Origins of the Concept of Collagen-Vascular Diseases

By Michael D. Reynolds

T HE RAPID RATE of scientific discovery in recent times has resulted in equally rapid

obsolescence of much medical knowledge. One

consequence is that present day physicians some- times believe that their ideas are of more recent origin than they in fact are. Awareness of the historical background of current ideas can give a new perspective on them.

The invention of the concept of collagen-

vascular diseases usually is attributed’ to the American pathologists Klemperer, Pollack, and Baehr. In 1942, these observers pointed out that systemic lupus erythematosus (SLE) and scle- roderma both were characterized microscopi- ca.lly by “fundamental alteration of the collage- nous tissues,” and could be viewed as “systemic diseases of the connective tissues.“’ They expressed this concept by the phrase di#iise collagen disease. Klemperer3 later emphasized that this phrase was a metaphor in which col- lagen stood for connective tissue in its entirety.

The term was used “because of the conspicuous morbid manifestations of the extracellular com-

ponents, ” not because it was believed that these

diseases specifically affected the substance col- lagen.

The utility of this concept was accepted quick- ly, and the term collagen disease has now been widely used for over 40 years. Variants of the term occur; collagenosis is used by some, and secretaries frequently transcribe the phrase as Cbllagen(‘s) disease in the mistaken belief that it is an eponym. The most frequent form of the name, however, is collagen-vascular disease, which was introduced by another pathologist, A.R. Rich. In 1946, he delivered a lecture on the

apparent role of anaphylactic hypersensitivity in a “group of diseases that are highly important because of their incapacitating or lethal poten-

tialities,” including polyarteritis (periarteritis) nodosa, rheumatic fever, SLE, and rheumatoid arthritis (RA).4 Speaking about the pathologic anatomy of SLE, Rich noted that the site of the

primary lesion had been placed by some in the vascular endothelium (in fact, the term diflise vascular diseases’ was used even earlier than

difluse collagen diseases), and by Klemperer et

al in “collagen. ” “The view that the lesions of disseminated lupus may be anaphylactic in ori- gin,” Rich asserted, “obviates the need of these

divergent interpretations, for both endothelial and collagen damage are characteristic effects of focal anaphylactic reactions.” He introduced the term collagen-vascular disease to express the union of the two views of pathology.

While the original reason for grouping these diseases was similarities in their pathological anatomy, the notion of collagen-vascular diseases might not have been accepted readily by physi-

cians had there not also been clinical resem- blances among these disorders. The most im- portant unifying feature was manifestations common to all the collagen-vascular disorders, chiefly arthritis, myositis, carditis, and dermati- tis.4*6 The clinical similarities were expressed most strikingly in overlapped or mixed cases in which, either simultaneously or sequentially, a physician could diagnose two or more collagen- vascular diseases.“’

Neither the pathologic anatomical nor the clinical features of the collagen-vascular diseases

define a perfectly discrete and distinctive group of disorders. Largely because of this indistinct- ness, agreement has been lacking about which disorders should be included in the group. To the original diseases of Klemperer et al-SLE and scleroderma-soon were added rheumatic fever, RA, polyarteritis (including various arteritides), and dermatomyositis.3*6 These six disorders con- stitute the traditional family of collagen-vascular diseases. However, many other conditions have been proposed, with varying degrees of justifica- tion, for admission to the group (Table 1). The list justifies Klemperer’s warning that collagen

From the Depariment of Medicine, College of Medicine,

Howard University, Washington, DC. Michael D. Reynolds, MD: Associate Professor of Medi-

cine, Howard University College of Medicine. Address reprint requests io Michael D. Reynolds, MD,

Department of Medicine, 2041 Georgia Ave. NW, Washing-

ton. DC 20060. o 1985 by Grune & Stratton, Inc. 0049-0172/85/1502-o004$5.00/0

Seminars in Arthritis and Rheumatism, Vol 15, No 2 (November), 1985: pp 127- 13 1 127

128 MICHAEL D. REYNOLDS

Table 1. Expansion of the Concept

of Collagen-Vascular Diseases

Original concept

Systemrc lupus erythematosus

Scleroderma

Tradrtional concept

The diseases above plus rheumatic fever, RA, polyarteritis,

and dermatomyositis

Some additions proposed later

Thromboangirtis obliterans (Suerger disease)

Anaphylactoid (Henoch-Schiinlein) purpura

Chronic relapsing nonsuppurative panniculitis (Weber-Chris-

tian syndrome)

Serum sickness

Acute glomerulonephritis

Pulmonary infiltration with eosinophilia (Loffler syndrome)

Fetal endocardial fibroelastosis

Amyloidosis

Thrombotic thrombocytopenic purpura

Lipophagic granuloma (nodular symmetrical liposclerosis)

Disseminated eosinophilic collagen disease

Sjiigren syndrome

Idiopathic midline granuloma

Cogan syndrome

Ankylosing spondylitis

Primary pulmonary hypertension

Scleredema adultorum

Idiopathic retroperitoneal fibrosis

Sarcoidosis

Relapsing polychondritis

Mixed connective tissue disease

Pulmonary fibrosis with pneumoconiosis

disease “may become a catch-all term for mala- dies with puzzling clinical and anatomical fea-

tures.“3 Although Klemperer, Pollack, and Baehr

called attention to the observation that connec- tive tissue is affected systemically in certain rheumatic diseases, this idea did not originate with them. They themselves credited the German pathologist Fritz Klinge with demonstrating in the 1930s “widespread involvement of the connective tissues in rheumatic fever,“* and Klemperer later averred that “the idea that the characteristic organ and tissue alterations in rheumatic fever and rheumatoid arthritis reflect a systemic involvement of the entire connective tissues of the human body was first proposed by Klinge.“3

A look at Klinge’s observations shows that his ideas were much broader in scope. Klinge regarded a distinctive reaction of the connective tissue as characteristic not only of rheumatic fever and RA, but also of osteoarthritis, spondyli-

tis, muscular rheumatism (fibrositis), and neu-

ralgia.sS9 In an important monograph on rheu- matism published in 1933, Klinge presented a contemporary classification of rheumatic dis- eases and commented, “such classification . . according to the anatomical-clinical viewpoint

. . . does not correspond to the real character of the diseases, the natural facts, if one regards all

individual forms of rheumatism as diseases dif- ferent from one another . . . the same ‘rheuma- tism’ affects the joint, the tendons, muscles, the nerves. . . .” Continuing, he asserted that “there is a uniform rheumatic reaction of the tissues” and that “the tissue . . . in which the principal events in rheumatism occur, the true rheuma- tism-tissue, [is] the mesenchyme, the loose and dense connective tissue, the vascular tissue.“’

Although Klinge’s writings were based on his own pathologic investigations of rheumatic dis- eases, his ideas were descendants of beliefs that

long antedated his studies. The idea of rheuma- tism, for most of Klinge’s predecessors in the 19th and early 20th centuries, included acute articular rheumatism (rheumatic fever), chronic articular rheumatism (which often was synony- mous with RA, and sometimes also meant osteoarthritis), and muscular rheumatism (fibro- sitis). This concept of rheumatism was still extant when Klinge discussed the classification of rheumatic diseases in the 1930~~ For genera- tions before that time, it was generally accepted that the seat of rheumatism was principally, if not exclusively, in fibrous tissues. Thus, 86 years

before Klinge’s monograph, a German medical text stated, “it is a proven fact, that the rheu- matic affections are localized preferentially in fibrous and serous parts-in tendons, muscles, articular membranes, in the intercellular tissue of muscle, in the serous membranes, in the neurilemma. . . . “lo This idea was expressed repeatedly by writers of German medical books,“-” and the same opinion about the histo- logic site of rheumatism was held by physicians in France and Britain.16

The only variation in the view that rheuma- tism was a disorder of fibrous tissue was found among physicians who believed that it also affected other tissues such as bone, cartilage, and skin.“-19 Because of the frequent occurrence of rheumatic symptoms in the muscles, some observers regarded both fibrous and muscular

CONCEPT OF COLLAGEN-VASCULAR DISEASES 129

tissues as the site of rheumatism,‘2*‘9,20 but others raised the question whether the muscular tissue itself, or the fibrous or intercellular tissue sur- rounding or within the muscle, was the seat of the manifestations of muscular rheumatism.“*‘4.‘5. 2’-23 A second apparent exception to the notion that rheumatism was a disease of fibrous tissue

was the obvious presence of synovitis in articular rheumatism, and the recognition during the 19th century that acute rheumatism affected the endocardium and pericardium. These phenom- ena were responsible for the frequent statements

that serous (or serofibrous or fibroserous) tissues also were a site of rheumatism.‘03’3-‘* As in the case of muscle, the question was raised whether the serous tissues were a primary location of the disorder, or whether they were affected only secondarily or incidentally.“*20,23

The idea that rheumatic diseases primarily

affect fibrous tissue is attributed’s324 to the founder of histology, the French physician Xa- vier Bichat. In his General Anatomy Applied to Physiology and Medicine,25 Bichat in 1801 clas- sified under the term jbrous system organs composed of tough fibers, including membranes such as the periosteum and dura mater, articular capsules, tendons and their capsules and aponeu- roses, and ligaments. This system thus corre- sponded closely to what today would be called dense connective tissue. What would now be called loose or areolar connective tissue was

regarded by Bichat as a separate system, the cellular system.

In discussing the fibrous system, Bichat

remarked that “rheumatism . . . appears very probably to affect this system,” and stated that “acute rheumatisms . . . affect principally the fibrous parts of the large joints of the shoulder,

the hip, the knee, the elbow, etc, the aponeurotic parts of muscles, etc.“25 In 1825, after Bichat’s death, a book based on notes made during his lectures was published under the title Pathologic ,slnatomy. In this work, Bichat is quoted as saying, “It is incontestable that rheumatism

sometimes is situated in fibrous tissue, as when it affects the joints. . . . It appears that this increased exudation of the synovial membranes ].in articular rheumatism] is purely symptomatic, and that the principal affection is in the ten- dons.” Discussing muscular rheumatism, Bichat remarked, “One does not know which is its

special seat; one can hardly believe that the muscles and the tendons, in view of their dif- ferent structure, share the seat of rheumatism. It appears to affect alternatively one and the other: the question is knowing if the malady is truly in the muscular fiber or in the tendinous

fiber. . . .“*(j Physicians who followed Bichat, although they

also wrote about fibrous tissue as the seat of

rheumatism, often included under that term the cellular system of Bichat, or loose connective tissue, as well. This is apparent from the refer- ences to cellular or interstitial tissue,“,“.” and to “fibroserous” structures, which surely included what Bichat described as submucous and subse- rous cellular tissue. That both dense and loose connective tissue were affected by rheumatism was most explicitly stated by William Balfour of

Edinburgh: “[It is] highly probable that there is in rheumatism, chronic as well as acute, an affection of the aponeurosis of the muscles, and perhaps of the whole cellular substance con- nected with them. . . . The cellular membrane abounds everywhere in the human body. It covers the whole, and connects every part.” Balfour specifically noted that blood vessels and the fasciculi and fibers of nerves and muscles are surrounded and connected by “cellular tissue.” “We know,” he continued, “that it officiates at once as fascia, a ligament, a mucous gland. . . .” Balfour then adduced several reasons for believ- ing that “the cellular membrane is principally affected in rheumatism.“22

Thus, for many 19th century physicians, fibrous tissue evidently corresponded to what a present day anatomist would call connective tis- sue, excluding cartilage and bone. The synonymy of these two terms was shown explicitly in early 20th century works on rheumatism, in which the term connective tissue supplanted$brous tissue. For example, Quincke in 1917 cited Virchow’s handbook of pathology in support of the view that “connective substances” are the principal

seat of rheumatism.*’ However, the handbook did not use the phrase connective tissue, but rather jibrous tissue.13 An identical meaning of the two terms was presumed without comment by Quincke. In Britain, the notion that nonar- titular rheumatism was an inflammatory disor- der of fibrous tissue came to be expressed in the term jbrositis. In the lecture in which he intro-

130 MICHAEL D. REYNDLDS

duced this word, the neurologist William Gowers regarded connective tissue as one type of fibrous tissue: “Fibrous tissue, or connective tissue, as it is termed in its looser form. . . .“‘* However, other British physicians of the early 1900s used the terms fibrous tissue and connective tissue interchangeably when describing the pathologic anatomy of chronic rheumatism or fibrositis.29*30

tissue in the affected organs; the same argument was put forth in the 19th century to account for supposed visceral manifestations of rheuma- tism.*’

The idea of rheumatism from Bichat to

Klinge, and the concept of collagen-vascular diseases, share other features besides their local- ization of rheumatic diseases in collagenous tis-

sue. Rheumatic fever and RA are included in both groups of disorders, although this is not always obvious, because of the variability of the names and descriptions of these two conditions during the period under consideration. (Muscu- lar rheumatism, as its name indicates, is not a systemic disorder, and was not subsumed in the collagen-vascular diseases. The connective tissue disorders SLE, scleroderma, polyarteritis, and dermatomyositis were described during the period 1845 to 1890,’ and did not enter into the development of the 19th century view of rheuma- tism. Even after they became generally recog- nized as disease entities, there was no tendency to regard them as forms of rheumatism. They are

not even mentioned in the classification of rheu- matic diseases presented by Klinge.)

Evidently, the concept of rheumatic diseases as systemic disorders of connective tissue was not

an invention of Klemperer and his associates, nor of Klinge, but has existed since the early 19th century. Klinge’s ideas about the nosology and histologic site of rheumatism were essentially the same as those of physicians a century earlier, although his theories about the etiology and pathogenesis of the disease were offsprings of the still young sciences of bacteriology and allergolo- gy. Insofar as it derived from Klinge’s views, the concept of collagen-vascular disease also has its roots in Bichat’s statement that rheumatism is situated in fibrous tissue.

Another feature common to the concepts of

rheumatism and collagen-vascular diseases is their characterization of rheumatic disorders as affecting not only the locomotor apparatus, but a large number of internal organs as well.‘“~“~‘6~‘7~20 Visceral involvement by collagen-vascular dis- eases is explained by the presence of the target

The idea of diffuse collagen disease introduced by Klemperer et al differed from the previous notion of rheumatism in two major ways. First, it defined a group of diseases in terms of their histologic site. (Conversely, rheumatism was already demarcated on other grounds before it

was postulated to affect a particular tissue.) Second, it ascribed diffuse involvement of con- nective tissue only to disorders whose systemic

features were prominent and indisputable. Thus revised, the idea that rheumatic diseases prefer- entially affect connective tissue has been useful to modern physicians. From a historical perspec- tive, however, it appears likely that the notion of collagen-vascular diseases will seem as quaint to our successors as the last century’s view of rheu- matism now seems to us.

REFERENCES

1. Benedek TG, Rodnan GP: A brief history of the rheu- tivity: So-called diffuse collagen disease. Am Practit 1: 113-

matic diseases. Bull Rheum Dis 32:59%68, 1982 121,195o

2. Klemperer P, Pollack AD, Baehr G: Diffuse collagen

disease: Acute disseminated lupus erythematosus and diffuse

scleroderma. JAMA 119:331-332, 1942

3. Klemperer P: The concept of collagen diseases. Am J

Pathol26:505-519, 1950 4. Rich AR: Hypersensitivity in disease, with especial

reference to periarteritis nodosa, rheumatic fever, dissemi-

nated lupus erythematosus and rheumatoid arthritis. Harvey

Lect 421106-147, 1947

5. Banks BM: Is there a common denominator in sclero-

derma, dermatomyositis, disseminated lupus erythematosus,

the Libman-Sacks syndrome and polyarteritis nodosa? N

Engl J Med 225:433-444, 1941

6. Kampmeier RH: Vascular diseases due to hypersensi-

7. Short CL: Rheumatoid arthritis: Historical aspects, J

Chronic Dis 10:367-387, 1959

8. Klinge F: Der Rheumatismus: Pathologisch-anatom-

ische und experimentell-pathologische Tatsachen und ihre

Auswertung ftir das irztliche Rheumaproblem. Ergeb Allg

Pathol 27:1-351, 1933

9. Klinge F: Zur pathologischen Anatomie des Rheuma-

tismus. Verh Dtsch Orthop Ges 28:44-50, 1934

10. Canstatt C: Die Specielle Pathologie und Therapie

vom Klinischen Standpunkte aus Bearbeitet. Vol 2, part 2.

Erlangen, Enke, 1847, pp 615,656-658

11. Eisenmann G: Die Krankheits-Familie Rheuma. Vol

1. Erlangen, Enke, 1841, pp 33-34, 167, 172

CONCEPT OF COLLAGEN-VASCULAR DISEASES 131

12. Hiibener EA: Specielle Pathologie und Therapie. Vol

2. Erlangen, Enke, 1852, p 114

13. Vogel J: Rheumatismus und Gicht, in Virchow R (ed):

Handbuch der Speciellen Pathologic und Therapie. Vol 1.

Erlangen, Enke, 1854, pp 471-505

14. Lebert H: Handbuch der Praktischen Medicin. Vol 2.

Tiibingen, Laupp, 1859, p 842

15. Kissel C: Handbuch der Speciellen Pathologie und

Therapie. Vol 1. Erlangen, Enke, 1853, p 585

16. Fuller HW: On Rheumatism, Rheumatic Gout, and

Sciatica, Their Pathology, Symptoms, and Treatment. New

York, Wood, 1854, pp 50-51

17. Macleod R: On Rheumatism in its Various Forms,

and on the Affections of Internal Organs, More Especially

the Heart and Brain, to Which it Gives Rise. London,

L.ongman, Brown, Green, and Longmans, 1842, pp 5, 8, 16

18. Todd RB: Practical Remarks on Gout, Rheumatic

Fever, and Chronic Rheumatism of the Joints. London,

Parker, 1843, pp 138-141

19. Hoffmann FA: Lehrbuch der Constitutionskrankheit-

en. Stuttgart, Enke, 1893, p 223

20. Fabre AFH: Rhumatisme, in Fabre AFH (ed): Dic-

tionnaire des Dictionnaires de Medicine Francais et Etran-

gers. Vol 7. Paris, Germer-Bailliere, 1841, pp 71-93

21. Chomel AF: Essai sur le Rhumatisme. Paris, Didot

Jeune, 1813, ~~9-12

22. Balfour W: Observations on the pathology and cure of

rheumatism. Edinb Med Surg J 11:168-187, 1815

23. Bouillaud J: Trait& Clinique du Rhumatisme Arti-

culaire, et de la Loi de Coincidence des Inflammations du

Coeur avec cette Maladie. Paris, Bailhere, 1840, p 3

24. Klinge F: Der “Rheumatismus’‘-Begriff in geschicht-

lither Betrachtung. Jahresk Aerztl Fortbild 24:1-16, 1933

25. Bichat X: Anatomie GinCrale Appliqute a la Physiol-

ogie et a le Medicine. Vol 3. Paris, Brosson, Gabon, 1801, pp

145-151, 174,167

26. Bichat X: Anatomie Pathologique. Paris, Bailliere,

1825, pp 251-252

27. Quincke H: Ueber Rheumatismus. Dtsch Med

Wochenschr 43:993-996, 1030-1033, 1917

28. Gowers WR: Lumbago: Its lessons and analogues. Br

Med J 1:117-121, 1904

29. Stockman R: The causes, pathology, and treatment of

chronic rheumatism. Edinb Med J 15:107-l 16, 223-235,

1904

30. Telling WHM: “Nodular” fibromyositis, an everyday

affection, and its identity with so-called chronic muscular

rheumatism. Lancet 1:154-158,191l