chains sjogren'ssyndrome: tocommonlyrheumatoid arthritis) the termsecondary ss is used. primary...

Annals of the Rheumatic Diseases 1986, 45, 210-219

Urinary monoclonal free light chains in primarySjogren's syndrome: an aid to the diagnosis ofmalignant lymphomaM T WALTERS,' F K STEVENSON,2 A HERBERT,3 M I D CAWLEY,'AND J L SMITH2

From the Departments of 'Rheumatology, 2lmmunology, and 3Histopathology, Southampton GeneralHospital, Tremona Road, Southampton S09 4XY

SUMMARY Three patients, two with typical primary Sjogren's syndrome (SS) and the third withseveral features of SS, including abnormal sialography and reduced tear secretion, developed Bcell non-Hodgkin's lymphoma (NHL) of parotid or lung, or both. Isoelectric focusing ofconcentrated urine specimens in agarose, followed by immunofixation, demonstrated thepresence in each patient's urine of monoclonal free light chains of the same class as that shown on

the tumour cells. In one patient the level of urinary free light chains was monitored and found tocorrelate with disease activity. Similar techniques showed no monoclonal light chains in the urinefrom a further 26 cases of SS with no clinical evidence of lymphoma. The detection of monoclonalurinary free light chains may provide an early diagnostic clue to the development of lymphoma inpatients with SS and be a means of tumour monitoring.

Key words: salivary glands, lung.

SS is an autoimmune, lymphocyte-mediated dis-order characterised in the uncomplicated form bythe destruction of exocrine glands and symptoms ofmucosal dryness. Thus the hallmarks of the condi-tion are keratoconjunctivitis sicca (KCS) and xero-stomia. When there is no other recognised connectivetissue disease (CTD) present the condition is calledprimary SS. When another CTD is associated (mostcommonly rheumatoid arthritis) the term secondarySS is used. Primary SS may be limited to glandulartissue or it may involve extraglandular sites, result-ing in pulmonary disease, arthritis or arthralgia,non-thrombocytopenic purpuric rashes, renal tubularacidosis, and other distinctive clinical and sero-logical abnormalities.'

It is well recognised that NHL can develop in bothprimary and secondary SS, with many case reportsto assert this point.26 In a prospective study Kassanet al.7 demonstrated an increased risk for thedevelopment of NHL of 43-8 times for SS patients

Accepted for publication 29 July 1985.Correspondence to Dr M T Walters, Department of Rheuma-tology, Southampton General Hospital, Tremona Road, South-ampton S09 4XY.

compared with controls. An increased risk ofWaldenstrom's macroglobulinaemia3 7 and myelo-proliferative disorder8 are also reported, and thereis one recorded case of light chain myelomadevelopment.9B Cell NHL arises from a clonal proliferation of

neoplastic B lymphocytes and may often reflectproperties of normal B lymphocytes 'frozen' at aparticular point in differentiation. Until recently itwas thought that such cells synthesised immuno-globulin (Ig) only for insertion into the cell mem-brane and were incapable of secreting Ig. However,in-vitro studies on neoplastic B cells from patientswith NHL and chronic lymphocytic leukaemia(CLL) have shown that these cells are capable ofsecreting small amounts of immunoglobulin forexport, often with an excess of light chain produc-tion.") If sufficient tumour load is present this lightchain might be expected to be found in the urine."

Previous work in this unit with the highly sensitivetechnique of isoelectric focusing of concentrated 24-hour urine specimens in agarose, followed byimmunofixation, has shown small amounts of mono-clonal light chain, of the same type as that displayed

210

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Urinary monoclonal free light chains in primary Sjogren's syndrome 211

at the tumour cell surface, in the urine of 44% and74% of patients studied with NHL and B cell CLLrespectively. No patient had a monoclonal immuno-globulin band detectable in either serum or con-centrated urine when analysed by electrophoresis orimmunoelectrophoresis. It was possible in two casesto show unequivocally that the urinary light chainwas produced by the tumour cells.'2We present the findings of two patients with

typical primary SS, one of whom developed malig-nant pulmonary lymphoma and the other malignantparotid lymphoma and a third patient with lympho-cytic infiltration of the parotid gland and features ofSS, who was subsequently shown to have malignantparotid and pulmonary lymphomata. In the urinefrom all three cases monoclonal light chains of onetype were found by the method described12 andwere associated with and aided the diagnosis oflymphoma. This non-invasive technique may beimportant in the early diagnosis of B cell neoplasiain SS.

Patients and methods

PATIENT 1This patient presented in 1982 at the age of 69 with a13-year history of a non-erosive, symmetrical poly-arthritis. Her sicca symptoms consisted of severexerostomia, KCS, and vaginal dryness. Oralprednisolone was commenced in 1973 but waschanged to ACTH injections due to the developmentof Cushingoid features. Investigation of frequenturinary infections led to a diagnosis of renal tubularacidosis. Other relevant features included recurrenttransient parotid swellings, non-thrombocytopenicpurpuric rashes, and multiple antibiotic allergies.Serological abnormalities included a sheep cellagglutination titre (SCAT) of 1/512, antinuclearantibodies (ANA) by indirect immunofluorescence(DNA binding normal), SS-A (Ro) and SS-B (La)antibodies, but no organ-specific antibodies.

In 1976 exertional dyspnoea developed. Chest x-ray (CXR) showed diffuse bilateral lower lobeshadowing and an 8lmKr, 99mTc ventilation/per-fusion scan showed matched patchy abnormalities.Pulmonary function tests showed a diminishedtransfer factor (TF), and a presumptive diagnosis ofpulmonary fibrosis was made. In 1982 owing toprogressive dyspnoea, transbronchial and then openlung biopsies were performed.

In 1983 death followed relentless progression ofthe pulmonary disease, despite four-months' treat-ment with chlorambucil and an increased dose ofsteroids. A postmortem examination was not per-formed.

PATIENT 2This patient developed polyarthralgia in 1972 at theage of 22. One year later she had an unexplainedepisode of pulmonary consolidation. In 1976 anacute right parotitis occurred, and a 10-year historyof intermittent swelling of the right parotid glandwas noted. Treatment with penicillin was instituted,but the gland remained enlarged and subsequently aparotidectomy was performed. Light microscopyshowed an intense lymphocytic infiltrate, inter-preted at that time as the benign lymphoepitheliallesion of SS.When seen in June 1982, aged 34, she described

Raynaud's phenomenon and had trophic changesaffecting several fingers of the left hand. A non-erosive synovitis involved the hands, knees, andankles. Photosensitivity and intermittent, transientpurpuric rashes affecting the arms and legs werenoted. She suffered from severe xerostomia andxerophthalmia. Examination showed no evidence ofsalivary gland enlargement or lymphadenopathy.Serological abnormalities included a SCAT of 1/64,ANA by indirect immunofluorescence (DNA bind-ing normal), SS-A, SS-B, and smooth muscleantibodies. The C4 component of complement wasreduced at <0-05 gil, and cryoprecipitate waspresent in the serum. Monoclonal kappa (K) freelight chains were present in the urine.She was not dyspnoeic and the CXR was normal,

but the pulmonary carbon monoxide TF was reducedat 4*59 mmol/min/kPa (predicted 8.3).

In March 1984 there was deterioration in hergeneral clinical condition and staphylococcal pneu-monia. She had previously suffered repeatedepisodes of lower respiratory infection. Afterresolution of the pneumonia plasmapheresis wasinitiated for worsening digital ischaemia (attributedto the cryoglobulinaemia), but little improvementfollowed. Cyclophosphamide was commenced inSeptember, resulting in significant clinical improve-ment and a marked fall in urinary light chain ex-cretion. It was not possible to obtain a lung biopsy.

PATIENT 3In 1975 this 68-year-old male was found to havediffuse bilateral patchy pulmonary shadowing on aroutine CXR taken during the course of radiotherapyfor a basal cell carcinoma of the nose. Pulmonaryfunction tests showed normal ventilatory capacitybut a reduced TF at 6*4 mmol/min/kPa (predicted8-75). A 10-year history of recurrent bilateralparotid swelling was noted, and several subsequentparotid sialograms confirmed main duct ectasia andsacculation, with diminished parotid secretions.The results of Schirmer's tests were 3 mm and 7 mmat five minutes.

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212 Walters, Stevenson, Herbert, Cawley, Smith

By 1979 TF had fallen to 5x54 mmol/min/kPa(predicted 7.9), but CXR appearances were un-

changed.In February 1982 a right parotid abscess occurred

after acute parotitis. At surgery a calculus was

removed from the main duct, and biopsy showed an

intense mononuclear cell infiltrate, associated withloss of parenchyma and one epimyoepithelial island.Autoantibodies were absent from the serum. TF hadfallen to 3-84 mmol/min/kPa, and the previous CXRchanges had progressed, with extensive bilateralinterstitial shadowing and focal consolidation andcavitation on the right. Transbronchial biopsy andbone marrow examination were performed, but notreatment was instituted at this stage.

In February 1983 there was rapid progression ofthe lung disease and clinical deterioration, withbilateral inguinal and axillary lymphadenopathy.Despite intensive treatment with steroids, he died.

IMMUNOHISTOLOGYSections of routine formalin fixed, paraffinembedded material were examined for immuno-globulin determinants by methods previously des-cribed.13 14

CELL MARKER ANALYSIS

Fresh biopsy material was minced through sterilewire mesh, followed by washing in minimal essentialmedium containing heparin (MEM, Gibco Ltd).Cell suspensions were prepared from biopsymaterial, blood, and marrow by density gradient

centrifugation over Lymphoprep (Nyegaard and Co.AS, Oslo, Norway) as previously described.15 Cellscollected at the interface were washed three times inphosphate-buffered saline, and viability tested bytrypan blue exclusion. After incubation at 37°C for60 min (to remove extraneous Ig) the cells were

washed in MEM containing 20% bovine serum

albumin. T Lymphocytes were identified in suspen-

sion by immunofluorescence with the mouse mono-clonal antibody OKT11,'6 in an immunoperoxidasemethod with the pan T cell mouse monoclonalantibody UCHT1 ? and on cytocentrifuge prep-arations by the spontaneous sheep erythyrocyte rosettetest (E). l Surface and cytoplasmic Ig was identifiedin a direct immunofluorescence test with fluorescein-conjugated polyclonal rabbit antisera (Dako Ltd) toIg heavy and light chain determinants as previouslydescribed. 14

URINE IMMUNOGLOBULINConcentrated urine samples were analysed formonoclonal free light chain by the method ofisoelectric focusing in agarose, followed by immuno-fixation, as described previously by two of thepresent authors (FKS and JLS).1 Levels of urinarylight chain were measured in 24-hour urine collec-tions by the enzyme linked immunosorbent assay as

described previously.'8

SERUM IMMUNOGLOBULINSerum immunoglobulins G, A, and M and comp-lement C3 and C4 were measured by laser nephelo-

Table 1 Cell marker analysis

Patient Specimen T Cell B Cell

E Rosettes MAb Surface Ig Cytoplasmic Ig(Ig class)

Heavy Lightchain chain

K1

1 (1982) Biopsy 75 90 (OKT11) NT 7 3 15 (KK)(lung)

Blood NTI NT NT 3 2 0Marrow 42 NT NT 3 2 2"

2 Blood (1)t 52 NT GMD§ 21 1 0Blood (2) NT 80 (UCHT1) NT 10 4 0Marrow NT NT NT 10 8 1"I

3 (1982) Blood 40 NT NT 1 4 20 (MX)Marrow 58 NT NT 1 3 5"t

All figures are expressed as percentages.MAb=monoclonal antibody.

t Blood (1) examined in 1982; blood (2) examined with marrow in 1984.4 NT=not tested.4 Cells staining for G 7%, M 18%, D 20%.Cells cytoplasm positive for K or X; no monoclonal population.

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Urinary monoclonal free light chains in primary Sj6gren's syndrome 213

metry (Hyland). Immune complexes were measuredby nephelometry after precipitation with 2% poly-ethylene glycol.

Results

HISTOLOGY AND CELL MARKER ANALYSIS(Table 1)Patient ITransbronchial biopsy showed a heavy lymphocyticinfiltration of the bronchial wall and an interstitialinfiltration consisting of lymphocytes and histiocytes.No interstitial fibrosis was present. The appearancewas highly suggestive of malignant lymphoma. Openlung biopsy confirmed malignant lymphoma with apattern of infiltration identical to that described aslymphocytic interstitial pneumonia (LIP). The histo-logical classification was diffuse follicle centre celllymphoma with plasmacytic differentiation arising inmucosa-associated lymphoid tissue (MALT) (Fig.1). Immunohistochemical staining showed a pre-dominant cytoplasmic (15%) IgMK lymphoplasma-cytoid and plasma cell population (Figs 2a and b).

Patient 2Review of the right parotidectomy specimen (1976)showed a follicle centre cell lymphoma withplasmacytic differentiation and appearances typicalof primary malignant lymphoma arising in MALT

IS A

Fig. 1 Diffuse infiltration ofalveolar walls by malignantlymphoma (patient 1) (H and E, x 70).

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Patient 3Analysis of peripheral blood lymphocytes showed amonotypic B cell population with cytoplasmic IgMlambda (X). An iliac crest marrow aspirate wasnormal, and a trephine biopsy specimen showed anoccasional lymphoid follicle but no evidence oflymphoma. Immunohistochemistry of the bonemarrow was not performed.

Transbronchial biopsy showed a dense lympho-cytic infiltration (with some histiocytes and centro-cytes) invading lung and bronchial epithelium,interpreted as malignant lymphoma. There wasinsufficient lung and parotid biopsy tissue forimmunohistochemical assessment.

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Fig. 3 Infiltration ofsalivary gland tissue by malignantlymphoma with surviving epimyoepithelial islands (patient2). (H and E, x280).

Postmortem examination showed extensive infiltra-tion of both lungs by malignant lymphoma. Bothparotids showed lymphoma, largely periductal,without evidence of sialadenitis in unaffectedsurrounding acini. Immunohistology of paraffinembedded tissue confirmed a monotypic IgMk cellpopulation. The malignant lymphoma showed adistribution within the lung and parotids typical ofmalignant lymphoma involving MALT. There wasno involvement of 4ymphnodes, liver, or spleen.

IMMUNOCHEMISTRY (Table 2)Patient 1 had 2-8 mg/24 h of monoclonal free light

chain present in her urine at the time of diagnosis ofmalignant lymphoma.

Patient 2 had a urinary excretion of monoclonal Kfree light chain of 143 mg/24 h in October 1983,

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Table 2 Immunochemistry

Patient Serum immunoglobulins Electrophoresis Complement* Immune complexest Urinarylight chain

C A M C3 C4 (mg/24 h)

1 (1982) 8-3 1-0 2-8 Normal 1-07 <0-04 IgG 0-717 1C2-8IgM 1-426

2 (1983) 10-1 0-5 1-4 IgMK+K (trace) 0-41 <005 IgG 1-145 IC143IgM 0-642

3 (1982) 4-4 1-2 28-7 IgMX 1-27 0-18 IgM 1-20 k32-2

Normal ranges (g/l): IgG=7-5-16-7; IgA=0-9-4-5; IgM=0-4-3-7; C3=0-892-09; C4=0-12-0-53.'Undetectablc in normal serum.

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STAPHYLOCOCCALPNEUMONIA

FIG. 5 Reduction in urinarymonoclonal light chain excretionand clinical improvement aftercyclophosphamide treatment(patient 2).

OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB1983 1984 1985

rising to 946 mg/24 h by March 1984, associated withclinical deterioration. A reduction in urinary lightchain excretion and clinical improvement followedcyclophosphamide treatment (Fig. 5).

Patient 3 had an IgMX paraprotein band on serum

electrophoresis (EP), and his urine contained 32-2mg/24 h of monoclonal X free light chain.

CONTROLS (Table 3)Eight patients with definite or probable primary SSand 18 patients with secondary SS and no clinicalevidence of lymphoma were examined for thepresence of urinary monoclonal free light chains.Diagnostic criteria for primary SS were the presenceof KCS (two of the following abnormalities:Schirmer's test <10 mm at 5 min, van Bijsterveldscore >4, tear break-up time <10 s) and xero-stomia (two of the following abnormalities: parotidsaliva flow rate <1 mlUmin under maximal stimula-tion with lemon juice,'9 2() abnormal sialography,abnormal salivary radionuclide imaging). Severalpatients also had other characteristic clinicalfeatures and serological abnormalities, which in-cluded anti-Ro and anti-La antibodies. Lip biopsywas not performed routinely but was abnormal incontrol patients 2 and 3. Secondary SS was presentwhen either KCS or xerostomia, or both, were

present with another connective tissue disease.Monoclonal free light chains were not detected inany patient's urine.

Discussion

The malignant lymphomas associated with SS are

usually B cell neoplasms producing monoclonalIgMK and occasionally IgMX.4 21 22 These lym-phomas often run an indolent course, involve a

wide variety of tissues, and may be compatible withmany years free of symptoms. Diagnosis is oftendifficult, because as with other malignant lym-phomas of MALT the histological appearance isoften deceptively benign, and they tend to remainlocalised for a long time.23 24The term 'benign lymphoepithelial lesion' intro-

duced by Godwin in 195225 is no longer tenable todescribe the histological appearance of the salivarygland in SS, as Schmid26 has shown that the cellularinfiltrates frequently contain monotypic populationsof B cells.

Lymphocytic infiltration of the lungs in SS is wellrecognised. Strimlan et al.27 reviewed 343 SS patientsand found pulmonary involvement in 9%. The term'lymphocytic interstitial pneumonia' was introducedby Carrington and Liebow28 to imply diffuse pul-monary infiltration by lymphocytes and plasma cellsbut without histological characteristics generallyaccepted as malignant, though progression to malig-nant lymphoma has been recognised.2 33 Thepresent authors believe that the histopathology ofLIP is typical of malignant lymphomas of MALTand that differences between this type of lymphomaand nodal lymphomas account for the difficulties indiagnosis. 24 34

The precise diagnosis of malignant B cell lym-phoma requires immunohistochemical methods todemonstrate monoclonal immunoglobulin pro-duction by lymphocytes.26 29Peripheral blood lymph-ocytes may show a normal distribution of immuno-globulin surface markers on B lymphocytes andserum and urine EP can be normal. Biopsy material

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may be readily accessible from superficially affectedtissues, e.g., lymph nodes, but is more difficult toobtain when deeper structures are involved,particularly the lungs. Furthermore, the indolentprogression of pulmonary lymphoma, as illustratedby these three cases, leads to irreversible lungdamage, which might have been arrested by earlyrecognition and treatment.Thus a dilemma may arise when lymphoma is

suspected but all conventional non-invasive tests arenormal. The finding of a tumour-related product inthe urine should lead to the institution of a morediligent search for NHL.The rationale for measuring urinary light chains to

detect malignant lymphoma, and in establisheddisease as an indicator of tumour load, has beendiscussed by Stevenson.35 Stevenson, Spellerberg,and Smith12 have developed a highly sensitivetechnique of isoelectric focusing in agarose, followedby immunofixation, that enables minute quantities(0-03 mg of light chain per 24-hour urine specimen)of monoclonal light chain to be detected against thenormal polyclonal excretion of light chain. By thismethod they have shown that in the B lymphocytediseases of CLL and NHL the majority of patientstested had monoclonal K or k light chains present intheir urine, which could be shown to be products ofthe malignant cells.'2

In a study with sensitive electrophoresis combinedwith immunofixation on sera from 21 patients withprimary SS Moutsopoulos et al. found free mono-clonal A light chains in 14 (67%); no urine analyseswere reported.36 This suggests that very largeamounts of k light chain were being synthesised,since investigations on CLL showed that secretedfree light chain was cleared rapidly from thecirculation and could be detected only in the urine.18Our three patients similarly showed good clearance,with only a trace of monoclonal K light chain foundin the serum of patient 2. Also our small studywould not suggest a special role for k light chains inSS as suggested by Moutsopoulos et al., since twoout of three produced K chains.In a more recent paper Moutsopoulos et al.37

have investigated serum and urine of patients withprimary SS. The incidence of homogeneous proteinbands in serum (47%) and urine (76%) of suchpatients seems very high. In fact they report that100% of patients with extraglandular SS showedsuch bands in the urine, sometimes with multiplebands. In our examination of 26 patients with SS(some of whom had extraglandular symptoms)(Table 3) and no evidence of a transition tolymphoma, by a technique which distinguishesmonoclonal from polyclonal light chain, we foundno evidence for monoclonal light chains in the urine.

Our experience with NHL suggests that such lightchains can only be found in urine when there issufficient tumour load.The striking and common clinical feature of all

three patients we have reported is pulmonarydisease with slow clinical progression. Patient 1 hadrespiratory symptoms for 11 years before hereventual rapid demise from malignant pulmonarylymphoma and had been mistakenly diagnosed ashaving pulmonary fibrosis. There were no changesin her serum immunoglobulins, serum EP, orperipheral blood and bone marrow lymphocytemarkers. It was the finding of K free light chains inher urine, in conjunction with lymphocytic infiltra-tion of the bronchial mucosa, that prompted anopen lung biopsy, enabling diagnosis of a folliclecentre cell lymphoma.

Patient 2 had a malignant clone of B cells withinthe parotidectomy specimen taken in 1976, despitethe apparently benign appearance on light micro-scopy. Although only a faint IgMK serum para-protein band was present, monoclonal K free lightchains were present in her urine. Peripheral bloodlymphocyte analysis also showed predominant stain-ing for IgMK. However, a bone marrow examina-tion was normal. This patient suffered severalunexplained episodes of pneumonia, with a progres-sive fall in TF despite a normal CXR. Theseobservations raised the possibility of lymphomatousinfiltration of the lungs, which has still not beenproved histologically. The curious increase in urinarylight chain excretion associated with the staphylo-coccal pneumonia is not easily explained. It was notdue to renal protein leakage, as no other serumproteins were present in the urine. It is possible thatthe pneumonia was a result of compromised immunefunction as a result of relapse in her lymphoma.Urinary light chain levels fell as the pneumoniaresolved but then rose again with further deteriora-tion in her clinical condition. The levels did not fallwith plasmapheresis but fell during treatment withcyclophosphamide, and her general conditionimproved.

Patient 3 was known to have pulmonary infiltratesfor at least eight years and was relatively asympto-matic until the final stages of his disease when therewas rapid progression of pulmonary lymphomaassociated with depression of serum IgG, increase ofserum IgM, an IgMk paraprotein band, a mono-typic B cell population in the peripheral blood, andmonoclonal k free light chains in the urine. Thesalivary gland lesion was subsequently shown to bemalignant lymphoma.

In these three cases no single serological orhaematological test was able to predict the presenceof the eventually proved malignant lymphoma.

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However, monoclonal urinary free light chain ex-cretion was a constant finding. The finding of lightchains in the urine of patients with leukaemia andlymphoma has been recognised for several years,but the methods of detection were insensitive andclinical disease already apparent. We suggest that thedetection of monoclonal free light chains in theurine of SS patients by the sensitive, non-invasivemethod described should lead to a careful search formalignant lymphoma, especially if there is evidenceof pulmonary disease. This is further supported byour own failure to detect urinary free light chains ineight further patients with definite or probableprimary SS (some with extraglandular features) and18 others with secondary SS, all without clinicalevidence of lymphoma. These preliminary obser-vations indicate the need for a more extensiveprospective study of urinary free light chains in SS.

We would like to thank Mrs Rajee Goswami and Mrs MyfSpellerberg for performing the immunochemistry tests and MissPauline Longman for secretarial assistance.

References

1 Moutsopoulos H M, moderator. NIH conference: Sj6gren'ssyndrome (sicca syndrome): current issues. Ann Intern Med1980; 92: 212-6.

2 Straid V, Talal N. Advances in the diagnosis and concept ofSjogren's syndrome (autoimmune exocrinopathy). Bull RheumDis 1980; 30: 1046-52.

3 Anderson L G, Talal N. The spectrum of benign to malignantlymphoproliferation in Sjogren's syndrome. Clin Exp Immunol1971; 9: 199-221.

4 Diaz-Jouanen E, Ruiz-Arguelles G J, Vega-Ortiz J M, VillarealG, Alarcon-Segovia D. From benign polyclonal to malignantmonoclonal lymphoproliferation in a patient with primarySjogren's syndrome. Arthritis Rheum 1981; 24: 850-3.

5 Pagani J J, Collins J D, Reza M J. Sjogren's syndromepresenting as pulmonary pseudolymphoma. Report of a case. JNatl Med Assoc 1979; 71: 677-8.

6 Ryan G P, James R A, Milazza S C. Malignant lymphomacomplicating Sjogren's syndrome. Aust NZ J Med 1974; 4:287-91.

7 Kassan S S, Thomas T L, Moutsopoulos H M, et al. Increasedrisk of lymphoma in sicca syndrome. Ann Intern Med 1978; 89:888-92.

8 De Couteau W E, Katakkar S B, Skinnides L, Hayton R C,Somerville E A. Sjogren's syndrome terminating as a myelo-proliferative disorder. J Rheumatol 1975; 2: 331-5.

9 Shearn M A, Moutsopoulos H M, Sawada S, Gak C. Sjogren'ssyndrome with light chain myeloma. West J Med 1975; 123:496-7.

10 Gordon J, Howlett A R, Smith J L. Free light chain synthesis byneoplastic cells in chronic lymphocytic leukaemia and non-Hodgkin's lymphoma. Immunology 1978; 34: 397-404.

11 Pierson J, Darley T, Stevenson G T, Virji M. Monoclonalimmunoglobulin light chains in urine of patients with lym-phoma. Br J Cancer 1980; 41: 681-8.

12 Stevenson F K, Spellerberg M, Smith J L. Monoclonalimmunoglobulin light chains in the urine of patients with Blymphocytic disease. Its source and use as a diagnostic aid. Br JCancer 1983; 47: 607-12.

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chains sjogren'ssyndrome: tocommonlyrheumatoid arthritis) the termsecondary ss is used. primary...

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