Asian Pacific Journal of Allergy and Immunology (1992) 10: 123-128

Monoclonal Gammopathies and the Related Autoimmune Manifestations in Taiwan

Chrong·Reen Wang1, Che·Yen Chuangl, Kuei·Tang Lin1, Maw·Yang Chen1, Gwon·Loon Lee1, Rhong·Phong Hsieh2 and Chen·Yen Chen 1

Plasma-cell dyscrasia (PCD) is SUMMARY A total of 50,000 patients were surveyed for the presence of mono· clonal immunoglobulins during the past two decades. There were 411 cases of usually associated with electrophore­ monoclonal gammopathles including 243 cases of plasma cell neoplasms and 168 ticaJiy homogeneous immunoglo­ cases of secondary plasma·cell dyscrasia. Among the 227 cases of multiple myeloma bulin or its subunit, which is used and Waldenstrom's macroglobulinemia, there were 49.3% IgG class, 22.9% IgA class, interchangeably with the term mono­ 9.7% IgM class and 13.2% light chain type. In addition, there were 1.3% of non· clonal immunoglobulin or M-com­ excretory myeloma including an IgM type. A relatively high frequency (4.8%) of ponent. I From the clonal concept, IgO M'proteins was detected but heavy chain disease was not encountered in the spontaneous and uncontrolled pro­ present series. Purified M'components from patients with possible autoimmune liferation of one clone of plasma manife_lltations were sublected to immunofluorescence studies. Autoimmune activity cells results in monoclonal gammo­ of M·proteins was found in a patient of Waldenstrom's macroglobulinemia with peri· pathy on an electrophoregram. 2 pheral neuropathy, and another patient of cryoflbrlnogenemla with recurrent purpura The wide application of immuno­ and gangrene. In conclusion, a high frequency of IgO myeloma is found In Chinese patients of this area. M'components may have autoimmune activity resulting in globulin quantitation and protein unusual clinical manifestations. electrophoresis (PEP) has contri­ buted greatly to the detection of M-component. 3 Since the introduc­ tion of immunoelectrophoresis (IEP), Chinese patients in this region. patients during the past two decades. and recently immunofixation (IF), The well-known clinical mani­ The simultaneous urine and/or other the heavy chain class and light chain body fluids were also screened. Heavy type have been more precisely deter­ festations related to M-components are renal failure from tubular light­ chain class and light chain type were mined with respect to M-components determined by IEP and IF. M-com­ 4 chain precipitation, hyperviscosity and their subunits. ,5 The relative ponents for further studies were frequency of each class and type of and cold intolerance caused by sys­ temic paraproteinemia, and com­ purified from those patients with monoclonal gammopathy is reflected unusual clinical manifestations. in the relative amount of each immu­ pression of surrounding tissue from noglobulin in the serum of normal extramedullary plasmacytoma. 8 In individuals. 6 However, genetic dif­ addition, there are some unusual autoimmune presentations caused ferences in various ethnic groups From the 1Department of Internal Medicine' may account for relatively high per­ by M-components against self anti­ gens. and 2Department of Clinical Pathology, centages of some paraproteins in College of MediCine, National Taiwan Uni­ patients with PCD. 7 A comprehensive In the present study, M-com­ versity. Taipei, Taiwan. report of immunochemical frequency ponents were surveyed by serum PEP of M-components is still lacking in in blood samples from 50,000 Chinese Correspondence : Prof. Che-Yen Chuang. 124 WANG, ET AL.

MATERIALS AND METHODS In selected specimens, agarose gels components were done initially by and polyacrylamide gels were used A total of 50, Chinese patients sepharose 4B gel filtration column, was examined per blood samples sent as electrophoretic media to more then recycled with Sephadex 0-200 clearly elucidate the M-compo­ 14, 16 from more than 20 hospitals in Taiwan gel column to obtain pure IgM. nents. 11,12 from 1972 to 1991. The sex ratio Immunofluorescence study was approxiamtely 1 to 1 with the age range from 15 to 95 years. The Immunoglobulin quantitation Sections of healthy human sciatic specimens were screened with serum Quantitation of immunoglo­ nerve tissue, cut at 5 J..Im, were incu­ PEP and interpreted by the members bulins was done by the Mancini's single bated with appropriate dilution of of immunological section, National radial immunodiffusion or nephelo­ purified M-components. 16 In addi­ Taiwan University Hospital. Simul­ metry (Beckman, USA). 9 tion to 5 M-components derived taneous PEP of urine and/or other from patients with peripheral neuro­ body fluids was done in patients IEP/IF pathy, other 3 M-components derived with M-components of blood, and from control patients without peri­ IEP was carried out with 1.2070 in those suspected to have PCD. In pheral neuropathy were also purified agar in Michael's buffer as previously blood and urine samples with mono­ and used in immunofluorescence described . 13 IF was done by Immu­ clonal immunoglobulins or their frag­ staining. Skin sections from the noflXation Electrophoresis Kit (Beck­ ments, quantitation of immuno­ cryofibrinogenemia were stained with man, USA) acccrding to the manufac­ globulin, IEP and IF were performed. various FITC-conjugated antisera turer's manual. In patients with unusual clinical mani­ specific to either heavy chains, light festations, monoclonal immunoglo­ chains, complements or fibrinogen. bulins were purified for further Purification of M-components The purified IgO component was studies. For IgO and IgA M-compo­ studied by double diffusion in agarose nents, ammonium sulphate salt frac­ gel to analyze its specificity with PEP tion was first adopted and followed fibrinogen. The cold saline-washed Electrophoresis was carried by DEAE-cellulose ion-exchange cryoprecipitate was also subjected out on a cellulose acetate membrane, chromatography as previously des­ to double diffusion to determine its in barbital buffer 0.075 M, pH 8.6. 10 cribed. 14,15 Separations of IgM M- compositions.

Table 1. Distribution and frequency of M-proteins in 243 cases of plasma cell neoplasms

IgG IgA IgM IgD lC Total /( A /( A /( A /( A /( A

MM 62 50 30 22 0 0 2 9 17 13 205 WM 0 0 0 0 11 11 0 0 0 0 22 EMP 2 3 2 0 0 0 0 0 1 0 8 SOP 0 1 0 0 0 0 0 0 0 2 PA 0 1 0 1 0 0 0 0 0 2 4 PCl 0 0 0 0 0 0 0 0 2 0 2

Total 64 55 33 23 11 11 2 9 20 15 243

Frequency 49.0% 23.0"10 9.1% 4.5% 14.4% 100%

lC = light chain, MM = MUltiple myeloma, WM = Waldenstrom's macroglobulinemia, EMP = Extramedullary plasmacytoma, PA Primary amyloidosis, SOP = Solitary osseous plasmacytoma, PCl = Plasma cell leukemia. MONOCLONAL GAMMOPATHIES IN TAIWAN 125

RESULTS M-components in the immunofluores­ neuropathy, iricluding 1 WM, 2 solitary There was a total of 411 cases cence study. A female patient pre­ osseous plasmacytomas (SOP) and of monoclonal gamrnopathy including senting with recurrent purpura and 2 secondary PCD without other 243 cases of plasma cell neoplasms gangrene on the distal extremities diseases except neuropathy. The and 168 cases of secondary PCD had cryofibrinogenemia and IgO associated M-components were 1 among the 50,000 patients. The dis­ monoclonal gammopathy. There IgM, 2 IgO and 2 IgA, respectively. tribution and frequency of M-com­ were 5 cases of monoclonal gammo­ Among the 5 cases with neuropathy ponents in plasma cell neoplasms pathy associated with peripheral and 3 cases without neuropathy, only are summarized in Table 1. Among the 227 cases of multiple myeloma (MM) and Waldenstrom's macro­ globulinemia (WM), there were 49.3"70 IgO class, 22.9070 IgA class, 9.7"70 Table 2. Diseases associated with 168 cases of secondary plasma IgM class, 4.8"70 IgO class, and 13.2"70 cell dyscrasia light chain type. In addition, there were 3 cases (1.3"70) of nonexcretory Classification No. of cases myeloma; among them one case was proved to be IgM class. Presence of Neoplasm: 56 intracytoplasmic IgM M-components Malignant lymphoma 23 was demonstrated by immunofluo­ Chronic lymphocytic leukemia 3 rescence and immunoenzymatic staining Other hematological neoplasm 12 of plasma cells obtained from bone Solid tumor 18 marrow. 17 The other 168 cases with various diseases and associated M­ Autoimmune: 31 proteins are listed in Table 2. They were classified into four types, in­ Systemic lupus erythematosus 10 cluding neoplasms other than plasma­ Rheumatoid arthritis 6 cell origin, autoimmune and rheumatic Primary Sjogren syndrome 6 diseases, inflammatory and infec­ Essential mixed cryoglobulinemia 2 tious diseases, and monoclonal gam­ Other 7 mopathy of unknown significance. Miscellaneous inflammation or infection 1 41 The most commonly encountered disease was malignant lymphoma, Monoclonal gammopathy of unknown significance 40 accounting for 13.7"70 of secondary PCD. 1= Including one IgG 'X lichen myxedematosus and one IgA K Table 3 shows the unusual cli­ pyogenic granuloma. nical manifestations associated with

Table 3. Unusual clinical manifestations associated with monoclonal gammopathy and immunofluorescence study

Clinical manifestations Associated PCD (No.) M-component Immunofluorescence

Cryofibrinogenemia Secondary (1) IgGK Strong positive Peripheral neuropathy WM (1) IgMK Strong positive Secondary (2) IgG'X ,lgG'X Negative Secondary (2) IgA'X ,lgA'X Negative Control patients WM (1) IgMK Negative MM (2) IgA'X ,lgA'X Negative 126 WANG, ET AL.

the IgM from a patient with neuro­ pathy had a strong immunofluo­ rescence staining with myelin sheaths of nerve sections (Fig. 1). Strong immunofluorescence was also detected in precipitates within blood vessel lumen of the dermis when stained with anti-kappa, anti-gamma and anti-fibrinogen antisera (Fig. 2). By double diffusion, the cryoprecipitate only reacted with anti-fibrinogen, anti-kappa and anti-gamma antisera. A positive precipitating line also formed between the purified IgG and fibrinogen.

DISCUSSION Although the relative frequency of heavy chain class and light chain type was approximately reflected to the relative serum concentration in Fig. 1 Indirect immunofluorescence of human sciatic nerve shows normal individuals, there was a high positive staining on the myelin sheaths. frequency of IgD monoclonal immu­ noglobulins and absence of heavy chain M-components in the present study. A high frequency of IgD myeloma, more than 5070 among myeloma patients, has been reported in Japanese, as compared with less than 3070 reported in Caucasians. 18,19 Approximately 5070 of myeloma patients were IgD type in Chinese from the present study. There is a tendency of Orientals to develop un­ differentiated forms of B-cell neo­ plasms, and IgD excretion involves a less-differentiated plasma cells. 7 A role of genetic factors is suggested by the high frequency of IgD myeloma in Orientals. Alpha heavy chain disease is frequently encountered in young adults around the Mediterranean, but it is not seen in this region in the present study. 20 M-components may have auto­ immune activity against self antigens, and the most weU known phenomenon is WM with peripheral neuropa­ thy. 16,2 1 The mechanism by which Fig. 2 Direct immunofluorescence of precipitates within ves.sel M-components cause peripheral neuro­ lumen of the dermis shows positive staining with anti­ pathy remains controversial, postu­ gamma chain antibody. lated roles including toxin injury, amyloid deposits, lymphoid cell infil­ tration, serum hyperviscosity and MONOCLONAL GAMMOPATHIES IN TAIWAN 127

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