Ann Rheum Dis: first published as 10.1136/ard.17.3.278 on 1 September 1958. Downloaded from Ann. rheum. Dis. (1958), 17, 278. SUBCUTANEOUS NODULES OF STILL'S DISEASE* BY E. G. L. BYWATERS, L. E. GLYNN, AND A. ZELDISt From the Rheumatism Research Unit, Medical Research Council, Canadian Red Cross Memorial Hospital, Taplow, and the Postgraduate Medical School, London The observations of Collins (1937) and of Bennett, rather atypical features in the clinical presentation. Zeller, and Bauer (1940) established clearly the It is uncommon for the pathologist who is familiar pathological differentiation of the ordinary sub- with this field to make a wrong diagnosis. cutaneous nodules in rheumatic fever and in rheu- In juvenile rheumatoid arthritis, however, we have matoid arthritis. been surprised to find over the last 10 years that the In brief, the rheumatic fever nodule is charac- nodule resembles closely that of rheumatic fever, terized by much fibrinoid material arranged in a and we have therefore surveyed all our nodule lattice with apparently clear spaces between the material and correlated the findings with clinical strands, considerable oedema, but relatively little data. Apart from Findlay (1931), who illustrates a cellularity. What cells are present are usually nodule from a probable case of Still's disease fibroblasts or histiocytes; they are sparsely dis- resembling those of rheumatoid arthritis, we have tributed in the meshes of oedematous connective found no reference to such a surprising finding in the tissue and accompanied occasionally by lympho- extensive literature on rheumatic and rheumatoid cytes or rarely by polymorphs near the vascular nodules (reviewed up to 1938 by Keil (1938); and "islands" (Fig. 1, opposite). There is little attempt more recently by Horwitz (1949)). by copyright. at zoning, although vascular "islands" are a promi- nent feature. Finally, fibrosis is not often a Material and Methods conspicuous feature, and may be entirely absent. Material was available from the following sources: In contrast, the rheumatoid nodule, as seen in (1) Twelve cases of Still's disease or juvenile rheu- adults, is clearly arranged in three zones. There is matoid arthritis with onset at or before the age of 16 years. an outer zone of fibrosis with considerable infiltra- (2) 57 cases of rheumatic fever (age range 3 to tion by lymphocytes, plasma cells, sometimes poly- 49 years, including ten cases up to 10 years and morphonuclears, and rarely eosinophils. The inner- ten cases aged 21 and over, all except twelve most zone comprises necrotic debris, sometimes being below the age of 16). http://ard.bmj.com/ containing fibrinoid material but more usually (3) 22 cases of adult rheumatoid arthritis (age a grumous granular mass with fibrin, fibrinoid, and range 20 to 73 years, all except one being aged swollen collagen fibres mixed in it, sometimes con- 37 or over). taining nuclear debris, fat globules, and cholesterol This material was reviewed against a general clefts. Between the inner and outer zones lies a background of over seventy nodule examinations well-orientated layer of palisade cells, fibroblasts at the Postgraduate Medical School (unlisted and with large nuclei forming a compact border to the mostly from adult patients with rheumatoid arthritis on September 24, 2021 by guest. Protected necrotic centre zone (Fig. 2, opposite). While there is or rheumatic fever). some overlap in their individual features, a correct After formol-saline fixation, routine paraffin histological diagnosis can be made in nearly every sections (stained with haematoxylin and eosin, case (Bennett and others, 1940, give a figure of 68 thionine, periodic acid Schiff, Gomori's silver correct diagnoses in 69 patients with a firm diagnosis impregnation, Mallory's phosphotungstic acid and one wrong diagnosis in a patient in whom the haematoxylin, and occasionally by Weigert's elastin clinical diagnosis was somewhat doubtful). The stain and Masson's trichrome method) were sur- exceptions show a mixed picture which gives the veyed, and the findings were tabulated in four pathologist difficulty and leads him to issue an grades (0-3), the patient's name and clinical data uncertain report. This usually corresponds to being unknown. This grading was then correlated * Paper read at the IX International Congress of Rheumatic with the clinical diagnosis (based on detailed in- Diseases, Toronto, in June, 1957. patient observation, serological studies, joint biopsies t British Council Fellow: present address-Condell 1176, Depto. 60, Valparaiso, Chile. occasionally, and long-term follow-up), and with 278 Ann Rheum Dis: first published as 10.1136/ard.17.3.278 on 1 September 1958. Downloaded from SUBCUTANEOUS NODULES OF STILL'S DISEASE 279 ~~~~4 rc S FJ*s 4v*,4*w8g;- .,.S....... '* . * AhL ''*;^ *^ -r *e ,b abs *4a. : ; " *.~. *~r~~%t'4*04jb`~~~~~~~~5~4,4%~ -S Haematoxylin ig1.ersttvaed* efmaty 'u'. :,rheumaticfeerinafealae~~~~~~~~~~~~~~~~Y4 ~ ~ ~ ~ W 19. 1P a x 16* V ~~~~~~~~~~~~~<~~~~~~~~~~~W.75a..a a a g ~~ ~ ~ ~ % ^_w*trre., W ,~~~~~~, zXV-# ' *' v Sj~~~~~~~~~~~~~~~~''#t *:it,;#', 4 S ~~.; * * -. w , * 'A *; . * a o *a1AA' ~w ~ 4r'tN a V.L "ror ~ 9 ~ Fi.1-ersnaieaeAftpclndl rmatpcl aeo huai ee nafml gd1.Heaoyi andeosinx163. ~ ~ ~ ~ ~ ~ 4 4AP /~~~~~~~~~~~~~~~~~~~~~wN by copyright. http://ard.bmj.com/ on September 24, 2021 by guest. Protected Fig. 2.-Representative area of typical nodule from a typical case of adult rheumatoid arthritis in a man aged 40. Haematoxylin and eosin x 160. 3 Ann Rheum Dis: first published as 10.1136/ard.17.3.278 on 1 September 1958. Downloaded from 280 ANNALS OF THE RHEUMATIC DISEASES the age, sex, duration of disease, erythrocyte sedi- some necrosis (Grade 1), and a Grade 2 palisade mentation rate, and Rose-Waaler differential titre (Fig. 7, overleaf). (performed by Dr. Francis Scott using a slight Only one other boy (aged 14, onset of arthritis modification of the original method: Scott, 1952). at age 7 years) showed palisading, but in this case Nine of the twelve cases of Still's disease showed the other features (Grade 3 fibrinoid lattice, etc.) gross multiple erosions at follow-up, and one of the were such as to suggest a diagnosis of rheumatic remaining three showed a positive joint biopsy. fever. All the last three showed repeatedly negative Rose By contrast, in the adult rheumatoid arthritis tests and permanent residual deformities. group, twenty out of 22 were correctly diagnosed: the two exceptions being diagnosed as "rheumatic Results fever" and "query rheumatic fever" respectively. are tabulated in two ways (Table 1): The results The first was a girl aged 20 (onset at age 19 years, (1) The percentage of patients showing each erythrocyte sedimentation rate 34 mm./hr, Rose- feature in each group. Waaler titre 1 : 64), who 4 years later showed (2) The mean grade for each feature in each typical erosions and deformities, and the second group. was a man aged 53 with bronchiectasis and rheuma- The only feature in the Still's disease group in toid arthritis of 8 months' duration (erythrocyte which the findings resembled those in the adult sedimentation rate 90 mm./hr, differential agglutina- rheumatoid arthritis group was fibrosis. Here, both tion titre 1: 64), who later showed typical bony the incidence and the mean amount of fibrosis was erosions and deformities. The nodules appeared greater than in rheumatic fever, although not so between 2 and 12 weeks before biopsy (Fig. 8, over- great as in adult rheumatoid arthritis. Otherwise, leaf). In neither of these cases was there necrosis, the nodules of Still's disease resembled and in most fibrosis, or palisading, although fibrinoid lattice instances were indistinguishable from those of was present. rheumatic fever, showing absence of necrosis and In the larger group of rheumatic fever nodules, the by copyright. palisading and the presence of oedema, well-marked only case incorrectly diagnosed as rheumatoid vascular islands, and a fibrinoid lattice (Figs 3-6). arthritis was a boy aged 8 with typical rheumatic In only one instance was a diagnosis of rheumatoid fever and chorea for 21 months (raised antistrepto- arthritis made. This nodule came from the elbow lysin-O titre, and an erythrocyte sedimentation rate of a boy aged 13 years whose rheumatoid arthritis which had fallen from 33 to 15 mm./hr), who was had started at the age of 5 years. The disease was left at the time of biopsy with residual apical systolic still active with an erythrocyte sedimentation rate and diastolic murmurs. This nodule showed some of 71 mm./hr and a Rose-Waaler differential titre fibrosis, Grade 2 necrosis, and Grade 1 palisading, of 1: 32. The nodule showed fibrosis (Grade 3), with no fibrinoid lattice (Fig. 9, overleaf). http://ard.bmj.com/ kBLE I HISTOLOGICAL FEATURES OF RHEUMATIC AND RHEUMATOID NODULES No. Fibrosis Palisade Necrosis Oedema Vascular Fibrinoid Diagnosis of Features Islands Lattice Histological CasesExamined (Grades (Grades (Grades (Grades (Grades (Grades Diagnosis Cases ~~~~0-3) 0-3) 0-3) 0-3) 0-1) 0-3) Percentage Rheumatic on September 24, 2021 by guest. Protected Present 33 19 10 74 89 91 Fever 56 Rheumatic Fever .. 57 Mean Rheumatoid Grade 0*4 0*3 0*1 1*2 - 2*3 Arthritis 1 Percentage Rheumatic Age 16 Present 83 17 8 75 91 100 Fever 11 or Under at Rheumatoid Onset 12 Arthritis 1 Mean (DAT ± Rheumatoid Grade 1*3 0*4 0*1 1*0 - 2*2 6/12) Arthritis . Percentage Rheumatic Present 91 87 91 14 27 59 Fever 2 Rheumatoid Age 17 Arthritis 20 or Over at 22 Onset Mean (DAT+ Grade 2-2 2-0 2-5 0-2 1*0 20/21) Ann Rheum Dis: first published as 10.1136/ard.17.3.278 on 1 September 1958. Downloaded from SUBCUTANEOUS NODULES OF STILL'S DISEASE 281 Figs 3-6.-Representative areas of typical nodules from four typical cases of Still's disease, aged 8, 10, 15, and 16 years.