Palindromic rheumatism with rheumatoid nodules: case ... · Tivoli, 34, Avenue Max Buset, B. 7100 Le Louviere, Belgium. functionalimpairment,appearingabruptlyatirregu-lar intervals

Annals of the Rheumatic Diseases, 1986; 45, 78-81

Case report

Palindromic rheumatism with rheumatoid nodules: acase report with ultrastructural studiesSERGE SCHREIBER,*l H RALPH SCHUMACHER,2 ANDP VARGHESE CHERIAN2

From the 'Department of Rheumatology, Hospital Erasme, University Libre de Bruxelles, Bruxelles,Belgium; and the 2Hospital University of Pennsylvania and Veterans Administration Medical Center,Philadelphia, PA, USA

SUMMARY Rheumatoid nodules developed on the finger tips of a patient with palindromicrheumatism. The patient had no bone cysts or erosions and had no rheumatoid factor. A lightmicroscopic and ultrastructural study of a nodule showed a necrotic centre with fibrin, collagen,and granular material surrounded by large histiocytes, fibrocytes, lymphocytes, and vessels withadjacent mast cells as has been seen with nodules in classical rheumatoid arthritis (RA). Wedescribe the first immunoperoxidase studies on a rheumatoid nodule and have identified reactionproducts for immunoglobulins and C3 in perivascular and endothelial cell vacuoles and in thenecrotic centre.

Key words: electron microscopy, immunoglobulins, immunoperoxidase, rheumatoid nodulosis.

Palindromic rheumatism has only infrequently beenassociated with rheumatoid nodules. In one reportthree cases of such nodules and large bone cystswere termed 'rheumatoid nodulosis'. We report acase in which typical palindromic rheumatism (PR)was followed by the appearance of rheumatoidnodules in finger pads without chronic synovitis orbone cysts. We give the first ultrastructural descrip-tion of a nodule associated with PR.

Case report

A 57-year-old Caucasian man evaluated in LaLouviere, Belgium had complained of recurrentarthritis for 10 years. This consisted of bouts ofsevere pain accompanied by swelling, redness, and

Accepted for publication 20 June 1985

Correspondence to: Dr H Ralph Schumacher, Jr, Professor ofMedicine, University of Pennsylvania School of Medicine, Direc-tor, Arthritis-Immunology Center, Veterans AdministrationMedical Center, University and Woodland Avenues, Philadelphia,PA 19104, USA.

*Present address: Service de Medecine Interne, Centre Hospital deTivoli, 34, Avenue Max Buset, B. 7100 Le Louviere, Belgium.

functional impairment, appearing abruptly at irregu-lar intervals in one or occasionally in two peripheraljoints and then vanishing without sequellae within48 hours at most. Small and large joints wereaffected, and the upper limbs were more ofteninvolved. In spite of multiple therapeutic attemptswith non-steroidal anti-inflammatory drugs and withcolchicine, the painful attacks progressively in-creased in severity and in frequency; about 200crises had occurred during the last three years.The patient also noted the development over the

past six months of pea-sized firm subcutaneousnodules in the pads of the left thumb and theright third finger. One of the nodules had beenbiopsied and recurred. Light microscopy of thatnodule showed central fibrinoid necrosis surroundedby a corona of mononuclear cells in a palisade-likemanner (Fig. 1). The patient denied any othercomplaints, and physical examination betweenattacks was unremarkable except for the nodules.Blood and urine uric acid levels were within

normal limits, as were the calcium, phosphorus, andalkaline phosphatase, the acute phase reactants,haemolytic complement, C3 and C4 fractions, renal

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Palindromic rheumatism with rheumatoid nodules 79

(DAB, Sigma); they were then incubated an addi-tional 20 minutes in trometamol buffer containingDAB and 0 05% H202 for demonstration of en-zymatic activity.

_1!

Fig. 1 Central necrosis (upper left) surrounded bypalisading mononuclear cells. Light micrograph.(Haematoxylin-eosin, x40).

function, protein electrophoresis, complete bloodcount, helper/suppressor lymphocyte ratio, andurine sediment. Rheumatoid factor, antinuclear andanti-DNA antibodies, and circulating immune com-plexes were repeatedly negative. Cryoglobulin was'detected but in too small an amount for quantitativedetermination. The HLA phenotype was Al, Bw44,B8, Cw4, DR2, DR7. Joint x-rays were normalwithout any sign of erosion, demineralisation, ar-ticular or para-articular calcification, or bone cyst.The patient was put on intramuscular gold salttherapy with a dramatic effect: after 335 mg sodium3-aurothio-2-hydroxypropane-l-sulphonate no newepisode of arthritis occurred, and after the comple-tion of a 1500 mg regimen he has remained free ofsymptoms for 26 months. The nodules have re-mained unchanged.

MethodsAnother nodule biopsy was performed (after institu-tion of gold therapy) for ultrastructural study. Thiswas processed as previously described for routineelectron microscopy (EM) and immuno EM.2 3 For K.immuno EM endogenous peroxidase activity wasblocked by incubating in 3% H202 in 1% methanolfor 30 minutes. Specimens were incubated in: (a) :100 1ig/ml (mg/l) of either rabbit antihuman IgG(RaHIgM), IgA (RaHIgA), C3 (RaHC3), albumin(RaHa), or fibrinogen (RaHFi); (b) goat antirabbitIgG 1:20 dilution in phosphate-buffered saline ( )(PBS); and (c) peroxidase-antiperoxidase (rabbit)1:40 dilution in PBS as described by Stemberger.3 Fig 2 (a) Dense reaction productfor IgA in vacuolesSpecfictyontolsereuse asdescibe beore2 above nucleus (N) ofperivascular mononuclear cell.Specificity controls were used as. described before. Electron micrograph. (x24 500). (b) Punctate dense

For the immunoperoxidase reaction specimens were reaction productfor C3 in vacuoles (V) ofperivascularincubated for 20 min in a medium containing 10 ml phagocytic cell. Much ofthe granular material in the C3trometamol (TRIS)-HCl buffer at pH 7-6 with containing vacuoles is not stainedfor C3. N=nucleus.0-05% 3,3'-diaminobenzidine tetrahydrochloride Electron micrograph. (x24 500).

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80 Schreiber, Schumacher, Cherian

Results

Tissue examined by electron microscopy includedpieces containing necrotic material and vascularconnective tissue apparently from the margin of thenodule. On routine transmission electron micro-scopy necrotic areas showed cell fragments, fibrin,finely granular material, and collagen. Intact tissuecontained essentially normal appearing vessels withonly slightly prominent endothelial cells withvacuoles. Some apparent oedema dissociated layersof the basement membranes. No electron densedeposits were seen in the basement membraneareas. There were intact perivascular mast cells,scattered lymphocytes, and some apparent increasein perivascular large histiocyte-like cells and fibro-cytes. Many fibrocyte-like cells had largehomogeneous lipid deposits.With immunoelectron microscopy strongly posi-

tive peroxidase reaction products labelling for IgG,IgM, IgA, and C3 were seen in perivascular mono-nuclear cell vacuoles (Fig. 2). Weaker but definitepositive labelling was also seen in vacuoles ofvenular endothelial cells (Fig. 3). Other unstainedgranular, vesicular, and membranous material wasseen in vacuoles together with the labelled proteins.IgA seemed more likely to label entire vacuoles insome cells. The necrotic areas were not seen in all

Fig. 3 Fibrinogen reaction product (arrow) in vacuole ofvascular endothelial cell. There is also unstained granularprotein-like material in the vacuole. L= vascular lumen.Electron micrograph. (x22 700).

portions of the biopsy specimen, and necrotic areaswere stained only for IgA and C3. Positive labellingfor both these antigens was seen scattered through-out the granular material. Control sections showedoccasional very small reaction products that inno instance could be confused with the specificreactions.

Discussion

In 1944 Hench and Rosenberg described a clinicalpattern of recurrent arthritis that they namedpalindromic rheumatism (PR).4 This consisted of'multiple afebrile attacks of acute arthritis, periar-thritis, and sometimes para-arthritis, with pain,swelling, redness, and disability, generally of onlyone but sometimes more than one small or largejoints in an adult of either sex'. Outstanding featureswere the very rapid onset and disappearance of thebouts, their recurrence at irregular intervals, theabsence of roentgenographic abnormalities, and theabsence of functional or deforming residues.

Since then there have been many reports ofpatients with comparable features. In a large seriesof patients with typical PR followed up for at leastfive years Ward and Okihiro found that more than athird eventually developed rheumatoid arthritis(RA).s This order of magnitude was laterconfirmed.69 The time period for the palindromicpattern to evolve into frank RA has been as long as20 years.9Although the absence of subcutaneous nodules

has been one of the suggested clinical criteria fordiagnosing PR,8 Hench and Rosenberg found tran-sient subcutaneous nodules in three out of theiroriginal 34 patients with PR. When biopsy waspossible only non-specific inflammatory changeswere observed.4 In the subsequent studies ofpatients with PR such nodules whenever noted werealso described as of short duration except when thedisease had already evolved into frank RA.510Fascinating cases described by Bywaters in 19491"had palindromic features, classical rheumatoidnodules, including some in finger pads, and para-articular cysts and erosions.

In 1975 Ginsberg et al. reported on a seropositivepatient with typical PR who presented multiplesubcutaneous nodules and cyst-like bony radio-lucencies. 1 Biopsy of one nodule from a fingershowed a necrobiotic centre surrounded by prolifer-ating fibroblasts and histiocytes arranged in pali-sades. They found three previously publishedaccounts of similar patients with nodules and thesame radiological features, two of whom had palin-dromic attacks, and called this 'rheumatoid nodulo-sis' (RN). Recently Kaye et al.'2 described four

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Palindromic rheumatism with rheumatoid nodules 81

seronegative patients with subcutaneous nodules;one had palindromic attacks. Thirteen patientsculled from their experience and the literature fit ina proposed classification as group IIA, which was

defined as the association of rheumatoid noduleswith musculoskeletal complaints and minimal or no

chronic synovitis. Some of these patients in fact hada palindromic syndrome. Radiographic cyst-likelesions were present in all but one patient, andrheumatoid factor was found in all cases testedexcept in their own patient. All were male patientswith ages at onset ranging from 24 to 52 years. A70-year-old woman described by Dreyfus andDaupliext3 and case 2 of Herzer's series14 also fellinto this category. Our patient seems similar topatients in this group. He suffered typical palindro-mic bouts of arthritis for 10 years without chronicsynovitis or systemic illness. Subcutaneous lumpsthen appeared which under optical microscopyshowed changes characteristic of rheumatoidnodules. In contrast with most other cases, however,there was no rheumatoid factor in his serum and no

significant roentgenographic findings.The mechanisms for disease in palindromic

rheumatism are not known. An unidentified cryo-globulin was detected in the serum of our patient,but the significance of this has to be weighedcautiously: this positive finding was made during an

asymptomatic phase of the disease and several otherdeterminations have been negative thereafter. Pre-vious studies and study in our patient have shown nodecreases in serum complement levels.9 10 Thomp-son did report circulating immune complexes de-tected by a Clq binding assay in four of 19 patients. 10In an ultrastructural study of synovial biopsy speci-mens from patients with PR who later developeddefinite or classical RA one of us (HRS) showeddramatic microvascular lesions, large amounts ofcellular debris, and electron dense deposits in vesselwalls, suggesting the possible involvement of im-mune complexes.t5 Immunoelectron microscopy ofthe nodule in our patient also gave some clue to thepossible participation of immune complexes by thedemonstration of immunoglobulins and complementin vacuoles of vascular endothelial cells and peri-vascular histiocyte-like cells. There were no depositsin the vessel wall interstitium.The ultrastructure of rheumatoid nodules has

received little study and no previous immunoelec-tron microscopy. Cochrane et al.t6 in the first EMdescription of rheumatoid nodules emphasised thepresence of cell debris, collagen and reticulin fibres,and non-collagenous filaments in the necroticcentre. Hashimoto et al. 17 also described cell debris,collagen, granular and fibrin-like fibrillar material inthe nodule centre surrounded by histiocytes and

fibroblasts. Lipid was prominent in histiocytes.Giesekingt8 noted similar findings in the necroticarea, but dense deposits of granular material weresuggestive of immune complexes. He also notedlipid in the nodule wall and considered that manycells in the wall seemed to be of vascular origin. Wenoted a number of similar findings in our patientwith PR. The composition of the necrotic area andthe lipid deposits seem to be identical to those ofprevious reports.

References

1 Ginsberg M H, Genant H K, Yu T F, McCarty D J.Rheumatoid nodulosis. An unusual variant of rheumatoiddisease. Arthritis Rheum 1975; 18: 49-58.

2 Cherian P V, Schumacher H R. Immuno-electron microscopiccharacterization of intra-cellular inclusions in synovial fluid cellsof patients with rheumatoid arthritis. Ultrastruct Pathol 1983; 5:15-27.

3 Sternberger L A. lmmunocytochemistry. 2nd ed. New York:Wiley, 1979.

4 Hench P S, Rosenberg E F. Palindromic rheumatism. ArchIntern Med 1944; 73: 293-321.

5 Ward L E, Okihiro M M. Palindromic rheumatism: a follow upstudy. Arch Interamer Rheumatol 1959; 2: 208-9.

6 Mattingly S. Palindromic rheumatism. Ann Rheum Dis 1966;25: 307-19.

7 Bywaters E G L, Ansell B. In: Copeman, W S C, ed. Textbookof rheumatic diseases. 4th ed. Edinburgh and London: ChurchillLivingstone, 1970: 524.

8 Williams M H, Sheldon P J H S, Torrigiani G, Elsen V,Mattingly S. Palindromic rheumatism: clinical and immunolo-gical studies. Ann Rheum Dis 1971; 30: 375-80.

9 Wajed M A, Brown D L, Currey H L F. Palindromic rheuma-tism: clinical and serum complement study. Ann Rheum Dis1977; 36: 56-61.

10 Thompson B, Mohammed I, Holborow E J, Currey H L F.Palindromic rheumatism. II. Failure to detect circulatingimmune complexes during acute episodes. Ann Rheum Dis1976; 38: 822-6.

11 Bywaters E G L. A variant of rheumatoid arthritis charac-terized by recurrent digital pad nodules and palmar fasciitis,closely resembling palindromic rheumatism. Ann Rheum Dis1949; 8: 1-30.

12 Kaye B R, Kaye R L, Bobrove A. Rheumatoid nodules: reviewof the spectrum of associated conditions and proposal of a newclassification, with a report of four seronegative cases. Am JMed 1984; 76: 279-92.

13 Dreyfus P, Daupliex D. La nodulite rhumatoid. A propos d'uncas. Revue de la litterature. Rev Rhum Mal Osteoartic 1981; 48:441-6.

14 Herzer P, Sholz S, Fuessl H S, Schattenkirckner M. Rheuma-toid nodules without rheumatoid arthritis. Rheumatol Int 1982;2: 183-7.

15 Schumacher H R. Palindromic onset of rheumatoid arthritis.Clinical, synovial fluid, and biopsy studies. Arthritis Rheum1982; 25: 361-9.

16 Cochrane W, Davies D V, Dorling J, Bywaters E G L.Ultramicroscopic structure of the rheumatoid nodule. AnnRheum Dis 1964; 23: 345-63.

17 Hashimoto K, Yamanishi Y, Dabbous M K, Maeyens E.Collagenase activity in rheumatoid nodules. Ultra-structural invivo/in vitro studies. Acta Dermat Venereol (Stockh) 1973; 53:439-48.

18 Gieseking R. Das feinmikroskopische Bild des RhumatismusNodosus. Beitr Pathol Anat 1969; 138: 292-320.

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