syndrome.

Long-term outcomes of the study. In the last cohort of patients, there were 38 lymphoproliferative disorders—4% of the total population and quite similar to that described in previous reports.  The probability of lymphoma development was 2.6% at 5 years, and 3.9% at 10 years and there were 39 deaths. The mortality ratio was 15% more than the mortality ratio of the general Greek population. Interestingly, only 7 out of 39 deaths were attributable to lymphoma, however all patients who developed lymphoma resulting in death (these 7 patients), had either low C4 levels or palpable purpura at the first study visit. The lymphoproliferative disease and the development of lymphoma was independently predicted by parotid gland enlargement, palpable purpura and low C4 levels.

Figure 9

Patients with parotid gland enlargement, palpable purpura or low C4 (predictors of lymphoma development), have the chance to develop later lymphoma while patients without predictors of lymphoma do not develop lymphomas.

Another group of investigators in Sweden showed that patients with hematologic malignancy had a higher standard mortality ratio of 7.89, patients with ischemic cardiovascular was 1.06 and other conditions was 0.94. The study showed that patients with Sjögren’s died from lymphoproliferative disease. Further results showed that the study mortality rate doubled for patients with low C3, and almost more than tripled for patients with low C4 levels. The same observation was also confirmed by a study in Barcelona.

The studies above have clearly shown that this picture should be revised.

Figure 10

This is not the case. It appears that the evolution from one stage to the other is not true. It appears that Sjögren’s Syndrome presents with two faces: one with the good predictors and the other is with the bad predictors.

Figure 11

Type-1 Sjögren’s, which is the high-risk group: 15% of patients with low C4, palpable purpura.
Type-2 Sjögren’s, which is low risk of lymphoma or death.

Adverse outcome in Sjögren’s Syndrome

  1. Predictor markers for poor outcome
  2. Lymphoproliferation
  3. Treatment of lymphoma

Lymphoproliferation is associated with Sjögren’s Syndrome and has the highest prevalence and highest relative risk for the development of lymphoma. Lymphomas were first described by Bunin & Talal at the NIH in 1964. In 1978, Kassan and Moutsopoulos presented the increased risk of lymphoma in Sjögren’s. In 1979, Zulman showed that this lymphoma is a B-cell lymphoma. From 1989 to 1991, studies showed that there is a monoclonal expansion of B-cells, which takes place in mainly the effected excretory glands. Since 1998, prediction models of poor outcome in large patient cohorts have been developed.

There are certain limitations for studying lymphoma in Sjögren’s that have to do with low incidence of Sjögren’s and the low incidence of lymphoma in Sjögren’s.  Because of this, we constructed a European study with six different laboratories to study the clinical picture of lymphoma. This study recruited 33 patients with malignant lymphoma; the average age was 58 years old. They were all Caucasians, and the majority of them were females. The medium time of Sjögren’s Syndrome to lymphoma diagnosis was 7.5 years.

This study showed lymphoma is a late sequela of primary Sjögren’s. The majority of these patients had a classic picture of clinical and serological primary Sjögren’s Syndrome.

Salivary gland involvement

%

Major salivary gland

91

Parotid gland

86

Bilateral

84

Permanent

28

Submandibular gland

17

Lacrimal gland

7

 

Systemic manifestations

%

Arthralias/ Arthritis

75

Fatigue

68

Raynaud’s phenomenon

49

Cutaneous vasculitis

33

Lung involvement

31

Low grade fever

25

Peripheral nerve involvement

24

Thyroid involvement

21

Kidney involvement

18

Liver involvement

6

The majority of the lymphomas were low grade, particularly MALT lymphomas. Thirty percent of patients had intermediate or high-grade lymphomas according to WHO Classification.

Clinical characteristics of lymphoma

%

Performance status (ECOGScale)

0-1

82

2-3

18

B-symptoms

24

Location

Nodal

18

Extranodal

36

Both

45

Mass size (>7cm)

16

Peripheral lymphoma was found in 86% of patients and has to do with cervical lymphadenopathy, and supraclavicular and axillary lymphadenopathy. Abdominal lymph nodes were affected in 29% of patients. Chest x-ray pathology found mediastinal lymphadenopathy in 38% of patients and hilar adenopathy 43% of patients. In patients with bad prognostic factor we asked for a chest x-ray every year to see what is going on.

Salivary gland was the most commonly affected extranodal site in 58% of patients, next common was the stomach (13% of patients). Lymphoma is not easily associated with Sjögren’s in lacrimal glands (which was rarely affected). There were four or five cases of primary lacrimal gland lymphomas associated with dry eyes. They did not have systemic manifestations of primary Sjögren’s.

Laboratory findings
Anemia

48%

Lymphopenia

78%

Cryoglobulinemia

50%

Hypogammaglobulinemia

10%

Nine out of 33 patients in this study died. Interestingly, death was related in patients with high-grade lymphomas and not with low grade-lymphomas. Four out of five patients with low-grade lymphomas died from unrelated lymphoma reasons.

Factors of increased death risk. B-symptoms, mass size of more than 7 cm and histological grade were the strongest predictors of lymphoma associated with living to death. The difference in medial survival in low-grade lymphoma and high-grade lymphoma is 1.8 versus 6.3 years.

Adverse outcome in Sjögren’s Syndrome

  1. Predictor markers for poor outcome
  2. Lymphoproliferation
  3. Treatment of lymphoma

We tried the combined B-cell depletion therapy and CHOP:

  • Cyclophosphamide (brand names cytoxan, neosar)
  • Adriamycin (doxorubicin / hydroxydoxorubicin (ref))
  • Vincristine (Oncovin)
  • Prednisone (sometimes called Deltasone or Orasone)

The aim was to (1) evaluate the efficacy of CHOP in six patients with diffuse large B-cell lymphoma versus nine patients that were treated only with CHOP alone; (2) determine the patient’s outcome; and (3) determine the clinical and serological picture of Sjögren’s patients that receive combination treatment.

Main clinical, serological and histopathological features at diagnosis

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6
Age (yr) 62 37 51 45 74 54
Type of lymphoma Diffuse large
B cell
Nodal marginal zone Diffuse large
B cell
Nodal
marginal
zone
Diffuse large
B cell
Diffuse large
B cell
B symptoms + +
Ann Arbor stage IV II IV II II IV
Bone marrow involvement + + +
ß2-microglobulin (mg/l)* 8.9 5 8.2 12 4.6 7.4
Extranodal involvement Salivary glands Salivary glands Lung,
Salivary glands
Salivary glands

All patients were still free of disease of lymphoma at 40 months. The three patients that had serum cryoglobulins were treated with the combination regimen and the cryoglobulins had disappeared. The disappearance of the cryoglobulins was associated with the normalization of C4 levels. The systemic extraglandular manifestations vanished by the end of treatment with peripheral neuropathy in two patients and cutaneous vasculitis vanished in three patients. Unfortunately, sicca symptoms were still persistent and this kind of combination therapy did not have any effect on dry mouth or dry eyes.

Conclusions

  • Combination treatment anti-CD20 and CHOP is superior to standard CHOP.
  • No life-threatening toxicities, but some side effects:
    • Fever & chills (2 patients)
    • Alopecia (6 patients)
    • Grade III neutropenia (5 patients)
    • Neutropenic fever (2 patients)
  • Sustained response (46 months at presentation time).

For CME credit,TAKE POST-TEST & EVALUATION

Updated: August 16, 2012

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