treatment of panniculitis

Annals ofthe Rheumatic Diseases 1990; 49: 788-792

Treatment with cimetidine of atypical fasciitispanniculitis syndrome

J E Naschitz, D Yeshurun, I Rosner, J E Abrahamson, I Misselevitch, J H Boss

AbstractThree patients presented with septal fasciitisand panniculitis, associated with clinical andlaboratory features which precluded straight-forward classification into eosinophilicfasciitis, localised scleroderma, or lupus ery-

thematosus profundus. Treatment with cime-tidine caused the remission of cutaneousmanifestations and the extracutaneousabnormalities, such as nailfold capillary dis-turbances and the presence of antithyroidantibodies, improved.

It is concluded that features of eosinophilicfasciitis or localised scleroderma and certainadditional atypical elements should be cat-egorised as atypical fasciitis-panniculitissyndrome.

Septal fasciitis associated with panniculitis is a

common feature of localised scleroderma, lupuserythematosus profundus, and eosinophilicfasciitis.' Although the latter disorders havebeen well characterised their pathogeneticmechanisms are elusive and their distinction isbased on descriptive rather than strict diagnosticcriteria; overlapping features are common.2We describe three patients, who, in addition

to similar and distinct fasciitis and panniculitis,featured diverse extracutaneous symptoms. Theclinical presentation and laboratory findings inthe individual patients did not fall into any ofthe well known fasciitis-panniculitis disorders.

Patients and methodsThree patients with what we termed atypical

fasciitis and panniculitis syndrome (AFPS) were

treated in our department over three years. Apatient was defined as having AFPS when thefollowing criteria were met: (a) an illnessresembling either eosinophilic fasciitis, localisedscleroderma, or lupus erythematosus profunduswas associated with additional features of a

collagen-vascular disease or a vasculitic disorder;(b) histological examination disclosed a primarilyseptal fasciitis and panniculitis.l5 Infectiousand paraneoplastic fasciitides were excluded.'Laboratory findings, being non-specific, were

not included among the criteria. Microscopicexamination of nailfold capillaries was per-

formed using previously described tech-niques.7 8 Cimetidine, given orally in a dailydose of 800 mg, was continued up to the time ofwriting. The relevant clinical and laboratorydata on the patients are summarised in thetable. Improvement was assessed by twoobservers (JEN and DY), who consecutivelymeasured the circumference and estimated theseverity as well as the extent of subcutaneousinduration of the affected segment; significantreduction ofthe circumference and normalisationof the palpatory findings were considered to bean indication of complete recovery (100%),while partial improvement was estimated andexpressed as a percentage.

Case historiesCASE 1

The patient's clinical course has been previouslydescribed in detail.9 Briefly, the 70 year oldpatient, who was under observation for a

Bnai Zion MedicalCenter and the Faculty ofMedicine, Technion,Israel Institute ofTechnology,Haifa, IsraelDepartment ofMedicine AJ E NaschitzD YeshurunRheumatology ServiceI RosnerDepartment of Surgery BJ E AbrahamsonInstitute of PathologyI MisselevitchJ H BossCorrespondence to:Dr J E Naschitz,Department of Medicine A,Bnai Zion-Medical Center,PO Box 4940, Haifa 31480,Israel.Accepted for publication3 November 1989

Clinical and laboratory data

Case I Case 2 Case 3

Age (years) 70 54 34Sex Male Female MaleCutaneous features

Site Forearms and calves Thighs and calves Abdomen, arm andforearm

Shape Diffuse Diffuse Plaque and linearType Tight induration Puffy to firm Induration and alopecia

Extracutaneous features Pericarditis, colitis, Polyarthritis Nonecarpal tunnel syndrome

Microscopy of nailfold capillaries Normal Normal Focal loss, distortion,and dilatation

Blood eosinophils (x109/l) 650 240 290Immunoglobulins Lambda spike Polyclonal increase IgE 820 U/mIllClinical course:

Duration (months)* 14 12 6Onset of regression (months)t 2 1 2

Grade of improvementCutaneous (%)N 90 80 80Extracutaneous (%)§ 100 0 80

Follow up (months)t 36 7 15

*Duration refers to time interval between first signs and diagnosis.tOnset of regression refers to time interval between start of cimetidine treatment and regression of cutaneous lesion by one or more

centimetres.*Follow up refers to observation period after start of cimetidine treatment.Percentage of improvement is an estimate of disease at the time of writing compared with that at the time of diagnosis.Normal value 100 U/ml.

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Treatment wiuh cimetidine ofatypicalfasciitis panniculitis syndrome

monoclonal gammopathy, developed bilateralcarpal tunnel syndrome and brawny indurationof the forearms and calves. Peripheral bloodeosinophilia and antithyroglobulin antibodieswere found. Biopsy specimens showed septalfasciitis and panniculitis with an eosinophil-richinfiltration. Treatment with cimetidine wasstarted. Improvement of skin induration wasnoted after two months and the eosinophilcounts returned to normal, but the patientdeveloped pericarditis and eosinophilic colitisthree and eight months, respectively, after thestart of treatment. In the absence of othercauses the pericarditis and colitis, which remittedwithin a few weeks, were attributed to theunderlying fasciitis-panniculitis syndrome.With long term cimetidine treatment thecutaneous manifestations disappeared almostcompletely; the thyroid antibodies were nolonger detectable.

CASE 2A 54 year old patient first noticed numbnessand swelling of the calves as well as morningstiffness of hand and ankle joints eight monthsbefore initial examination. Symmetrical arthritiswas observed. A variety of non-steroidal anti-inflammatory drugs was taken without benefit.Four months later, at admission to our ward,the legs were swollen and indurated, andsymmetrical, non-erosive polyarthritis wasnoted. Nuclear antibodies and rheumatoid factorwere not found. A biopsy specimen showedseptal and lobular panniculitis, a fibroticallythickened and mildly inflamed fascia (fig 1),

Figre I Severely thickenedfascia (F), coalescent with asomewhat thickened septum (S). Thefascia is composed ofdense collagenous connective tissue and contains severalfociofmononuclear cell infiltrates. (Haematoxylin and eosin.)

lymphocytic phlebitis (fig 2), dermal as well assubcutaneous perivascular, mononuclear cellinfiltrates, a rare occluded small vein in thedense collagenous tissue of the thickened sub-cutaneous septa, and a few epithelioid celledgranulomas (fig 3). The inflammatory infiltrateconsisted predominantly of lymphocytes withsome admixed histiocytes and plasma cells;eosinophils were not evident. Extensive clinicaland laboratory work-up and imaging proceduresdid not show that other organ systems wereaffected. At this time, the patient was givencimetidine. After four months of treatment theindurations decreased to a considerable extent.As morning stiffness and joint tenderness per-sisted, prednisone (40 mg daily) was given for10 days and the articular symptoms (but not theresidual skin induration) improved. The patientwas still taking cimetidine at the time ofwriting.

CASE 3Two years before presentation the 34 year oldpatient had a myocardial infarction and wastreated with quinidine bisulphate for six months.During the intervening period he was asympto-matic and did not take any drugs. The patientfirst noticed paraumbilical and forearm skinindurations six and three months, respectively,before admission. He had no fever. The lesionswere not painful or tender but enlarged progres-sively. On admission, a whitish, alopecic, ovaland firm lesion, measuring 5 x 3 cm, was foundin the right paraumbilical region. A linear, firm,skin coloured lesion, about 1 cm in diameter,extended from the radial aspect of the rightwrist to the axillary fold. A biopsy specimen ofthe forearm lesion showed extensive chronicdermatitis, panniculitis, and fasciitis. There wasbroad-banded collagen fibrosis of the lowerdermis with entrapment of the adnexae. Theseverely thickened subcutaneous septae andfascia contained infiltrates of lymphocytes,plasma cells, and histiocytes as well as manymast cells. The blood vessels were thick walledand a mural, mononuclear cell infiltrate wasapparent in many veins. Microscopical examin-ation of the capillary nail bed showed extensiveavascular areas as well as occasional aneurysmaldilatation of capillary loops. After treatmentwith cimetidine the linear induration of theupper extremity disappeared completely withineight months, while the paraumbilical plaquedecreased to a size of 3 x I 5 cm and softened.The normal skin colour reappeared and the hairregrew. Repeat microscopical examination ofcapillaries showed regular capillary loops withoccasional avascular areas.

DiscussionThe atypical fasciitis-panniculitis syndromepertains to the scleroderma syndrome complex,which, by current classification, includessystemic sclerosis, CREST (calcinosis, Ray-naud's phenomenon, oesophageal dysmotility,sclerodactyly, telangiectasia) syndrome, local-ised scleroderma, chemically induced symptomssimilar to scleroderma, eosinophilic fasciitis,

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Naschitz, Yeshuun, Rosner, Abrahamson, Misselevitch, Boss

Figure 2 Lymphocyticphlebitis. A normal arteryadjacent to a severelyaffected vein, the lunen ofwhich is subtotally occludedby an intimal cushion, thelatter as well as the mediaand adventitia being heavilyinfiltrated by apredominantly lymphocyticinfiltrate. (Haematoxylinand eosin.)

Figure 3 Subcutaneousgramdoma. Discreteaggregate ofepithelioidhistiocytes and lymphocytesin the subcutaneous fattissue. (Haematoxylin andeosin.)

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pesudoscleroderma, and a variety of rarescleroderma-like disorders.2 Within this frame-work panniculitis with associated fasciitis ishistologically distinct and has been described ineosinophilic fasciitis, localised scleroderma, andlupus erythematosus profundus.' 3 10 Theclinical diagnosis of any one of the latterconditions is easily made in patients with typicalsymptoms.

Eosinophilic fasciitis is characterised bysymmetrical, usually widespread inflammationand sclerosis of the fascia, subcutis, and dermis,primarily affecting the extremities. Raynaud'sphenomenon, ulceration of the finger tips,telangiectasias and visceral disease are rare.Eosinophilia, hypergammaglobulinaemia, and

an increased erythrocyte sedimentation rate arethe main laboratory findings.' 3 Localisedscleroderma presents as either the morphoea orlinear variant. The former manifests porcelaincoloured indurations with sharp violaceousborders; in the latter there is a band-like, skin-coloured induration confined to the limb orfacial skin. Raynaud's phenomenon and visceraldisease are absent. In contrast with the histo-logically identical progressive systemic sclerosis,the prognosis of localised scleroderma is favour-able.'0 11 Lupus erythematosus profundus is alupus variant which affects the dermis andsubcutis and is histologically similar to eosino-philic fasciitis. The patient presents with wellcircumscribed, subcutaneous nodules that are

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Treatment with cimetidine ofatypicalfasciitis panniculitis syndrome

not tender. Lupus erythematosus profundusfrequently occurs as an isolated disorder, but itmay be associated with discoid or systemiclupus erythematosus.' 11

In our experience, in a patient with panni-culitis-fasciitis the clinical diagnosis may beuncertain because of several atypical features:the concurrent presence of two different derma-tological lesions, variable intensities of thecutaneous features, diverse extracutaneousmanifestations, and unusual laboratory orcapillary microscopical findings. The variabilityof the clinical picture may give rise to perplex-ing diagnostic dilemmas. Thus in our firstpatient, eosinophilic fasciitis evolved in theframework of a multisystem disease9 contradict-ing the dictum that, while involvement of one

visceral organ occurs in less than 10% of cases,

several organs being affected is practicallyunknown.2" The clinical importance of thyro-globulin antibodies and monoclonal gammo-

pathy in this patient was unclear. Concurrentseronegative polyarthritis and eosinophilicfasciitis, found in our second patient, haverarely been described.2 12 13 Whether the twoare aetiologically related or merely constitute anincidental association cannot be determined atpresent. In case 2 a few epithelioid cell granu-lomas and phlebitis were found in the inflamedsubcutaneous tissue; though not characteristicof eosinophilic fasciitis, both these findingshave been previously described in rare

instances.2 14 The plaque-like morphoea andlinear scleroderma in our third patient were

found simultaneously with severe abnormalitiesof the nailfold capillaries, which were some

distance from the site of the cutaneous lesions.Although such microvascular injury does notcharacterise localised scleroderma, it is associatedwith progressive systemic sclerosis.7 8 As thepatient's illness does not satisfy any of theAmerican Rheumatism Association's criteria forscleroderma,'5 the diagnosis of progressivesystemic sclerosis cannot be entertained, thoughthe abnormalities of the nailfold capillaries maypredict the development of this disease. More-over, the increased serum IgE concentrationand tissue mast cell infiltration are not com-

ponents of any of the subtypes of sclerodermaand add to the lack of defmnition of the AFPS inthis instance. Thus, in conclusion, we proposethat a definite diagnosis in these patients is bestdeferred and a tentative diagnosis of atypicalfasciitis-panniculitis syndrome is preferred.The prognoses of typical fasciitis-panniculitis

syndromes are favourable, whereas the outcomeof AFPS, as we have presented it, is currentlyunknown. The treatment ofpatients with typicaleosinophilic fasciitis and localised sclerodermais controversial and the efficacy of any modalityof treatment has only recently been questioned.2Initial reports have suggested that eosinophilicfasciitis responds favourably to cortico-steroids.'4 16 This has not been universallyvalidated, however, and a satisfactory responsehas been witnessed in less than two thirds ofpatients.2 Other drugs have been tried, includ-ing azathioprine,17 D-penicillamine,17 chloro-quine,'5 and cimetidine.'9 Because of the smallnumber of reported patients treated with these

drugs, the therapeutic efficacy has not beenclearly established. Furthermore, the obser-vation that four of five untreated patients inone series improved spontaneously2 casts doubton the value of any modality of treatment.Our patients' disease improved with cime-

tidine. We submit that a true therapeutic effectoccurred rather than a merely coincidentalimprovement for the following reasons. Beforecimetidine treatment was started the patients'disease progressed for eight to 18 months; whilereceiving cimetidine, a turning point was evidentwithin one to two months, which interval isconsiderably less than that usually required forcorticosteroids to be effective in similar dis-orders.2 It should be noted that we did not addany anti-inflammatory drugs to the patients'regimen. Similar beneficial effects have beenreported in the treatment of eosinophilic fasciitiswith cimetidine by others.'W22 Four of fivepatients improved within several days to a fewmonths after starting treatment. Finally, con-comitant with the remission of the cutaneousmanifestations, extracutaneous abnormalities ofthe AFPS also improved in our patients. Anti-thyroid antibodies were no longer detectable(case 1) and nailfold capillary disturbancesimproved (case 3). Pericarditis and colitis,which developed early in the course ofcimetidinetreatment (case 1), remitted without additionalmedication. On the other hand, smoulderingpolyarthritis (case 2) remained unchanged.The pharmacological effects of cimetidine on

immunologically mediated disorders are at leastpartly attributed to its interference with theaction of histamine on membrane bound H2receptors of suppressor T lymphocytes.2125 Itis of interest in this context that there was aconspicuous mastocytic infiltration of the lesionin the patient with localised scleroderma. Theexcellent response of mast cell-associated dis-orders to H2 antagonists is well known.26Although neither the pathogenetic mechanismsoperative in patients with AFPS nor the path-ways of the beneficial effects of cimetidine areclear, our observations encourage further trialsof this agent in scleroderma-like conditions.

In conclusion, we have described threepatients with features of eosinophilic fasciitis orlocalised scleroderma and certain additionalatypical elements. The histological findings ofthe patients' lesions had fasciitic and panniculiticchanges in common. A favourable therapeuticresponse to cimetidine was observed. We sug-gest that it is inappropriate to include thesecases within the well established nosologicalentities of eosinophilic fasciitis or localisedscleroderma but that it would be more appro-priate to categorise them separately as atypicalfasciitis-panniculitis syndrome. Our experienceindicates that these patients and possibly otherswith similar disorders may benefit from treat-ment with cimetidine.

We thank Mr Eliahu Srugo for his photographic assistance.

1 Ackerman B A. Histologic diagnosis of inflammatory skindiseases. A method by pattern analysis. Philadelphia: Lea andFebiger, 1978: 792.

2 Lakhanpal S, GinsburgW W, Michet C J, Doyle J A, Moore

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S B. Eosinophilic fasciitis: clinical spectrum and therapeuticresponse in 52 cases. Semin Arthritis Rheum 1988; 17:221-31.

3 Barnes L, Rodnan G P, Medsger T A Jr, Short D.Eosinophilic fasciitis. A pathologic study of 20 cases. AmJPathol 1979; 96: 493-507.

4 Rocco V K, Hurd E R. Scleroderma and scieroderma-likedisorders. Semin Arthritis Rheum 1986; 16: 22-69.

5 Shiel W C Jr, Prete P E, Jason M, Andrews B S. Palmarfasciitis and arthritis with ovarian and non-ovarian carcino-mas. New syndrome. AmJ Med 1985; 79: 640-4.

6 Pfingsgraff J, Buckingham R B, Killian P J, et al. Palmarfasciitis and arthritis with malignant neoplasms: A para-neoplastic syndrome. Semin Arthritis Rheun 1986; 16:118-25.

7 Rozboril M B, Maricq H D, Rodnan G P, Jablonska S, BoleG G. Capilary microscopy in eosinophilic fasciitis. Acomparison with systemic sclerosis. Arthritis Rheum 1983;26: 617-21.

8 Wong M L, Highton J, Palmar D G. Sequential nailfoldcapillary microscopy in scleroderma and related disorders.Ann Rheum Dis 1988; 47: 53-61.

9 Naschitz J E, Yeshurun D, Misselevitch I, Boss J H. Colitisand pericarditis in a patient with eosinophilic fasciitis. Acontribution to the multisystem nature of eosinophilicfasciitis. J Rheumatol 1989; 16: 688-90.

10 Jablonska S, Rodnan G P. Localised forms of scleroderma.Clin Rheum Dis 1979; 5: 215-41.

11 Winkelmann R K. Panniculitis in connective tissue diseases.Arch Dermnatol 1983; 119: 336-44.

12 Rosenthal J. Benson M D. Diffuse fasciitis and eosinophiliawith symmetric polyarthritis. Ann Intern Med 1980; 92:507-9.

13 Olson N Y, Lindsley C B, Kepes J J. Eosinophilic fasciitispresenting as inflammatory polyarthritis. Pediatrics 1986;78: 512-4.

14 Moore T L, Zucker J. Eosinophilic fasciitis. Semin ArthritisRhewn 1980; 9: 228-35.

15 Masi A T, Rodnan G P, Medsger T A Jr. Preliminary criteriafor the classification of systemic sclerosis (scleroderma).BuU Rheum Dis 1981; 3: 1-6.

16 Shulman L E. Diffuse fasciitis with hypergammaglobulinemiaand eosinophilia: A new syndrome? J Rheumatol 1974; 1(suppl): 46.

17 Nassonova V A, Ivanova M W, Akhnazarova V D. Eosino-philic fasciitis. Review and report of six cases. Scand JRheunatol 1979; 8: 225-33.

18 Michet C J Jr, Doyle J A, Ginsburg W W. Eosinophilicfasciitis. Report of 15 cases. Mayo Clin Proc 1981; 56:27-34

19 Solomon G, Barland P, Rifkin H. Eosinophilic fasciitisresponsive to cimetidine. Ann Intem Med 1982; 97: 547-9.

20 Loftin E B. Cimetidine and eosinophilic fasciitis. Ann InternMed 1983; 98: 111-2.

21 Laso F J, Pastor J, De Castro S. Cimetidine and eosinophilicfasciitis. Ann Intern Med 1983; 98: 1026.

22 Garcia-Morteo 0, Maldonado-Cocco J A, Barreira J C,Barcelo H A. Cimetidine and eosinophilic fasciitis. AnnIntern Med 1984; 100: 318-9.

23 Plaut M, Lichtenstein L M, Henney C S. Properties ofsubpopulation of T cells bearing histamine receptors.J Clin Invest 1975; 55: 856-74.

24 Rocklin R E. Modulation of cellular immune response in vivoand in vitro by histamine receptor-bearing lymphocytes.J Clin Invest 1976; 57: 1051-8.

25 Hansbrough J F, Zapata-Sirvent R L, Bender E M. Preven-tion of alterations in postoperative lymphocyte sub-populations by cimetidine and ibuprofen. AmJ7 Surg 1986;151: 251-5.

26 Hirschowitz B I, Groake J F. Effect of cimetidine on gastrichypersecretion and diarrhea in systemic mastocytosis.Ann Intern Med 1979; 90: 769-72.

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