Case 3 -

Primary Sjögren Syndrome (PSS) Carmen Avila-Casado Instituto Nacional de Cardiología Ignacio Chávez Mexico City, Mexico

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Clinical History The patient, a 50 year old Hispanic woman presented with dry mouth, dry eyes, Raynaud phenomenon, a sensitive neuropathy of the lower limbs and enlargement of parotid glands, over several weeks. One year latter, she complained also of polyarthralgia, and easy fatigue. Past history: She had no medical history of exposure to radiation, continuous antinflammatory drug therapy or pyelonephritis Case 3 - Figure 1 - The sample consists of renal cortex. There were, on average, twenty glomeruli in the sample submitted for light microscopy. In this field, seven (7) glomeruli are present; two (2) of them are globally sclerosed. The interstitium reveals focal and mainly periglomerular inflammation.( PAS 10X) Case 3 - Figure 2 - Other low power field showing three (3) glomeruli that appeared slightly increased. A focal area of inflammation is also observed. (PAS 10X) Case 3 - Figure 3 - Interstitial fibrosis affected less than 10% of the sample as evidenced on the trichrome stain (Masson 10X) Case 3 - Figure 4 - Glomerulus showing open capillary loops and the absence of inflammatory infiltrates. Glomerular basement membranes appear normal without wrinkling or double contours. One capillary loop appears aneurysmatic. A small synechia and hypertrophy of the yuxtaglomerular apparatus are also observed. (PAS 400X) Case 3 - Figure 5 - A detail of the inflammatory infiltrate surrounding the glomeruli, Glomeruli show small synechya to the Bowman's capsule. Case 3 - Figure 6 - Small foci of mononuclear inflammatory infiltrates in the interstitium in different fields. These inflammatory cells correspond to lymphocytes and plasma cells and are often seen infiltrating tubular epithelial cells. (PAS 40 X) Case 3 - Figure 7 - Small foci of mononuclear inflammatory infiltrates in the interstitium in different fields. These inflammatory cells correspond to lymphocytes and plasma cells and are often seen infiltrating tubular epithelial cells. (PAS 40 X) Case 3 - Figure 8 - Small foci of mononuclear inflammatory infiltrates in the interstitium in different fields. These inflammatory cells correspond to lymphocytes and plasma cells and are often seen infiltrating tubular epithelial cells. (PAS 40 X) Case 3 - Figure 9 - Small foci of mononuclear inflammatory infiltrates in the interstitium in different fields. These inflammatory cells correspond to lymphocytes and plasma cells and are often seen infiltrating tubular epithelial cells. (PAS 40 X) Case 3 - Figure 10 - Tubular atrophy was difficult to find although isolated tubules with luminal hyaline casts and others presenting thickening of the tubular basement membrane where also observed. This field also shows and small area of scarring with some inflammatory infiltrate. Case 3 - Figure 11 - The sections were incubated with antibodies specific for the heavy chains of IgG, IgA, and IgM; for kappa and lambda light chains, C3c, C1q, Albumin and fibrin-related antigens. Sample for immunofluorescence contained ten (10) glomeruli. There were no significant immune deposits present. Arterioles show focal C3 Case 3 - Figure 12 - The sections were incubated with antibodies specific for the heavy chains of IgG, IgA, and IgM; for kappa and lambda light chains, C3c, C1q, Albumin and fibrin-related antigens. Sample for immunofluorescence contained ten (10) glomeruli. There were no significant immune deposits present. Arterioles show focal C3 Laboratory evaluation disclosed: Arterial blood pH 7.32 Hematocrit 33% Hemoglobulin 9.8 g/dL Creatinine Clearance 35mL/min Serum Creatinine 2.4 mg/dL Urinalysis: specific gravity 1.005, pH 8, proteinuria ++ 24- Hour proteinuria of 1.8 g/24 h Rheumatoid factor 1/640 ANA 1/1,280 Anti-Ro (SSA) and Anti-La (SSB) antibodies Low C4. Positive Schrimer test I Positive Rose Bengal test Salivary gland biopsy: Focal lymphocytic infiltration with more than 50 lymphocytes per foci with two foci in 4mm2 Diagnosis: Primary Sjögren Syndrome (PSS) The diagnosis was based on the presence of of sicca complex symptoms and positive Schrimer test I and Rose Bengal staining tests, SSA and SSB antibodies and characteristic histopathological changes at the labial minor salivary gland. Renal biopsy: The diagnosis of interstitial nephritis was based on the presence of small lymphocytes, plasma cells and monocytes in the interstitium combined with foci of tubular atrophy and fibrosis affecting less than 25% of the tissue. Immunofluorescence was negative for immune complex deposition of IgG, IgM, IgA, Kappa and Lambda. Drops of albumin were identified within the tubules. Electron dense deposits were not identified by EM. Glomerular capillary basement membranes appear normal and visceral epithelial foot processes obliteration were not identified. Follow up and treatment She was treated with prednisone, chloroquine and methotrexate. A diagnosis of metabolic acidosis was established and she received oral bicarbonate potassium. She remained stable over the last year. Discussion Primary Sjögren Syndrome (PSS), a chronic systemic autoimmune disease, is characterized by keratoconjunctivitis sicca (KCS) and xerostomia (XT) resulting from immune lymphocytes that infiltrate the lacrimal and salivary glands [1]. It also presents B–cell hyperactivity that result in the production of autoantibodies and immune complexes. Damage to the kidney could be the result of both processes although; the real prevalence of clinically significant renal involvement in PSS is unknown. Prevalence of SS Although SS has been considered presumably the most common connective tissue disease, epidemiological data is scarce. Epidemiological studies about the prevalence of SS are limited in part, because of the heterogeneity of the populations studied, the use of different diagnostic tests for the evaluation of lacrimal and salivary gland involvement, and the use of different classification criteria for the disease. In addition, since the disease may have an insidious onset, variable course, and a wide spectrum of clinical manifestations [1] patients with SS may be missed or misclassified [2, 3], or the diagnosis be delayed. Using a structured approach in ambulatory patients attending a tertiary care center, a minimum prevalence of SS of 13.3%, according to the American-European Consensus Group (AECG) criteria [3] was detected in Mexico [4]. Several sets of classification criteria for SS have been proposed. Recently, the AECG published a revised version of the European criteria. Authors consider the modified criteria set probably the best possible instrument presently available for the classification of patients with SS [3]. Frequency of renal involvement varies between 2 and 67% in different studies [5]. Diagnosis of SS Classification criteria for Sjögren syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These criteria were re-examined by consensus group members, who introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria [3]. Since the sensitivity and specificity of classification criteria are both close to 100%, these criteria can be used as diagnostic criteria. A certain proportion of patients may be misclassified, particularly in the early stages of the disorder. The revised international classification of the European criteria for PSS by the American-European Consensus Group includes: Ocular symptoms (dry eyes every day for more than three months, recurrent sensation of sand or gravel in the eyes or use of tear substitutes more than three times a day). Oral symptoms (daily feeling of dry mouth for more than three months, recurrent or persistently swollen salivary glands, or use of liquids to aid in swallowing dry food). Ocular signs, objective evidence of ocular involvement (positive Schrimer test or a Rose Bengal score of at least four according to the van Bijsterveld scoring system) Histopathology with focal lymphocytic sialoadenitis, evaluated by an expert pathologist, with a focus score >1 defined as a number of lymphocytic foci that contains more than 50 lymphocytes per 4 mm 2 a minor salivary gland Salivary gland involvement: objective evidence documented by positive result in Parotid sialigraphy, salivary scintigraphy, or salivary flow testing (<1.5 ml in 15 minutes). The presence of autoantibodies to Ro (SSA) or La antigens (SSB) or both For the diagnosis of primary SS: The presence of any 4 of the 6 items is indicative of primary SS as long as either item 4 (histopathology) or VI (serology) The presence of any 3 of the 4 objective criteria (3, 4, 5 y 6) For secondary SS: In patients with potentially associated disease, the presence of item 1 or item 2 plus any 2 from among items 3 and 5 may be considered as indicative of secondary SS. Exclusion criteria: Past head and neck radiation treatment Hepatitis C infection AIDS Pre-existing lymphoma Sarcoidosis Graft versus host disease Use of anticholinergic drugs Renal involvement in SS The real prevalence of clinically significant renal involvement in PSS is unknown. . Most cases of IN are asymptomatic and they escape to clinical attention [6]. An European study [7] has been conducted to investigate the clinical and serologic differences between patients with interstitial nephritis and those with immune complex glomerulonephritis based on the evaluation of a large series of cases with clinically significant and biopsy-documented renal involvement in Primary Sjögren Syndrome (pSS). They also studied the evolution and clinical outcome of these entities in a large cohort of pSS patients using strict eligibility criteria. In this series that include 471 patients, about 25% of them were described to present interstitial nephritis due to the periepithelial involvement while glomerulonephritis secondary to immune complex deposition was a far rarer syndrome with only few cases described From the 471 patients followed, only 20 patients (4.2%) presented overt renal involvement that fulfilled requirements to perform a renal biopsy during follow-up (1 to 15 years). Renal involvement can be defined by at least 1 of the following criteria: elevated creatinine level (>1.6 mg/dL) and or impaired creatinine clearance (<50 mL/min) Persistent proteinuria (>500 mg/24 h) for more than three months Positive urinary sediment with > 10 RBC per high power field or RB casts Persistently low specific gravity (<1010 after 12 hours of water deprivation associated with persistently alkaline urine pH (>7) for more then 6 months (with or without symptomatic hypokalemia) Recurrent renal colic with imaging findings of urolithiasis or nephrocalcinosis Fanconi syndrome without any other identifiable cause. Histopathology: Salivary gland: Minor salivary glands should be obtained through normal-appearing mucosa by an oral surgeon. All biopsies should be evaluated by an expert pathologist, blinded to previous results and medical diagnosis. The diagnosis of Focal lymphocytic sialoadenitis is based on the analysis with a focus score >1, defined as a number of lymphocytic foci containing more than 50 lymphocytes per 4 mm2 of glandular tissue [8]. Kidney: Interstitial nephritis The diagnosis of IN is defined by the presence of small lymphocytes (T), plasma cells and monocytes in the interstitium combined with tubular atrophy and fibrosis [3, 7]. This interstitial involvement of the kidneys is compatible with the pathophysiology of the disease process, since pSS is considered a systemic autoimmune epithelitis [9]. The autoreactive infiltrates can affect several extraglandular epithelial tissues including the renal tubular epithelium and the lymphocytic infiltrates around the renal tubules are similar to those observed in salivary glands. Those cells consist mainly of activated T-lymphocytes bearing the CD4 phenotype and exhibiting junctional oligoclonality [7]. Clinically these patients have hyposthenuria, renal tubular acidosis type I with or without academia, or the Fanconi syndrome. Glomerulonephritis: Membranoproliferative (MP) GMN is characterized by diffuse proliferation of mesangial cells, mesangial matrix increase, thickening and reduplication of glomerular basement membrane and infiltration of glomeruli by macrophages. Thrombi within the capillary loops can also be observed in those cases associated to cryoglobulinemia. The pathogenesis of GMN in pSS is attributed to immune complex deposition formed by cryoprecipitation of monoclonal IgMK RF along with polyclonal IgG and IgA in a similar manner to hepatitis C-associated mixed monoclonal cryoglobulinemia [7, 9]. The clinical manifestations are combinations of nephritic and nephrotic syndrome with active urine sediment, moderate proteinuria and an acute decline in the glomerular filtration rate (GFR), although no patient has been reported to develop overt renal failure due to GMN. Besides MPGN, other type of glomerulopathies have been described in SS patients: Membranous nephropathy [10], Mesangial proliferative GN [7] and Crescentic GN [10, 11] Conclusions: Kidney involvement is a frequent extraglandular manifestation of primary Sjögren´s Syndrome although it is rarely overt. Inadequate renal acidification capacity, as well as mild proteinuria are frequently found in pSS patients. Interstitial nephritis results in latent or overt tubular disease that may manifest itself as distal renal tubular acidosis, nephrocalcinosis, nephrogenic diabetes insipidus or even Fanconi Syndrome. References Fox RI, Stern M and Michelson P. Update in SS. Curr Opin Rheumatol 2000; 12:391-8. Kelly CA, Foster H, Pal B, et al. Primary SS in North East England -A Longitudinal Study-. Br J Rheumatol 1991;30:437-42. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002: 61:554-8. Jorge Sánchez-Guerrero, Francisco, CárdenasVelázquez, Adriana Pérez-Reguera, Erika Celis-Aguilar, Armando E. Soto-Rojas,.1 Carmen Avila-Casado.Prevalence of Sjögren Syndrome in ambulatory patients according to the American-European Consensus Group Criteria. Rheumatology ,2004 Petrovaara M, Korpela M, Kouri T, Pasternack A. The occurrence of renal involvement in primary Sjögren´s Syndrome : a study of 78 patients. Rheumatology 38: 1113-1120, 1993 Bossini N, Savoldi S, Franceschini F, Mombelloni S, Baronio M, Cavazzana I,et al. Clinical and morphological features of kidney involvement in primary Sjögren syndrome. Nephrol Dial Transplant 16: 2328- 2336, 2001 Andreas G, Stavroula M, tzioufas, Athanasiois g, Ioannidis, John PA, Skoupoli FN, Moutspolos HM. Clinically significant and biopsy documented renal involvement in Primary Sjögren Syndrome. Medicine 79: 241-249, 2000 Daniels TE. Labial Salivary Gland Biopsy in Sögren's Syndrome. Assessment as a Diagnostic Criterion in 362 Suspected Cases. Arthritis Rheum.1984;27:147-56. Skopouli FN. Kidney injury in Sjögren Syndrome. Nephrol Dial Transplant 16 (Suppl 6): 63-64, 2001 Tatsumi H, Tateno S, Hiki Y, Shigematsu H, Kobayashi Y. Crescentic GN associates with membranous nephropathy in a case with primary Sjögren´s Syndrome. Nephrol Dial Transplant 13: 2624-2627, 1998