Infection and chronic rheumatic disease in children

Infection

and Chronic

Rheumatic

Disease

in Children

By Paul E. Phillips

I

in the role of microbial agents in NTEREST the chronic rheumatic diseases of children has waned somewhat over the last 3 yr.’ This is partly due to increased recognition and interest in genetic factors, and partly to the failure to implicate specific microbial agents2 However, considerable interest persists, although the players-investigators, microbes, and methods-have changed somewhat. Few would argue that a genetic predisposition, an immune response to some inciting and/or perpetuating antigen, and resulting inflammation are involved in diseases like juvenile rheumatoid arthritis (JRA). But probing a little deeper, there are many specific, yet unanswered questions. What are the genetic factors and how do they operate? What are the inciting and/or perpetuating antigen(s), what are their origins, when are they present, and where are they? Is the immune response to such antigens abnormal and if so, why? In addition, the importance of various factors may change as the disease evolves in individual patients, and different host and environmental factors may be involved in different patients having the same disease clinically. This communication reviews how microbe-host interactions might lead to diseases such as JRA using rheumatic disease with known infections as possible models and recent attempts at implicating specific microbes in childhood rheumatic disease. Because host genetic factors are the starting point for almost any hypothesis involving microbial infection, one must first consider how they

From Special

the Department Surgery

sity Medical

of Medicine,

The Hospital

and New York Hospital-Cornell

for

Univer-

Center, New York, N.Y.

Supported

in part

by grants from

New York Chapter of The Arthritis

the USPHS

and the

Foundation.

Presented in part at the 80th Ross Conference on Pediatric Research

“Arthritis

in Childhood,”

Freeport,

Bahamas,

December 2-5, 1979.

Paul E. Phillips, M.D.: Associate Professor of Medicine, Cornell University Address reprint Hospital

for

York, N. Y.

0

Medical

College.

requests to Paul E. Phillips,

Special

Surgery,

10021

1980 by Grune & Stratton,

0049~)172/80/1002-0002$01.00/0

92

535 East Inc.

M.D.,

The

70th Street,

New

could influence microbe-host interactions. There are two major theories explaining the remarkable association of certain HLA antigens with various rheumatic diseases (Table 1). The linkage disequilibrium, or two-gene theory postulates that a linked Ir gene determines a disordered immune response. This could be an increased response to host antigens-true autoimmunity, to microbial antigens from normal flora, or to some combination of crossreactive host and microbial antigens. Alternatively, a decreased response might allow enhanced multiplication of endogenous flora, or more frequent or persistent infection with exogenous microbial agents. Any of these could theoretically lead to rheumatic disease. The one-gene theory, on the other hand, postulates that the HLA gene directly determines susceptibility to the disease. In the present context, its HLA antigen product is postulated to cross react with a microbial antigen. This could result in rheumatic disease in two principal ways, depending on the location of the crossreactive host antigen. If it is principally recognized on lymphocytes by an immune response to the microbial antigen, a disordered immune response to other host and/or environmental antigens could result, either increased or decreased, with the same possible results as discussed for the two-gene theory. Alternatively, if the host antigen is principally recognized on cells other than lymphocytes, the cross-tolerance hypothesis3 postulates decreased recognition of the cross-reactive microbial antigen initially, resulting in enhanced infection and microbial antigen load, thus stimulating an increased immune response to the microbial antigen and, concurrently, to the cross-reacting host antigen. If the latter is in the joints, arthritis results. Another possibility is that the HLA gene product only becomes cross-reactive after alteration by some initial inflammatory event. Which of these genetic mechanisms might operate in JRA, for instance, is unknown, but any role of microbial infection-primary, secondary or none-must be considered within such a framework. A major difficulty in testing hypotheses for

Seminars in Arthritis andRheumatism,

Vol. 10. No. 2 (November). 1980

INFECTION AND RHEUMATIC DISEASE

Table 1. Relationship

93

of Genetic Factors to infection and

Rheumatic

Table 2. Factors Influencing Outcome of Exogenous Infection: The Microbe-Host Interaction

Oisease

1. HLA-linked lr gene determines disordered immune response A. Increased immune response

Host susceptibility Genetic

(1) to host antigens: autoimmunity (2) to endogenous microbial antigens (3) to cross-reactive host and endogenous or exogenous microbial antigens

Pre-existing immunity Dose and route of microbe Microbe tropism Species/cells/organs infected

B. Decreased immune response

Local/systemic infection

enhanced/recurrent/persistent

endogenous or

exogenous infection

Damage caused by replication/toxins Host response

2. HLA gene determines host antigen cross-reactive with

Nonimmune (early)

endogenous/exogenous microbial antigen

interferon

A. Host antigen on lymphocytes:

Complement activation

Immune response to microbial infection cross-reacts with lymphocytes, results in disordered immune response:

(1)

increased

Local inflammation Immune (later) Antibody (immune complexes)

(2) decreased

Cellular immunity

B. Host antigen elsewhere (not on lymphocytes): Crosstolerance hypothesis

Inflammation Outcome

Decreased immune response to microbial infection

Recovery: microbe eliminated

Enhanced/recurrent/persistent

Recurrent or chronic inflammatory disease

infection

Increasing immune response to microbial and crossreactive host antigens

Host immune response to: persistent microbe/reinfection altered or cross-reactive self antigen

microbial roles in the connective tissue diseases (CTD) are the multiple variables in microbehost interactions (Table 2). Although several recent hypotheses are based on endogenous infection,2*4 most have stressed acquired or exogenous infection. Many of the factors in endogenous microbe-host interactions are similar to exogenous infections, but the latter are better understood and will serve as a general background. Presuming the microbe can infect man, host susceptibility determines whether infection occurs. This may involve genetic factors in addition to those discussed, for instance, determining the presence of specific microbial receptors on cells. Susceptibility also involves any preexisting immunity, including towards antigenically-related microbes, and the dose and route of invasion, These factors may also influence the course and outcome of infection, but more important are the tropism of the microbe and the hostimmune response to it. Tropism refers to the cell type, tissue, and organs preferentially invaded by the microbe, and to whether infection is local or systemic. This varies not only with different microbes, bacteria, viruses, etc, but also with different strains of the same microbe. Multiplying bacteria may release toxins having local or distant effects, and virus replication may

damage cells and cause organ malfunction. In the nonimmune host, microbial replication and spread proceed unchallenged initially except by mechanisms such as interferon production, complement activation, and local inflammation. Pyrogens and other toxic substances having distant effects may be released. During the following several weeks, the host develops specific immunity and additional mechanisms for cell and tissue damage may become operative. The importance of each immune mechanism in eliminating infection varies with the kind of microbe, but systemic spread is generally reduced or terminated by development of circulating antibody. However, immune complexes with microbial antigens may be formed and, if not cleared by the reticuloendothelial system, their deposition elsewhere may result in inflammation. Specific cellular immunity may destroy intact bacteria or virus-infected cells, with further degradation and elimination of residual or released microbes and their components by specific humoral and cellular recognition, inflammation, and phagocytosis. Recovery follows microbial elimination, but if the microbe or its antigens persist, or if reinfection occurs, recurrent or chronic inflammatory disease could result. This could also happen if

PAUL

94

the host responds immunologically to self antigens, either altered by the inflammatory process, or which crossreact with microbial antigens. Rheumatic disease results if any of these mechanisms involve joint or other connective tissues and, depending on the particular microbe-host interaction, could be of variable severity and duration. In children, biologic and sexual maturity are additional factors in the microbe-host interaction. Many virus infections are minor or nonspecific illnesses in young children compared to adults or older children; some are not associated with any recognizable illness. These differences may reflect maturation of the immune system, perhaps including an effect of sex hormones, as well as other factors. They may also be involved in the differences between juvenile and adult RA, as well as in the different types of onset in JRA. The latter thus need not reflect different etiologic agents, although this may be the case; they could equally well result from varying host responses to the same agent. The acute and subacute rheumatic symptoms occurring with known microbial infections’-’ are potential human models for the pathogenesis of RA, both juvenile and adult, as well as for the other CTD (Table 3). Although the precise pathogenesis of these diseases is also not entirely clear, a broad classification can be made according to the relative importance of (1) local presence of the microbe or its antigens in the joint (or heart), (2) the host-immune response to the microbe, and (3) local presence in the joint (or heart) of a host antigen cross-reactive with the microbe. In the first category, rheumatic disease results primarily from local presence of the microbe, the immune response being relatively unimportant and cross-reactive antigen absent (Table 4). An Table 3.

Models

Table 4.

E. PHILLIPS

Model Category 1: Vaccinia Arthritis Important: Virus

in joint

tissue

Not important: Host

immune

response

Cross-reactive

antigen

Sequence: Virus

repkation

locally

Local cell damage Local

inflammation

Immune

response

Infection

terminated

Applicable

to JRA:

Pauciarticular-doubtful Polyarticular-no Systemic--no

example is the arthritis occurring very rarely after smallpox vaccination.‘.’ About 10 days after vaccinia virus inoculation at a distant site, viremia occurs with dissemination to the synovial membrane. The virus replicates there, resulting in cell necrosis, inflammation and a monarthritis lasting several weeks. The virus is then eliminated by the host-immune response, inflammation resolves and the arthritis does not recur. Arthritis thus results primarily from direct virus-induced cell damage and the major contribution of the immune response is to eliminate the virus. Varicella5~8~9 and acute bacterial arthritis are other examples in this category. Even adding the possibility of a local host antigen altered by inflammation so as to become a perpetuating stimulus, this model seems unlikely for JRA. In the second category, rheumatic disease results from the immune response to the microbe or its antigens present elsewhere than in joint tissues (Table 5). The arthritis occurring with acute hepatitis B (HB) virus infection is an example.‘.5 Polyarthralgias, arthritis, and urticaria occur here early, with hypocomplemen-

for Pauci/Polyarticular Juvenile Rheumatoid Arthritis: Human Arthritis with Known Infections Modal Category 1

2

3

Acute V&XXW

Local

infection

Host

immune

Local

cross-reactive

response host antigen

Hepatitis B

4

Rheumatic Rubella

Fever

Arthritis

Arthritis

Arthritis

With Carditis

+

0

+

0

0

+

+

f

0

0

0

t

INFECTION AND RHEUMATIC DISEASE

Table 5. Model Category Hepatitis

2: Acute Type 6 (Serum) Arthritis

Important: Host immune response Not impwtant: Virus in joint tissue Cross-reactive antigen Sequence: Virus replication systemically Immune response Immune complexes Inflammation Infection terminated (usually) Applicable to JRA: doubtful

temia and HB antigenemia. These symptoms resolve with appearance of clinical hepatitis and HB antibody, disappearance of HB antigen, and normalization of serum complement. The rheumatic disease thus results from a serum sicknesslike reaction to the formation and deposition of circulating HB antigen-antibody immune complexes. The joint symptoms associated with adenovirus” and some arbovirus and bacterial infections are other examples probably in this category.‘*’ Persistent HB infection will be considered later, but without any perpetuating antigen, this model also seems unlikely for JRA. In the third category, rheumatic disease results from the immune response to the microbe or its antigens present locally (Table 6). Rubella, acquired either naturally or by immunization, is the best example.‘35 Polyarthralgias and, less often, arthritis occur following viremia and with Table 6. Model Category

95

or after appearance of antibody. Virus may be present in the joint early in infection and possibly as late as 4 mo after vaccination. Thus, although rubella replication generally does not destroy cells, it might directly cause joint disease early in infection. However, most rheumatic symptoms occur later5.” and more likely result from the immune response to virus or its antigens persisting for a few weeks or months in joint tissues. An inflammation-altered host antigen might also contribute to perpetuation. In animals, other examples in this category are protein antigen- and mycoplasma-induced arthritis.2S’2This model seems quite applicable to both articular JRA and to adult RA, and has been the generally favored hypothesis for several decades, but no evidence has been obtained to support it.2 In the fourth category, the immune response to a local host antigen cross-reactive with a microbial agent is important, and local presence of the microbe is not (Table 7). Rheumatic fever, with carditis as the local target, is the modelI since there are no such virus infections known. Following a distant streptococcal infection in the pharynx, the host antibody response to a streptococcal antigen appears to cross react with a host antigen present in the heart, which results in local inflammation. The cycle is repeated or intensified with recurrent infections. Although the cross-reactive host antigen has been demonstrated, its pathogenic role is less certain; it has not been found in other affected tissues such as synovium. Thus although this explanation seems best, others are possible.‘4 This general model,

3: Rubella Arthritis

Important: Virus in joint tissues Host immune response Not important: Cross-reactive antigen Sequence: Virus replication locally (and systemically) ? local inflammation Immune response Local inflammation

Table 7. Model Category 4: Rheumatic

Fever with Carditis

Important: Local cross-reactive host antigen Host immune response Not important: Local streptococcal infection Sequence: Distant streptococcal infection

Local virus persistence (?I

Immune response

Continuing immune response and local

Local host antigen cross-reactive with

inflammation Infection terminated eventually Applicable to JRA:

microbial antigen Local inflammation Applicable to JRA:

Pauci/polyarticular-yes

Pauci/polyarticular-yes

Systemic-doubtful

Systemic-doubtful

PAUL

96

postulating a host antigen in joint tissues crossreactive with some microbial antigen, is also an attractive hypothesis for articular JRA, although supporting evidence is again lacking.2 Combining the last two model categories provides a reasonable, although complex, hypothesis for a microbial role in articular JRA (Table 8). Here all three factors could be important: local microbial and/or cross-reactive host antigen, and the immune response. A microbial infection, possibly in joint tissues, induces an immune response resulting in local inflammation due to the local presence of the microbial antigen, an inflammation-altered host antigen, and/or a cross-reactive host antigen. Local persistence of one of these antigens provides the perpetuating stimulus for recurrent or chronic arthritis, possibly with microbial reinfections as an additional stimulus for exacerbations. A variation of this scheme is the bacterial debris hypothesis,4 where the source of microbial antigen is endogenous gut bacteria, with various immune complexes formed by antibody to the antigen, alteration of host IgG, and rheumatoid factor. Formation or deposition of these complexes locally in joints then leads to articular JRA, and systemically to systemic JRA. Alternatively, such endogenous or exogenous microbial antigens might cross react with host antigens, either HLA-determined3 or otherwise, and so induce rheumatic disease by one of the various pathways described earlier. None of these models are applicable to systemic JRA, except for the bacterial debris hypothesis. However, an excellent viral model

Table 8. Currant Hypothesis for PaucilPolyarticular JRA Important:

Microbial

replication

microbial/cross-reactive/altered

Local

inflammation

systemically

response

important: Cross-reactive

antigen

Sequence: Virus

replication

systemically

Immune

response

Immune

complexes

lnflammatlon Virus

persistence

Applicable

to JRA:

Pauci/polyarticular-doubtful Systemic--yes

for systemic JRA does exist: necrotizing vasculitis associated with chronic HB virus infection (Table 9). Here the immune response to persistent systemic virus replication seems to result in circulating immune complex formation and deposition, with resulting vasculitis.‘,2 Although no cross-reactive host antigen has been found, one could be involved in a similar hypothesis for systemic JRA (Table 10). This differs from the hypothesis for articular JRA only in the systemic distribution of microbial and/or host antigens and of immune interactions with them. As mentioned, antigenic debris from endogenous gut bacteria could also be involved in this scheme. Both hypotheses (Tables 8 and 10) attempt to include various alternatives considering the uncertain mode of action of genetic factors, and the uncertain nature and location of an inciting/perpetuating microbial or host antigen(s). The most readily testable aspect may be identification of an immune response to such an antigen, whatever its origin, present in joint

antigen

immune

persistence

systemically

response antigen

host

antigen

Microbial

replication

(? endogenous

antigen

(host/microbial)

persistence

possibility: bacterial

Rheumatoid

factors

bacterial antigens

debris

Immune

hypothesis

(? cross-reactive)

Immune

complexes

(? rheumatoid

complexes,

Recurrent/chronic

factors)

host antigen systemic/?

Inflammation Microbial/host

immune

systemically bacteria)

response

? Cross-reactive

local inflammation

Endogenous

(and systemic)

immune

Sequence:

Local

Perpetuating

persistence

Host

? Cross-reactive

(? locally)

response

Recurrent/chronic

Virus

Not

Host

Immune

Local

Importam:

Microbial

response

Sequence:

Alternative

and Chronic Hepatitis 6 Virus Infection

Important:

(? cross-reactive) immune

Table 9. Model for Systemic JRA: Necrotizing Vasculitis

Table 10. Current Hypothesis for Systemic JRA

Host/microbialantigenin joint tissues Host

E. PHILLIPS

antigen

persistence

inflammation

local

INFECTION AN0

RHEUMATIC DISEASE

tissues of at least some articular JRA patients. Thus, while complex and not very satisfying, these hypotheses provide a framework for future experimentation. Like the earlier studies reviewed previousIy,‘** recent attempts at implicating microbial agents in childhood rheumatic diseases have been generally negative. The lack of association between rubella and JRA was further confirmed serologically.’ In adult RA, there has been increasing interest in the possible role of Epstein-Barr virus (EBV), based on the high prevalence of serum antibody to an antigen present in EBV-transformed lymphoblastoid cell lines.16 Whether this reflects an etiologic role for EBV,” or some type of increased immune response to microbial/host antigens as discussed earlier, is unclear. Lymphocytotoxic antibodies, which often arise during viral infections, were not more prevalent in JRA but, interestingly, were in their relatives.‘* The reason for this is unclear as is the specificity of such antibodies both antigenically” and regarding their various disease associations.’ Given the general failure of attempts to implicate viruses, there is a resurgence of interest in bacteria.3X4 A recent study*’ confirmed the earlier finding*’ of a higher prevalence of antibodies to a streptococcal mucopeptide in JRA and acute rheumatic fever, and extended the finding to adult RA as well. To demonstrate the specificity of such associations, future studies need to show that controls with other inflammatory diseases have a lower prevalence. In ankylosing spondylitis, which often presents as childhood pauciarthritis, the controversial findings suggesting cross-reactivity between Klebsiella pneumoniae and the HLA-B27 antigen, and linking Klebsiella bowel infection to the disease3,22.23 received additional support.24 These findings, although needing further confirmation, are an interesting new approach to the pathogenesis of chronic rheumatic disease,3*4 as discussed earlier. Reiter disease has been increasingly recognized in children and chlamydial infection was suggested in several cases.*’ The role of these intracellular microorganisms in the adult disease remains speculative.* There is strong evidence for a tick-transmitted infectious agent in Lyme arthritis, a pauciarthritis with additional symptoms often found in children.26

97

In systemic lupus erythematosus (SLE), a higher prevalence of immune interferon was found in both SLE and other CTD seTa,*’ but again controls with other inflammatory diseases need to be studied. Interest in viruses has generally decreased following the largely negative studies on type C oncornaviruses.2*28329 However, a further study suggested a role for Anaplasmataceae (Haemobartonella) in adult SLE3’; these cell wall-deficient microorganisms may be more involved in human disease than previously recognized.3’ The potential lesson is further emphasized by the recognition of new bacterial species, such as Legionella pneumophila, as causes of human disease.32 In polydermatomyositis, picornaviruses continue to be implicated in at least some patients,2.33.34 but as well other kinds of microbes have been associated with the disease: toxoplasma in some adults,35 and bacille CalmetteGuerin (BCG) vaccination in two children.36 Vasculitis in children has only rarely been associated with viral infections’; the same is true for the distinctive mucocutaneous lymph node syndrome, or Kawasaki disease.37 In adults, HB virus infection continues to be associated with vasculitis3* as well as other immunologicallymediated diseases,‘.* recently including mixed cryoglobulinemia in adults39 and membranous glomerulonephritis in children.40,4’ Various HB antigen-antibody immune complexes have been directly implicated in these diseases. Hepatitis B virus infection continues to be unique in man because of the wide spectrum of associated immunologic disease, particularly in adults.‘~*~ 384’ In children, the wide variety of antigens possibly involved in glomerulonephritis4’ is interesting; the role of streptococcal infection as one of these has long been recognized although, as with rheumatic fever, the exact mechanism remains obscure.42 SUMMARY

It is clear that various microbial agents can cause acute and chronic rheumatic disease by several mechanisms, that different agents, some perhaps yet unknown, may cause the same disease in different patients, and that genetic factors are important, perhaps crucial, to this host response. In trying to elucidate how microbe-host interactions result in chronic rheu-

PAUL E. PHILLIPS

98

matic disease, interest currently centers on the roles of genetic factors, of bacterial infections including endogenous flora, of cross-reactive microbial and host antigens, and of the immune response to them. As in the past, progress in

understanding these complex interactions probably be incremental and intermittent.

will

ACKNOWLEDGMENT I thank Hjordis

Kerezman

for secretarial

assistance.

REFERENCES I. Phillips PE. The role of infectious agents in childhood rheumatic diseases. Arthritis Rheum 1977; 20:459-66, 1977 (suppl). 2. Phillips PE, Christian CL. Infectious agents in chronic rheumatic diseases. In: McCarty DJ ed. Arthritis and Allied Conditions. 9th ed. Philadelphia: Lea & Febiger, 1979: 320. 3. Young CR, Ebringer A, Archer JR. Immune response inversion after hyperimmunization: possible mechanism in the pathogenesis of HLA-linked diseases. Ann Rheum Dis 1978; 37:152-58. 4. Bennett JC. The infectious etiology of RA: new considerations. Arthritis Rheum 1978; 21:531-8. 5. Phillips PE. Viral arthritis in children. Arthritis Rheum 1977; 20584-9 (suppl). 6. Hyer FH, Gottlieb NL. Rheumatic disorders associated with viral infection. Semin Arthritis Rheum 1978; 8:17-31. 7. Sauter SVH, Utsinger PD. Viral arthritis. Clin Rheum Dis 1978; 4:22549. 8. Brook I. Varicella arthritis in childhood. Clin Pediatr (Phila) 1977; 16:1156-57. 9. Priest JR, Urick JJ, Groth KE, Balfour HH. Varicella arthritis documented by isolation of virus from joint fluid. J Pediatr 1978; 93:99&2. 10. Utsinger PD. Immunologic study of arthritis associated with adenovirus infection. Arthritis Rheum 1977; 20: 138, (abstr). Il. Spruance SL, Metcalf R, Smith CB, et al. Chronic arthropathy associated with rubella vaccination. Arthritis Rheum 1977; 20:741-7. 12. Washburn LR, Cole BC, Ward JR. Mycoplasmainduced arthritis of rabbits: results of a one-year study. Arthritis Rheum 1979; 22:670-l, (abstr). 13. Kaplan MH. The cross-reaction of Group A streptococcus with heart tissue and its relation to induced autoimmunity in rheumatic fever. Bull Rheum Dis 1969; 19:560-7. 14. Markowitz M. The changing picture of rheumatic fever. Arthritis Rheum 1977; 20:369-74, (suppl). 15. Schnitzer TJ, Ansell BM, Hawkins CT, Marshall WC. Significance of rubella virus infection in juvenile chronic polyarthritis. Ann Rheum Dis 1977; 36:468-70. 16. Alspaugh MA, Jensen FC, Rabin H, Tan EM. Lymphocytes transformed by Epstein-Barr virus: induction of nuclear antigen reactive with antibody in RA. J Exp Med 1978; 147:1018-27. 17. Vaughan JH. Rheumatoid arthritis, rheumatoid factor and the Epstein-Barr virus. J. Rheumatol 1979; 6:381-8. 18. Raum D, Glass D, Soter NA, et al. Lymphocytotoxic antibodies: HLA associations, disease associations and family studies. Arthritis Rheum 1977; 20:933-6. 19. Searles RP, Messner RP, Bankhurst AD. Cross-

reactivity of antinuclear and anti-lymphocyte antibodies in SLE. Arthritis Rheum 1979; 22:657, (abstr). 20. Pope RM, Rutstein JE, Straus DC, Chang D. Antibodies to the immunodominant portion of streptococcal mucopeptide (pcntapeptide) in patients with rheumatic disorders. Arthritis Rheum 1979; 22:648, (abstr). 21. Heymer B, Schleifer KH, Read S, et al. Detection of antibodies to bacterial cell wall peptidoglycan in human sera. J Immunol 1976; 117:23-6. 22. Ebringer RW, Cawdell DR, Cowling, P, Ebringer A. Sequential studies in ankylosing spondylitis: association of Klebsiella pneumoniae with active disease. Ann Rheum Dis 1978; 37:146-51. 23. Editorial: Klebsiella and ankylosing spondylitismolecular mimicry? Lancet 1979; I : IO 12-3. 24. Seager K, Bashir HV, Geizy AF, et al. Evidence for a specific B27-associated cell surface marker on lymphocytes of patients with ankylosing spondylitis. Nature 1979; 277:68-70. 25. Rosenberg AM, Petty RE: Reiter’s disease in children. Am J Dis Child 1979; I33:394-8. 26. Steere AC, Gibofsky A, Patarroyo ME, et al. Chronic Lyme arthritis: clinical and immunogenetic differentiation from RA. Ann Intern Med 1979; 90:896-901. 27. Hooks JJ, Moutsopoulos HM, Geis SA, et al. Immune interferon in the circulation of patients with autoimmune disease. Clin Res 1979; 27:328A, (abstr). 28. Hicks JT, Aulakh GS, McGrath PP, et al. Search for Epstein-Barr and type C oncornaviruses in SLE. Arthritis Rheum 1979; 22:845-57. 29. Phillips PE, Tarassichin LA, Alekberova ZS. et al. Lack of oncornavirus-related antigens in SLE tissues (submitted for publication). 30. Kallick CA, Thadhani KC, Rice TW. ldentitication of Anaplasmataceae (Haemobartonella) antigen in glomeruli of lupus nephritis and identification of antibodies against Anaplasmataceae in the serum of patients with SLE. Arthritis Rheum (in press). 31. Ristic M, Kreier JP. Hemotropic Med 1979; 301:937-9. 32. lsenberg HD. Legionella. WIGA, gens? Ann Intern Med 1979; 91:7856

bacteria.

N Engl J

et cetera:

patho-

33. Travers RL, Hughes GRV, Cambridge G, Sewell JR. Coxsackie B neutralization titers in poly/dermatomyositis. Lancet 1977; 1: 1268, (letter). 34. Fukuyama Y, Ando T, Yokota J. Acute fulminant myoglobinuric polymyositis with picornavirus-like crystals. J Neurol Neurosurg Psychiatry 1977; 40:775-8 1. 35. Phillips PE, Kassan SS, Kagen LJ. Increased toxoplasma antibodies in idiopathic inflammatory muscle disease. Arthritis Rheum 1979; 22:209-14.

INFECTION AND RHEUMATIC DISEASE

36. Kass E, Straume S, Munthe E. Dermatomyositis after BCG vaccination. Lancet 1978; 1:772, (letter). 37. Keim DE, Keller EW, Hirsch MS. Mucocutaneous lymph node syndrome and parainfluenza 2 virus infection. Lancet 1977; 2:303, (letter). 38. Gower RG, Sausker WF, Kohler PF, et al. Small vessel vasculitis caused by hepatitis B virus immune complexes. J Allergy Clin lmmunol 1978; 62:222-8. 39. Levo Y, Gorevic PD, Kassab HJ, et al. Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 1977; 296:lSOlA.

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40. Takekoshi Y, Tanaka M, Miyakawa Y, et al. Free “small” and IgG-associated “large” hepatitis B e antigen in the serum and glomerular capillary walls of two patients with membranous glomerulonephritis. N Engl J Med 1979; 300:814-9. 41. Kleinknecht C, Levy M, Gagnadoux MF, Habib R. Membranous glomerulonephritis with extra-renal disorders in children. Medicine 1979; .58:219-29. 42. Nissenson AR, moderator. Poststreptococcal acute glomerulonephritis: fact and controversy. Ann Intern Med 1979; 91:76-86.