REMING
`ROOM
`
`r
`
`SATURDAY 5 DECEMBE (cid:9)
`
`vr7111))
`
`CLES
`LEADING ARTI
`Placental Insufficiency page 569 Whooping-cough due to Adenovirus page 570 Penicillin
`Abnormal Bile or Faulty Gall Bladder? page 571
`Instability in Infusions page 571 (cid:9)
`Tuberculin Anergy page 573
`Ileorectal Anastomosis for Ulcerative Colitis page 572 (cid:9)
`Descent from the Ivory Tower page 574
`
` 582
`
`PAPERS AND ORIGINALS
` 575
`Mesothelioma in Scotland J. MCEWEN, ANGELA FINLAYSON, A. MAIR, AND A. A. M. GIBSON (cid:9)
`Effects of Isoprenaline Plus Phenylephrine by Pressurized Aerosol on Blood Gases, Ventilation, and Perfusion in
` 579
`Chronic Obstructive Lung Disease L. H. HARRIS (cid:9)
`Idiopathic Hypercalciuria and Hyperparathyroidism
`PETER ADAMS, T. M. CHALMERS, L. F. HILL, AND B. MCN. TRUSCOTT (cid:9)
`Glucose Tolerance and Insulin Response in Atherosclerosis
`J. M. SLOAN, J. S. MACKAY, AND B. SIIERIDAN (cid:9)
`Urinary Tract Dilatation and Oral Contraceptives P. B. GUYER AND D. DELANY (cid:9)
`Anticoagulation by Ancrod for Haemodialysis G. H. HALL, HAZEL M. HOLMAN, AND A. D. B. WEBSTER (cid:9)
`Fingerprint Changes in Coeliac Disease T. J. DAVID, A. B. AJDUKIEWICZ, AND A. E. READ (cid:9)
`Fibrosing Alveolitis Associated with Renal Tubular Acidosis
`A. M. S. MASON, M. B. MCILLMURRAY, P. L. GOLDING, AND D. T. D. HUGHES (cid:9)
`
` 586
` 588
` 591
` 594
`
` 596
`
`MEDICAL MEMORANDA
`Multiple Gastrointestinal Haemangiomata NEIL MCINTOSH AND J. HARRIS (cid:9)
`
` 600
`
`MIDDLE ARTICLES
`Reactions of Psychiatric Outpatients to Teaching
`Interviews
`R. LEVY AND J. M. M. MAIR (cid:9)
`Personal View NICHOLAS COHEN (cid:9)
`
` 613
` 616
`
`BOOK REVIEWS (cid:9)
`
`OBITUARY NOTICES (cid:9)
`
`NEWS AND NOTES
`Medicolegal—Expert Evidence (cid:9)
`Epidemiology—Fowl Pest in Man (cid:9)
`Medical News (cid:9)
`
` 611
`
` 625
`
` 627
` 628
` 629
`
`CURRENT PRACTICE
`Rheumatoid Arthritis
` 601
`Aetiology A. M. DENMAN (cid:9)
` 602
`Medical Management R. BLUESTONE (cid:9)
`Surgical Treatment G. P. ARDEN, S. H. HARRISON, AND
` 604
`BARBARA M. ANSELL (cid:9)
`Any Questions? (cid:9)
` 609
`CORRESPONDENCE (cid:9)
` 617
`SUPPLEMENT
`B.M.A.: Proceedings of Council (cid:9)
`Private Practice Committee (cid:9)
`General Medical Services Committee (cid:9)
`Medical Administrators Group (cid:9)
`G.M.C.: President's Address (cid:9)
`Association Notices (cid:9)
`
` 45
` 48
` 49
` 53
` 53
` 54
`
`No. 5735 (cid:9)
`BRITISH MEDICAL ASSOCIATION, TAVISTOCK SQUARE, LONDON WC1H 9JR
`
`British Medical Journal, 1970, Volume 4, 569-630
`
`Weekly. Price 7s.
`TEL: 01-387 4499
`
`Ex. 1036 - Page 1
`
`(cid:9)
`(cid:9)
`

`

`&441:11:4". CffTffIlf.1.41..
`5 December 1970
`
`ti,teAttne04.4{4Z4S:41-
`
`Discount Houses-contd.
`
`EVERYTHING ELECTRICAL UP TO 25%
`discount most makes. Radios. rape recor-
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`most England and S. Wales. H.P. terms. Part
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`7566.-Vanguard Electrics Ltd., 1034 Ux-
`64
`bridge Road. Hayes. Middx. (cid:9)
`
`STAFFORDS
`21% Cash Discount. Full After Sales Ser-
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`Postal Business welcome. Export enquiries
`invited. Open 6-day week. All branded
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`fully insured during transit. Write, 'phone
`or call Staffords Furnishers, Dept. 77/12,
`3 Horn Lane, Actors, London W.3. Tele-
`64
`phone 01-992 6851. (cid:9)
`
`WATCHES & JEWELLERY 25%
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`Ltd., 3 shops in Oxford St. London, all
`nr. Oxford Circus. (No dis. on Omega
`watches.) Credit terms and full discount
`now available from ALL our branches.
`Bromley (Kent), Bristol, Luton, Nor-
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`64
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`First for carpets. Up to 30% discounts
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`64
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`FURNITURE & CARPETS ETC.
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`64
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`As carpet specialists we are able to
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`Write or phone for introduction card to
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`dova Carpets, 2/4 Cross Green, Formby,
`Nr. Liverpool. Tel. Formby 74839. (cid:9)
`64
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`AZAT OFFER YOU BEST TERMS
`up to 30% discount on all electrical
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`Specialists in personal export to Pakistan,
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`visit our Show Room. Open 10 to 6
`Mondays to Fridays, Saturdays 10 to 4.
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`64
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`Coldharhour Lane, Brixton. S.W.9. 20%
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`count over the full retail price. Home and
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`64
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`UP TO 30% DISCOUNT
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`quest. London and Manchester show-
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`London, E.6, 'phone 01-472 3219. (64)
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`COHAR DISTRIBUTORS LTD.
`Up to 331% carpets, up to 271%
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`*Write giving details of your require-
`ments: Cohar Distributors Ltd. (Dept. 2),
`16 Jacob's Well Mews, George Street,
`London W.1 (mail only) 534 Sauchiehall
`Street, Glasgow C3 and 47 Oswald
`Street, Glasgow C.1 or phone Glastrow
`041-221 2771, London 01-242 2345. Bir-
`mingham 021-643 8333, Manchester
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`64
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`Save up to 40% buying wholesale/duty
`free. Cameras, etc., Radios, Hi-Fi, Tape
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`Also save on Air Travel to India, Paki-
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`day. Rockford Marketing Ltd. (Dugal
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`64
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`
`M.B.M. FURNISHERS
`Save up to 33% carpets, 271% furniture,
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`All leading makes can be supplied, free
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`delivered throughout U.K., showrooms in
`most cities. Write stating requirements, or
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`M.B.M. Furnishers, 211 Hope Street,
`Glasgow C.2.
`Tele 041 332 6170. or mail only Suite 1,
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`
`64
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`CUTLERS WAREHOUSE
`Up to 33% off branded carpets for British
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`cludes Wiltons, Axminsters, Orientals and
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`from our vast Broadloom stock. Carpet
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`Friday 9-5.30 p.m. Saturday 9.30-4.30
`p.m. Oriental Carpet Bonded Warehouse
`open Monday-Friday 10-4.30. We are now
`the proven leaders in the cut price carpet
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`
`ThiS (cid:9)
`
`E • apk2d
`
`_ (cid:9)
`
`La,.:s
`
`Ex. 1036 - Page 2
`
`

`

`5 December 1970
`
`Current Practice
`
`CLINICAL PROGRESS
`
`BRITISH
`LIRDICAL JOURNAL
`
`601
`
`Rheumatoid Arthritis
`
`Aetiology
`
`A. M. DENMAN,* M.B., B.S., M.R.C.P.
`
`British Medical journal, 1970, 4, 601-602
`
`Two fundamental questions about rheumatoid arthritis have
`Yet to be answered. What is the nature of the stimulus which
`initiates inflammation of the joints? What are the factors
`which lead to its chronicity?
`
`Role of Infection
`_rRocently interest has revived in the possible role of micro-
`organisms in rheumatoid arthritis and, indeed, in many othere
``n°11ns of chronic inflammatory disease accompanied by intendse.
`ivernunological activity." This revival is due to two main ' s
`ainpfteucPtzennts. Firstly, we now know that many forms of virus
`infection may
`not give rise to obvious signs.' Secondly, many
`Y autoimmune phenomena are found in chronic. in
`101 "nrnatory diseases known to be provoked by
`nurgmarti>isills. Furthermore, there have been an incrinealmseirnaeng-
`inna er of reports incriminating infective agents in
`
`hu
`diseatTuTiat°rY diseases of unknown aetiology and of analogous
`ses in animals.
`It is difficult to assess the significance of the reported isola-
`.
`of (cid:9)
`
`tions
`of patients with
`micro-organisms from the joints
`„,.rheumatoid arthritis. Since a true analogue of this disease
`produce
`nt0
`not occurin other species, it is not feasible to try to (cid:9)
`ani 01Y, injecting material isolated from inflamed joints
`can be
`h
`rejts• It has been claimed' that chronic polyarthritis (cid:9)
`froi7arlY transmitted to newborn mice by injecting extractstii.
`ritis, the synovial membrane of patients with rheumatoidhaerre.
`eipienand that the disease is congenitally transmitted in
`needed,
`how,.._t through three generations. Great caution is
`od ents
`rodents
`afre„`v,er• in interpreting histological appearances in
`nee'd tmlecting fairly crude material, and these experiments
`d
`be rigorously controlled.
`Particular (cid:9)
`hniques
`einpie
`attention must be given to the techniques
`is
`in culturing material from inflamed joints.
`a risk of
`isit's's1,(v)f introducing from other sources precisely those organs
`ose isolation has been most frequently claimed.One
`Por
`8 8 s. stated that diphtheroid bacilli were isolated from
`
`21 of
`of
`synovYinc'vial membranes and from 12 of 126 specimenst ..
`do oal fluid obtained from patients with rheumatoid ar lvie
`ioints telf the other hand, there were few isolations from th
`technique
`patients
`with other diseases. In contrast,, a
`in Whi (cid:9)
`
`ine„, ch the specimens were washed initially and then
`the
`fre,zted under germ-free conditions greatly redusce
`4 rtcY with which diphtheroid bacilli were isolated. d then
`
`Recovery of Mycoplasma
`There ,
`positive and
`he
`negative "aye been numerous reports—both (cid:9)
`joints
`of patie about the recovery of mycoplasma from t
`tarnin-
`ating nts with rheumatoid arthritis. The chances of connv
`iron-
`cultures With
`•
`mycoplasma from the laboratory e
`Meltbe
`Mitidjes°efx1".R.C. Scicntific Staff, Clinical Research Ccntrc, Harrow,
`
`ment are high,' and tissue culture cell lines used for inocula-
`tion may already carry this kind of organism. Despite these
`reservations, however, reports of mycoplasma infection in
`rheumatoid arthritis should not be dismissed simply on the
`grounds of probable contamination. Collateral evidence that
`patients from whose joints organisms were recovered have
`some form of specific immunological response to the same
`organisms would indicate that mycoplasmas are a genuine
`cause of infection. In general, antibodies to diphtheroids"
`or mycoplasma' have not been detected more frequently or in
`higher titre in patients with rheumatoid arthritis than in other
`conditions or in controls.
`In a recent study Mycoplasma fermentans was cultured
`from 31 of 79 synovial fluids taken from patients with
`rheumatoid arthritis, compared with 3 of 37 fluids from
`patients with other conditions.' In vitro techniques showed
`that 67% of 43 patients with rheumatoid arthritis had delayed
`hypersensitivity to Mycoplasma fermentans, a form of
`immunological reactivity not shown by control subjects. Prob-
`ably delayed hypersensitivity is important in the pathogenesis
`of rheumatoid arthritis,' perhaps synergistically with circulat-
`ing antibody."
`Another finding has been that fibroblasts derived from the
`synovial membranes of patients with rheumatoid arthritis are
`resistant to infection with rubella virus.'" This suggests that
`these cells are already colonized by some form of intracellular
`organism. Clearly, these observations need extensive confir-
`mation since most attempts at demonstrating mycoplasmal or
`viral infection by direct culture as well as more complex
`techniques have given negative results.'" Furthermore, the
`finding that a joint is infected by a particular micro-organism
`does not prove that this has a primary aetiological role. The
`hypervascular synovial membrane with its rich content of
`macrophages is an obvious nidus for secondary infection, and
`septic arthritis is a recognized complication of the disease
`even in patients who are not receiving corticosteroids."
`Nevertheless, if similar organisms are repeatedly isolated in
`different parts of the world by reasonably standardized tech-
`niques the significance of such findings will be greatly
`increased—particularly if the patients are also shown to have
`definite immunological reactions. Isolations of infective agents
`would be particularly convincing if they were made early in
`the course of the disease, preferably from patients with acute
`undiagnosed polyarthritis, before the issue was obscured by
`the secondary effects of chronic disease and its treatment. In
`many forms of experimental virus arthritis the agent can be
`recovered only in the early stages of the infection.'"
`
`Host Responses
`
`The suspicion that patients with rheumatoid arthritis suffer
`from some form of peculiar tissue response to antigens in
`
`This .-nat (cid:9)
`at the ;..L (cid:9)
`
`is!
`3-
`
`Ex. 1036 - Page 3
`
`(cid:9)
`

`

`602 5 December 1970
`
`Rheumatoid Arthritis: Aetiology—Denman
`
`BRITISH
`JOURNAl
`
`microbial agents has stimulated an intensive study of the
`factors which influence host responses in chronic inflamma-
`tion." Population studies have mostly shown only minor
`differences in the 'incidence of rheumatoid arthritis in various
`regions and have not produced any clues to its aetiology.
`Again, though seropositive rheumatoid arthritis may have a
`familial aggregation," no simple genetic mechanism can
`explain its incidence and distribution." Rheumatoid arthritis
`seems likely to be a syndrome with differing forms of clinical
`expression, representing either diseases of different aetiology
`or a wide spectrum of response to a single agent.
`Epidemiological studies in Western Nigeria suggest that the
`incidence and expression of polyarthritis may be strikingly
`modified by immunological factors. The incidence of rheuma-
`toid arthritis there was low judged by hospital data and
`population surveys," while its clinical and serological features
`differed from those in Caucasians," possibly reflecting the
`effects of chronic parasitic infection in the Nigerian
`patients."
`
`Rheumatoid Factor
`
`The role of rheumatoid factor in the pathogenesis of
`rheumatoid arthritis is still controversial, though it is known
`to be an antibody against some antigen present in the serum
`immunoglobulin G (IgG)." Rheumatoid factor is found in a
`variety of diseases characterized by prolonged antigenic stim-
`ulation, including chronic parasitic and bacterial infections"
`and in patients who have had transplants." Titres diminish
`after successful treatment of infections. Nevertheless, rheuma-
`toid factor is found more commonly and in higher titre in
`rheumatoid arthritis than in other conditions, and apparently
`healthy persons with rheumatoid factor in high titre have a
`greater than average chance of developing rheumatoid arthri-
`tis." There is a recognized correlation between vasculitis and
`other extra-articular features of rheumatoid arthritis and the
`presence of a high titre of rheumatoid factor." In synovial
`effusions aggregated IgG and globulin could combine with
`rheumatoid factor and form soluble complexes." Possibly
`these complexes fix complement," and this would explain the
`reduced concentration of complement observed in synovial
`effusions" and the rapid flux of polymorphonuclear
`leucocytes through synovial effusions.
`
`Factors in Chronicity
`
`The mechanisms concerned in continued inflammation arc
`better understood than the factors which initiate the process.
`
`Lysosomal enzymes released from polymorphs and fronl
`macrophages in the hyperplastic synovial membrane probably
`account for much of the progressive erosion of the articular
`surfaces." Nevertheless, it is unlikely that the primary defect
`in rheumatoid arthritis is an abnormal leakiness of
`lysosomes70 in the synovial membranes, whose enzymes thell
`provoke an inflammatory reaction. The functions of rheuma,
`toid factor may be primarily protective by regulating antibody
`production" or helping the clearance of antigen-antibody
`complexes from the blood." Rheumatoid factor neutralize%
`infectious virus-antibody complexes in the presence of corn,
`plement,32 while serum hepatitis antigen has been identified in
`the lesions of some patients with diffuse vasculitis.17 Clearly,
`rheumatoid factor may have many roles in the pathogenesi%
`of rheumatoid arthritis, but their relative importance is stilt
`unknown.
`This description of the immunopathological processes con,
`cerned still fails to explain why rheumatoid arthritis is 4
`chronic disease. Experiments in animals have suggested sev,
`eral possibilities including sensitization of the products of
`inflammation with a resulting autoimmune phase,"" or 4
`similar response to a virus antigen. There is little convincing
`evidence that analogous processes arc operating in the humati
`disease. No characteristic pattern of response or
`immunological aberration has consistently been shown in
`patients with rheumatoid arthritis, whether in the form of
`increased or reduced responsiveness to antigenic challenge. It
`is attractive to postulate that rheumatoid arthritis is initiated
`by delayed hypersensitivity to micro-organisms replicating
`within macrophages in the synovial membrane. If these
`widely distributed micro-organisms do initiate this chronic
`destructive process host factors must also play a major part in
`determining why only a small percentage of the population
`develop the disease. Similarly, only a minority of people
`exposed to Group A streptococci develop rheumatic fever.
`Though the belief that rheumatoid arthritis is primarily an
`autoimmunc disease has lost ground in recent years, many
`would agree that patients with this disorder may have an
`immunological defect as a result of which short-lived stimuli
`induce a persisting response, either to microbial antigens or
`cross-reacting tissue antigens.
`Possibly several micro-organisms provoke a pattern of
`immunological response in patients with rheumatoid arthritis
`which is qualitatively or quantitatively abnormal. This could
`involve cellular or antibody mediated immunity. The attrac-
`tion of this concept is that it offers a variety of experimental
`approaches.
`
`British Medical Journal, 1970, 4, 602-604
`
`Medical Management
`
`R. BLUESTONE,* M.R.C.P.
`
`The medical management of patients with rheumatoid arth-
`ritis has not benefited from any recent dramatic advances in
`therapy and is still governed by one major consideration.
`This is that the disease may be life-long and is characterized
`by spontaneous remissions and relapses. Inflamed joints may
`become so disorganized and stiff that considerable disability
`may continue long after the active synovial inflammation has
`regressed. The management must therefore concern the gen-
`eral well-being of the patient as a whole within his or her
`daily environment. Therapeutic guidelines are necessary for
`the immediate and long-term care of the patient. These
`guidelines must be flexible, designed to cope with relapses,
`and practicable to allow a relatively normal life.
`
`* Registrar and Tutor in Medicine, Department of Medicine, Royal
`Postgraduate Medical School, London, W.I2.
`
`Rest
`
`General Care
`
`Patients with painful polyarthritis, often accompanied by
`malaise, benefit greatly from a spell of rest in bed, which
`may be best achieved within hospital. After ambulation, rest-
`periods during the day and early bed-times are advisable.
`The use of mild sedatives at night is useful but drugs of
`addiction should be avoided because of the risks entailed in
`their persistent use.
`
`Diet
`
`No special dietary measures are indicated for rheumatoid
`arthritis. Nevertheless, it is worth stressing the wisdom of a
`well-balanced diet containing adequate iron, folate, and
`
`Ex. 1036 - Page 4
`
`