Q J Med 2000; 93: 825-829
© 2000 Association of Physicians
Immune cytopenias as the presenting finding in primary Sjögren's syndrome
From the Department of Medicine and 1 Hematology Unit, Kaplan Medical Center, Rehovot, and the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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Summary |
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 Top Summary IntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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A diagnostic delay of several years in primary Sjögren's syndrome is common, even in patients who present with sicca symptoms. It is much more likely in cases with prominent symptomatic extraglandular involvement. We report on three such patients who presented as Coomb's positive haemolytic anaemia, systemic symptoms with agranulocytosis and gingival bleeding due to immune thrombocytopenia, to alert clinicians to the fact that primary Sjögren's syndrome may present as clinically significant immune-mediated cytopenia in the absence of sicca symptoms. Sjögren's syndrome, a common autoimmune disorder, should be considered in the differential diagnosis of apparently ‘idiopathic’ cytopenias and actively sought by directed history, Schirmer test and autoantibody screening.
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Introduction |
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TopSummaryIntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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Patients with primary Sjögren's syndrome (pSS) are readily diagnosed when they present with the classic sicca symptoms of keratoconjunctivitis sicca and xerostomia.1 However, not uncommonly these complaints are absent, or they may be considered too minor to be mentioned to the examining physician, who frequently forgets to ask. Thus, with its capacity to affect many different systems, pSS may occasionally present in an atypical way which may defy correct diagnosis for a considerable period of time. Extraordinary tiredness and weightloss, peripheral neuropathy, proximal myopathy, interstitial lung disease or urolithiasis and renal tubular acidosis have all been reported as the initial manifestations of pSS.2–6 Other patients may present with symptoms of dryness which may fail to be ascribed to SS such as pruritus, chronic dyspareunia, chronic bronchitis or dysphagia.7–10 Occasionally, symptoms related to a disease which is associated with pSS, such as symptoms of lymphoma or an autoimmune liver or thyroid disease predominate, and may be noted first.10
We report on three patients who presented with clinically significant immune-mediated cytopenias and were subsequently found to have occult sicca symptoms, to alert clinicians to these atypical presentations of pSS.
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Patient 1: ‘Hidden behind pallor and jaundice’ |
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TopSummaryIntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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A previously-healthy 32-year-old woman complained of unusual fatigue for a fortnight and was admitted when anaemia was found. She looked ill and pale with mildly icteric sclerae and rapid pulse (116/min). A tender spleen palpated 3 cm below the left costal margin was the only other notable physical finding. Laboratory tests showed: Hb 6.6 g/dl (MCV 108, reticulocytes 13%), WBC 12.3x103/l and platelets 228x109/l. Peripheral blood smear (PBS) showed anisocytosis, macrocytosis, spherocytes, orthochromatic normoblasts and neutrophilia. The bone morrow (BM) showed severe normoblastosis. Decreased serum haptoglobin, indirect bilirubinaemia (2.7 mg/dl) and urobilinogenuria were found, with normal liver and kidney function tests, serum complement and protein electrophoresis. The direct antiglobulin (Coombs’ test) was positive (warm, polyspecific IgG). Antinuclear antibodies (Ab) (ANA) were weakly positive (1:10 diffuse pattern), rheumatoid factor (RF) 149 U (N<20), anti-DNA Ab were not found. Diagnosed as idiopathic autoimmune haemolytic anaemia (AIHA), she was given 4 units of packed cells and prednisone 60 mg/day with good clinical response. Since the patient remained steroid-dependent, azathioprine 100 mg/day was added and the prednisone tapered to 10 mg/day. The Hb level increased to 13 g/dl and after 8 months, all treatment was stopped uneventfully. Coomb's test remained negative and follow-up was continued. New complaints of dry mouth and itching of the eyes then led to a Schirmer tear test which was positive, a labial biopsy showing lymphoplasmocytic infiltrates within the salivary glands consistent with a focus score of 2 and the finding of Ab to SS-A and SS-B. After pSS was diagnosed, she was seen regularly over 5 years. She had occasional fatigue and arthralgia, but no other disease developed.
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Patient 2: ‘Puzzling agranulocytosis’ |
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TopSummaryIntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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A 77-year-old woman who had hypertension and angina presented with marked fatigue, drenching night sweats, and weight loss (>10%) over 2 months. She was afebrile, and physical examination was normal. ESR was 85 mm/h, Hb 10.3 g/dl (normocytic), WBC 1.7x103/l with 10% neutrophils, and platelets 435x109/l. Biochemistry tests, urinalysis, chest X-ray and a whole-body CT scan were normal. A careful work-up for infection, endocrine disease and temporal arteritis was negative. PBS showed severe neutropenia, and BM biopsy showed polymorphous hypercellular marrow with myeloid hyperplasia, and increase of myeloid precursors. Lymphocyte subpopulations were normal, with no increase of natural killer cells or large granular lymphocytes. Immunoelectrophoresis of serum proteins revealed hypergammaglobulinaemia and a small monoclonal peak of IgM-
(0.4 g/dl). There was no paraprotein in urine immunoelectrophoresis. ANA (+1, homogenous) and RF 296 U were persistently found, whereas other autoAb and cryoglobulins were not demonstrated. CRP was 34 mg/dl (N<6). The patient remained leukopenic and neutrophil counts fluctuated between 0.17–0.92x103/l (median 0.34). The markedly positive RF in the absence of either rheumatoid arthritis or cryoglobulinaemia was considered suggestive of possible pSS.11 When questioned, the patient admitted dry mouth for many years and dry eyes for several months. During evaluation, intense generalized pruritus appeared, ascribed to ‘senile dry skin’. Liver function tests remained normal and serum antimitochondrial Ab were not found. Schirmer's test and Rose-Bengal corneal staining were positive. A minor salivary gland biopsy was consistent with SS, showing a focus score of 3. She was started on prednisone, 20 mg/day, which resulted in gradual resolution of her symptoms, and normalization of all blood tests. Slow tapering of the prednisone dose was associated with a transient appearance of palpable purpura—leukocytoclastic vasculitis by skin biopsy. At that time neutrophil counts fell again and serum analysis, performed as described,12 revealed antineutrophil Ab. She is currently asymptomatic on prednisone 5 mg/day, neutrophils 3.85x103/l and no haematopoietic malignancy developed over a follow-up period of 4 years.
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Patient 3: ‘Gingival bleeding and failure to cry’ |
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TopSummaryIntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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A healthy 58-year-old woman presented with gingival bleeding over 2 years and a normal physical examination. The ESR was 25 mm/h, Hb 13 g/dl, WBC 7.2x103/l; platelets 60x109/l; coagulation studies were normal; serum globulins 3.5 g/dl, 1.87 g/dl gammaglobulins and a small IgG-
paraprotein identified by immunoelectrophoresis. BM material was polymorphic, with numerous immature megakaryocytes and no myeloma cells. Biochemistry tests were normal, cryoglobulins and autoAb were not found, and a full work-up for an underlying disease was negative. Later she developed acute monarthritis of the wrist, a transient skin eruption and complaints of dry mouth and irritation of the eyes. After mentioning that ‘she could not cry at the funeral of her best friend ...’ a Schirmer test was done and was strongly positive (0 mm per 5 min, bilaterally). A labial minor salivary gland biopsy showed a focus score of 3, establishing the diagnosis of SS. During the episode of arthritis, her platelet count had decreased to 30x109/l. Analysis of a frozen sample of the patient's serum at a later date, revealed anti-platelet Ab of both IgG and IgA subtypes, binding to the major platelet membrane glycoproteins (IIb/IIIa). Hepatitis C virus serology and PCR were negative. Oral prednisone was started (40 mg/day), and the arthritis subsided, but steroid-induced diabetes necessitated substitution for cyclophosphamide 100–50 mg/day, with subsequent increase of the platelets. The paraprotein remained stable throughout a follow-up period of 9 years. Over that time, the patient felt well under the same treatment and did not develop either lymphoma or SLE. Her Ab profile changed however, in that she developed positive ANA (1:128, speckled), RF (171 U) and anti SS-A (1:64), whereas anti SS-B and antiphospholipid Ab remained negative. |
Discussion |
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TopSummaryIntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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Primary SS is a common chronic inflammatory autoimmune disorder associated with B lymphocyte hyperreactivity, whose hallmark is that the salivary and lacrimal glands become infiltrated with lymphocytes and functionally impaired.1 Although 100% of patients have exocrine glands involvement,13 their clinical presentation is not uncommonly quite non-specific and diverse, leading to an average diagnostic delay of 3–8 years following the appearance of the first symptoms.14,15 This is true even for patients presenting with sicca symptoms, who in fact may comprise fewer than half of pSS patients;15 more so for patients who have prominent extraglandular involvement, usually involving pulmonary, neurological or renal symptomatology.2–6 Haematological manifestations of pSS are not uncommon, but they are mostly recognized as mild laboratory abnormalities of no clinical significance in patients whose pSS is already diagnosed.16 In contrast, our three cases clearly demonstrate that different types of immune-mediated cytopenias may be severe, clinically significant, and occur as the presenting symptom of pSS in patients with no overt sicca symptoms.
Patient 1 is an example in whom AIHA thought to be idiopathic was in fact related to occult pSS, which was diagnosed 1 year later when the patient first noticed sicca symptoms. While Coombs positivity is one of the most common haematological abnormalities in SS, noted in 22–47% of patients,17,18 haemolysis in SS is rarely reported.19 Our long follow-up rules out associated SLE or lymphoma which may cause AIHA in SS. Another type of probably immune-mediated anaemia is pure red-cell aplasia (PRCA). We have not encountered PRCA associated with SS in our referral center over 20 years; however, a review of the literature reveals isolated cases,20 suggesting that SS should also be sought in patients presenting with this disorder. Although chronic atrophic gastritis is common in pSS, pernicious anaemia is rare—but may occur.21 Markers of B-cell hyperreactivity (hyperglobulinaemia, RF), other cytopenias and anti SS-A (Ro) Ab may coexist,1,13,17 supporting an autoimmune pathogenesis. In contrast, the most common type of anaemia in pSS is a mild normocytic anaemia of chronic inflammation22 which is probably due to pro-inflammatory cytokines.13,23
In patient 2, who presented with impressive systemic symptoms but non-contributory examination and imaging, three simple laboratory findings directed attention to the correct diagnosis of pSS, despite the decidingly rare presentation. Polyclonal hypergammaglobulinaemia is usually seen in patients with prolonged infections, chronic liver disease and some types of lymphoma. Once excluded, an autoimmune-mediated inflammation is suggested, and consistent with the IgM- paraprotein.10 Rheumatoid factors may occur in many different diseases, as well as in old age. However, persistently high titres in patients with no joint involvement are suggestive of either mixed cryoglobulinaemia, or pSS.11 Finally, agranulocytosis or severe neutropenia (<0.5x103/l) in the presence of a ‘reactive’ hypercellular BM can only be due to ‘peripheral’ accelerated neutrophil turnover or destruction (decreased t1/2). In the absence of severe infection or hypersplenism, autoimmune neutropenia remains, and was later confirmed by the demonstration of antineutrophil Ab. As many as 30–40% of patients with pSS may have moderate leukopenia (2–5x103/l).7,10,22 In contrast, severe immune granulocytopenia or agranulocytosis is rare in autoimmune diseases in general and in pSS in particular with about 10 cases reported in the literature.24,25 Antineutrophil Ab, specific for actin or the neutrophil-specific Fc gamma receptor RIIIb, may be responsible26 and were detected in as many as 30/66 (45%) of patients with pSS in one series.27 Anti-CD4 antibodies have also been reported in 12.6% of pSS patients28 and both may predispose patients to recurrent infections. Although our patient had no infections, autoimmune agranulocytosis and systemic symptoms of SS necessitate treatment and they responded remarkably well to low doses of corticosteroids. Thus, autoAb-mediated chronic agranulocytosis should be added to the presenting manifestations of primary SS, again, even in patients with a paucity of sicca symptoms.
Patient 3 displayed symptomatic thrombocytopenia (platelet nadir of 30x109/l) which preceded the appearance of symptoms of dryness by over 2 years. Although thrombocytopenia is infrequent in pSS patients (5–16% only),1,15,17 three other such patients have been encountered in our teaching hospital over the last 3 years. Thus, patients whose presentation may mimic that of idiopathic thrombocytopenia purpura should be screened for occult pSS.18 Immune-mediated platelet destruction similar to that of SLE is likely,29,30 and indeed, associated lupus, lymphoma,31 and the antiphospholipid Ab syndrome32 must be sought or may develop later.
As illustrated by our patients and supported by the literature, clinically-significant haematological cytopenias are generally susceptible to immunosuppressive therapy, sometimes remarkably so. Corticosteroids are the mainstay of therapy, and occasional refractory or steroid-dependent patients are managed by adding a second-line agent such as hydroxychloroquine,33 or azathioprine, although the efficacy of the latter drug was unsubstantiated by a recently published trial.34 Methotrexate might also prove useful for these patients, although we are not aware of any actual supporting data.
In conclusion, we report three patients whose primary SS presented as AIHA, immune agranulocytosis with systemic symptoms and bleeding due to immune thrombocytopenia. Clinically important immune-mediated cytopenia (or a combination of cytopenias) may be the first manifestation of an occult SS. Thus pSS should be considered in the differential diagnosis of all patients who have otherwise inexplicable cytopenias, whether silent or symptomatic. Simple clinical data such as a middle-aged patient, female sex and co-occurrence of either high-titre RF, hyperglobulinaemia or a small monoclonal peak support a possible diagnosis of primary SS, which should be actively sought by directed history, ocular examination and autoAb screening.
Sjögren's syndrome is amongst the most common autoimmune disorders, affecting as many as 3–4% of the adult population.35 Its capacity for a varied presentation, haematological or otherwise, may be not uncommonly encountered and should be well recognized.
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Notes |
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Address correspondence to Professor A. Schattner, Department of Medicine, Kaplan Medical Center, Rehovot 76100, Israel. e-mail: amiMD{at}clalit.org.il
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References |
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TopSummaryIntroductionPatient 1: ‘Hidden behind...Patient 2: ‘Puzzling...Patient 3: ‘Gingival...DiscussionReferences |
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