Systemic Involvement in Papular Mucinosis and Scleromyxedema

R.Rondinone, F.Rongioletti°, A.Doria, A.Rebora°, S.Todesco

Division of Rheumatology, University of Padova, and ° Division of Dermatology, University of Genova, Italy

On-line Arch Rheumatol 1999; 3: 1
published on April 3, 1999
last update on April 3, 1999

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Introduction

Papular Mucinosis (PM) or lichen myxedematosus (LM) is a rare connective tissue disorder of unknown etiology.
It is clinically characterized by the eruption of cutaneous papules, plaques and/or nodules caused by mucin deposition and a variable degree of sclerosis, involving the face, upper extremities and to a lesser extent the trunk.
PM tends to have a chronic, progressive evolution although rare cases of spontaneous resolution have been described [Hardie et al, Kwon et al, Kubba et al].
Montgomery and Underwood (1953) proposed the classification of PM into four clinical subsets:

1. discrete papular form
2. generalized lichenoid papular eruption
3. localized or generalized lichenoid plaque form
4. urticarial plaques and nodular eruption

PM may therefore show a wide range of possible clinical manifestation: in 1956 McCuistion wrote that "one is struck by the varied clinical pictures that have been noted in cases of lichen myxedematosus [...]. In all cases, however, the common denominator and diagnostic criterion is the histologic picture".

A more immediate classification has been proposed by De Graciansky et al who divided patients with PM into three groups:

1. with papules alone
2. with papules and underlying induration
3. with papules and both underlying induration and erythema

while, on morphological basis alone, Perry et al described three types of papules:

1. discrete papules
2. coalescent papules forming plaques
3. nodules

In 1954 Gottron et al identified a variant of PM with a more severe cutaneous involvement characterized by a massive papular eruption with confluence and sclerosis of the dermis which he called Scleromyxedema (SMX) and corresponds to extreme cases of generalized lichenoid papular eruptions, according to Montgomery and Underwood's classification.
On the other hand some cases of PM with a very limited involvement have been described with papules located exclusively on the back of the hands and on the extensor surface of the wrist, for which Rongioletti et al proposed the term Acral Persistent Papular Mucinosis (APPM).
Whether SMX or APPM should be considered as extreme manifestations of PM or as separate entities is still a matter of debate. Nonetheless, besides more or less aesthetically distressing cutaneous manifestations, recent reports described various patterns of systemic involvement in patients with PM and more frequently with SMX, in some cases with a very poor prognosis.
Many authors have therefore suggested that SMX should be considered as a systemic disease. The present paper is a review of the existing medical literature about the extracutaneous manifestations of PM and SMX.

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Paraproteinemia and other hematologic disorders

Osserman et al first discovered the presence of an abnormal globulin in the serum of patients with PM that migrated to an extreme cathodal position on routine serum electrophoresis (post-gamma region).
James et al reported that the paraprotein found in the sera of 5 different patients had the same electrophoretic mobility because of its extreme basicity (due to an increased lysine content in the lambda chain).
Since these early reports, rare cases of mid-gamma or beta electrophoretic mobilities have also been observed.
The paraprotein, usually an IgG with lamda light chains, is found in the majority of patients with SMX (23 of 26 in Dinneen et al's series) although some cases with k light chains have been reported.   Moreover, even few patients with biclonal paraproteinemia IgA + IgG [Dinneen et al, Gabriel et al, Harris et al] or with a polyclonal gammopathy without any monoclonal spike [Alligood et al, Harvey et al, Kwon et al] have been observed.
The paraprotein differs from normal IgG by its marked basicity and smaller molecular weight (110,000 daltons), due to the absence of a significant antigenic portion of the Fd fragment [Kitamura et al], and is antigenically homogeneous in any given patient [Lawrence et al] although Wells et al demonstrated the lack of common idiotypic determinants among the paraproteins found in different patients (i.e. they were directed against different antigens or at least different components of the same antigen). Whether the serum paraprotein plays a role in the pathogenesis of the disease is still unknown.
There is no correlation between serum levels of the paraprotein and the severity or the activity of the disease; moreover, in one patient the paraprotein appeared only some years after the onset of cutaneous manifestations [Lowe et al] while in others the paraprotein was never found during follow-up.
The paraprotein level shows a variable responce to treatment and may persist despite resolution of the cutaneous lesions.
In a study on 6 SMX patients treated with melphalan, the monoclonal Ig disappeared in 1, was reduced in 2 and remained unchanged in 3 [Harris et al].
Bone marrow examination shows only a modest increase in normal plasma cells.

Initially the paraprotein was thought to have a direct stimulatory effect on fibroblast proliferation and synthesis of GAGs but experimental evidence did not confirm this hypothesis.
Harper et al demonstrated that the whole serum of 4 patients with PM had a stimulatory effect on fibroblast DNA synthesis and proliferation in vitro but no effect on primary cell cultures of normal human keratinocytes.
One of the patients' serum had no detectable paraprotein but had the same stimulatory effect, thus suggesting that the abnornal globulin had in itself no influence on fibroblast methabolism. To confirm this hypothesis, the paraprotein was then purified and added to normal fibroblast cultures on which no stimulatory effect was observed.
Yaron et al later showed that LM serum stimulated hyaluronic acid and prostaglandin E production by human fibroblasts but not their proliferation.
The addition of hydrocortisone and indomethacin interfered with fibroblast activation and it was therefore suggested that prostaglandin E could be the mediator of the stimulatory effect of LM serum on fibroblast hyaluronic acid production.
Subsequent studies [Ferrarini et al] determined that fibroblasts from the dermis of a patient with SMX have a reduced rate of 3H-thymidine incorporation when compared to normal control fibroblasts.
The addition of the patient's serum produced an increase in 3H-thymidine incorporation in the fibroblasts of both patient and control.
GAG synthesis is greater in PM fibroblast than in control when measured as weight per cell, and does not increase with the addition of PM serum, thus  suggesting that "the increased GAG production may be an intrinsic property of PM fibroblasts [...] unrelated to the effects of the serum on cellular proliferation".
The paraprotein could then be the secondary immunologic response to the dermal mucin deposition.
On the other hand, perhaps another factor exists which is capable of activating both the bone marrow (with subsequent paraproteinemia) and the connective tissue fibroblasts (with subsequent proliferation and mucin synthesis).
Some Authors demonstrated the presence of IgG bound to dermal areas of mucin deposition by direct immunofluorescence staining [Helm et al, Howsden et al, McCarthy et al] while others failed to confirm this finding [James et al, Shapiro et al] .
It might be postulated that the globulin deposition is a secondary event, due to a simple physicochemical attraction of charged dermal glycosaminoglycans for the cationic paraprotein (non-specific entrapment).
Alternatively, the paraprotein could be specifically directed against some unidentified antigens in the connective tissue matrix. Few cases of associated multiple myeloma have been reported.
Two out of 19 patients in from Gabriel et al's series developed multiple myeloma (1 after melphalan treatment) and the Authors suggested that it "represented a progression of the monoclonal gammopathy rather than a treatment complication".
Nonetheless, the paraprotein found in SMX is quite unlike mieloma-produced proteins: fewer than 10% of mieloma-produced proteins migrate towards the cathode (most of them remain at the point of application or move slowly towards the anode and therefore fall within the gamma or beta zone) and no more than one third have lambda chains.
Moreover, rare cases of non-Hodgkin lymphoma have been observed in patients with SMX, which could represent more than a casual association as other mucinosis (i.e. follicular mucinosis) may be related with lymphoproliferative disorders [Gabriel et al, Gimenez et al.]
Other hematologic malignancies have been reported and might be induced by melphalan treatment [Gabriel et al, Helm et al].

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Muscle involvement

The presence of muscle involvement was first described by Montgomery and Underwood in 1953: 2 of their patients had muscle weakness (in one involving the shoulders and associated to mild cramping of the legs when climbing the stairs).    In both patients no sign of myopathy was found on muscle histology.
Since then several othes cases have been reported (see table) and therefore myopathy is now considered to be of the most frequent visceral disorders in association with SMX.
In rare cases it may preceede the cutaneous eruption [Fudman et al, Harvey et al].
It may manifest as dysphagia (with difficulty in swallowing liquids or solid foods, and in severe cases nasal regurgitation), as slight to severe proximal muscle weakness (with difficulty walking up stairs or raising the arms over the head), and may rarely be accompanied by muscle tenderness and pain.
In addition, one patient had severe weakness of the neck muscles besides proximal muscle weakness (though with some atypical features such as a plaque-type PM, the absence of paraprotein, and severe interstitial myositis with vasculitis at muscle biopsy) [Harvey et al], and another forearm muscle weakness [Kubba et al].
Serum muscle enzymes range from normal to highly increased.
Most of the patients with clinical evidence of myositis had an electromyography pattern consistent with an inflammatory myopathic involvement.

Inflammatory EMG pattern in SMX myopathy

at rest: membrane instability with positive sharp waves and fibrillation potentials

during volitional contraction: early recruitment with multiple motor unit action potentials firing at rates greater than 5-10 Hz; single motor unit potentials are of short duration and low amplitude;
2 patients have been described with myotonic discharges [Harris et al, Kubba et al].

Histological examination of muscle biopsy shows a non-specific vacuolar myopathy with more or less pronounced muscle fiber necrosis and interstitial inflammatory infiltrate.

Histological features of SMX myopathy

diffuse,scattered vacuolated fibers

fiber atrophy; in some reports perifascicular fiber atrophy

fiber necrosis and myophagocytosis

internalization of nuclei

scattered interstitial infiltrate, generally without blood vessels involvement

endomysial fibroplasia

regenerating myofibers

Mucin deposition was found in only two cases of muscle biopsy [Johnson et al, Rothe et al].
The electron microscopic features are grouped in the following table.

Electron microscopic features of myopathy in SMX [Verity et al]

Sarcolemmal membranes in degenerating fibers show folding and caveolae-like areas

Extensive myofilament disruption in the necrotic and degenerating fibers, separation and grouping of myofilament bundles;
myofilament masses surrounded by loose aggregates of glycogen and mytochondria;
Z-band abnormalities: fragmentation, streaming, nemaline-like bodies

Vacuoles lined by a single unit membrane; many vacuoles are empty while others contain a finely granular material similar to glycogen

The myopathy has a variable responce to corticosteroids and therefore the association of immunosuppressive drugs (methotrexate or melphalan) has been proposed: one case by Espinosa et al improved with prednisone 5 mg/daily plus weekly oral MTX 7,5 mg while the patients reported by Harvey et al received 60 to 100 mg prednisone daily with only transient and incomplete responce.
In the case by Rothe et al, on the contrary, the myositis, although clinically significant, resolved spontaneously with intravenous fluids and bed rest before steroid and immunosuppressive treatment were started for the cutaneous involvement.

Author	patient's number & reported diagnosis	clinical presentation	CPK	muscle biopsy	treatment	response
Johnson et al, 1973	1, LM	proximal + dysphagia	>>>	vacuolar changes, atrophy	prednisone	initial improvement
Kubba et al, 1975	1, SMX	proximal	normal	non diagnostic	prednisone + melfalan	improved
McAdam et al, 1977	1, PM	proximal	>>>	vacuolar changes, necrosis	prednisone
Verity et al, 1978	1, SMX	proximal + dysphagia	>>>	vacuolar changes, necrosis	prednisone + MTX	improved
Harris et al, 1979	3, SMX	not specified + dysphagia	not specified	inflammatory 1/3	melfalan + prednisone	improved 1/3 not specified 2/3
Fudman et al, 1986	2, SMX	proximal + dysphagia	>>>	vacuolar changes, necrosis	prednisone + melfalan	improved
Harvey et al, 1986	3, SMX	proximal 2/3 truncal 1/3	>>> in 1/3	interstitial myositis + vasculitis 1/3 atrophy, necrosis 1/3 degeneration/regeneration 1/3	prednisone	initial / incomplete improvement
Gabriel et al, 1988	5, SMX	proximal 5/5 + dysphagia 3/5	>>> in 3/5	inflammatory (not specified) 3/5 non diagnostic 1/5 not done 1/5	prednisone	no improvement
Helfrich et al, 1988	1, SMX	proximal + dysphagia	>>>	vacuolar changes, necrosis	prednisone + MTX	improved
Ferrarini et al, 1989	1, SMX	proximal	normal	vacuolar changes, necrosis, scattered inflammatory cells	prednisone + MTX	improved
Harris et al, 1989	1, SMX	not specified + dyshagia	>>>	myopathy (not specified) + neurogenic atrophy	prednisone + MTX	mild improvement
Rothe et al, 1989	1, SMX	proximal + dysphagia	>>>	acute necrosis and phagocytosis	fluid infusion +  bed rest	excellent improvement
Espinosa et al, 1993	1, SMX	proximal + dysphagia	>>>	vacuolar changes, necrosis	prednisone + MTX	improved
Dinneen et al, 1995	5, SMX	not specified	not specified	inflammatory (not specified) 3/5	melphalan	not specified

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Neurologic involvement

Spinal or CNS involvement in patients with SMX has been reported with symptoms such as memory loss, confusion, clouded sensorium, hallucinations and depression, which have in some cases presented with a clinical picture of acute psychosis [Kantor et al].
Moreover, transient aphasia, dysarthria, gait problems, seizures, paresthesia and paralysis, changes in the level of consciousness and even some cases of coma of otherwise unexplained origin have been reported.

Reports of coma in patients with Scleromyxedema
Author	patient's sex & age (years)	number of episodes	parapro- teinemia	fever	seizure	other neurological manifestations	outcome
Rudner, 1966	m, 51	1	not reported	not reported	+	aphasia, dizziness	died 2 weeks after onset of coma
Lai a Fat, 1973	m, 43	1	+	no	+	headache, mental deterioration, dysarthria	died 2 days after onset of coma
Ochitil, 1978	m, 65	1			+	changed mental status	recovery
Verier, 1987	f, 52	3	+	no	no	headache, vertigo, tinnitus, paresthesia	recovery in 2-8
Reid, 1987	m, 37	1	+	+	+	memory loss, piramidal signs	recovery in 24 hours after plasmapheresis
Milam, 1988	m, 37	2	+	+	+	confusion, + Babinski, restlessness, personality change	recovery with plasmapheresis
Bonneblanc, 1991	m, 66	1	+	+	no	headache, confusion, dysarthria	recovery in 15 days
Webster, 1993	m, 36	1	+	not reported	+	hypoesthesia, dizziness, dysequilibrium	recovery in 3 weeks
River, 1996	m, 60	1	+	no	+	none	recovery in 6 days with plasmapheresis
Godby, 1998	m, 35	3	+	+	+	none	recory after several days

Coma and other neurological manifestations may accompany the worsening of the cutaneous manifestations [River et al, Verier et al] though in one case it preceded the onset of the eruption [Webster et al].
In some cases it was preceded by seizures, a flue-like illness, or by other neurologic symptoms such as dysarthria and/or confusion, which were thought to represent possible important prognostic signs [Bonneblanc et al].

Sensory neurologic complaints have rarely been reported.
Bazek et al described a patient with hyperesthesia; Perry et al a patient with leg numbness; Webster et al one patient with paresthesia (onset with dysathria and syncope, progression to a hemiparesis) and one with intermittant hypoesthesia of the hands and feet accompanied by dizziness and dysequilibrium (preceded by coma and seizures of unexplained origin); McFarlane et al a patient with dysesthesia of the right arm (accompanied by dysarthria, bilateral arm weakness, and other neurologic symptoms with a clinical picture resembling that of a transient ischaemic attack).
EEG and CT scans were normal or showed only non-specific finding.
Elevated CSF protein level has been reported in a patient and this was supposed to indicate the presence of the abnormal paraprotein but later investigation failed to confirm IEF abnormalities in CSF [Verier et al].
Post mortem examination revealed focal demyelination, gliosis, and cerebral oedema of unknown origin; nevertheless, mucin deposition in the brain has not been reported.
A pathogenetic role of the paraprotein has been proposed to explain the various neurologic manifestations in SMX: it was thought to cause an increased blood viscosity or increased tendency of leukocytes to aggregate with sludging of the CNS microcirculation [River et al].
A link between neurological manifestations and paraproteinemia has been confirmed in multiple myeloma and benign monoclonal gammopathies: the monoclonal Ig binds to neural gangliosides and myelin proteins and localizes in regions of myelin splitting [Webster et al] with subsequent functional impairment. Whether this is also the case of SMX with monoclonal gammopathy has yet to be demonstrated.
Moreover, the suggestion of increased levels of endogenous benzodiazepines has been proposed following the observation of an immediate arousal response after the administration of flumazenil to a SMX patient in deep coma [River et al].
Nonetheless, melphalan, cyclophosphamide, prednisone and plasmapheresis have been proposed as first choice treatment for patients with neurologic signs and symptoms.
Carpal tunnel syndrome has been reported in many patients.
In some cases its manifestations precede the onset of the cutaneous involvement and these may therefore be occasional associations.
In other cases the temporal relationship existing between the carpal tunnel syndrome and SMX makes it possible to postulate a common pathogenic link.
The pathologic features of carpal tunnel syndrome in patients with SMX have never been described and therefore it is not possible to confirm the hypothesis of a local mucin or Ig deposition.
An isolated report of mononeuritis multiplex hypertrophicans has been described in a patient with SMX, with progressive development of sensitive and motor disturbances and consequent muscle atrophy [Hallen].

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Cardiovascular involvement

Cardiovascular diseases such as hypertension, atherosclerosis and myocardial infarction (also in patients with no risk factors for cardiovascular disease) have been reported in association with SMX.
The significance of these associations is unclear.
At post mortem examination, mucin deposits were found in the media and the inner region of the adventitia of some coronary vessels [Godby et al, McCuistion et al].   Nonetheless, the majority of the Authors have failed to detect mucin within the cardiac muscle.

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Rheumatologic manifestations

Raynaud's phenomenon has frequently been reported.
Moreover, a sclerodermoid appearance of the hands, and less frequently of the feet, may be present with sclerodactyly, stiffness and flexion contractures.
A review by Lang et al on 57 cases, reported sclerodactyly in 9 patients, which became clinically evident after an average of 4 years of disease duration (range 1 to 9 years).
Sclerodactyly in SMX patients was not associated with Raynaud's phenomenon;  nail dystrophy, digital pitted scars or loss of substance of the finger pad were not observed.
Treatment with melphalan (2mg/daily) improved the appearance of the skin (which became softer and more elastic) in Lang's observation but did not reduce flexion contractures and sclerodactyly.
Acro-osteolysis involving the terminal phalanges with a typical scleroderma pattern has been described in a patient with a 7 year history of the disease [Harris et al] and in another with associated sclerodactyly, sicca complex and an erosive seronegative RA-like arthropathy [Frayha et al].
Nailfold capillary microscopy showed dilated loops and avascular areas [Fudman et al] in one patient.
Joint involvement such as arthralgia, migratory arthritis, seronegative non-erosive polyarthritis or erosive arthropathy has been reported.
Synovial biopsy from a patient with seronegative non-erosive polyarthritis involving the hands, wrists, and knees revealed slight hypervascularity of the villi and focal mesothelial cell hyperplasia [Verity et al].
One case by Espinosa et al with seronegative non-erosive polyarthritis involving the MCF, IF, wrists, elbows, shoulders and knees improved on indomethacin treatment (50 mg/daily).
Jamieson described two cases of SMX with an erosive arthropathy.
In one patient, joint involvement was initially limited to the forefoot and later symmetrically extended to the hindfoot and ankle.   During a follow-up of 9 years no other site of joint involvement was observed.
The other patient had hand and wrist arthritis with multiple bilateral involvement of the MCP and PIP joints.
Both patients had concomitant cutaneous manifestations of SMX at skin sites   overlying the affected joints.
Bone biopsy in both cases revealed a chronic non-specific periostitis and mucoid alteration of the supporting tissues; no birefringent crystals were seen.
Radiologic appearance of an erosive arthropathy suggested an underlying proliferative synovitis, similar to rheumatoid arthritis or gout.   Nonetheless, both patients were seronegative for rheumatoid factor, had normal or minimally elevated ESR, normal serum uric acid levels and no other clinical features of RA or gout.
The Authors postulate that the accumulation of mucin in the joint might induce synovial inflammation with subsequent joint narrowing and erosions.
An association with other rheumatic diseases (dermato/polymyositis, systemic sclerosis, rheumatoid arthritis, sicca syndrome) has rarely been reported.

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Renal involvement

Mucin has been found in the perivascular connective tissue of the kidney and in the Bowman's capsule in only one case and was accompanied by an acute glomerulitis with also occasional crescents [McCuistion et al].
Scleroderma renal disease with an abrupt onset of hypertension and progression towards renal failure has rarely been described [Harris et al, Kantor et al] in patients with SMX.
Another patient (though normotensive) developed a progressive renal dysfunction and post-mortem examination disclosed a histological pattern characteristic of scleroderma renal disease [Gabriel et al].
The association between scleroderma renal disease and SMX is interesting due to the similarities in the pathogenesis of the two diseases and their relationship to stimulated skin fibroblast activity.

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Gastrointestinal involvement

Dysphagia is the most common gastrointestinal complaint.
A study by Dinneen et al on 26 cases of SMX seen at the Mayo Clinic from 1966 to 1990, reported 12/20 patients with dysphagia.
8 of the 12 patients also had radiographic evidence of esophageal aperistalsis with dilated atonic esophageal body.
Alligood et al reported a case of SMX with significant induration of the tongue and dysphagia due to esophageal aperistalsis; pulmonary function tests showed mild obstruction and moderate restriction while repeated serum electrophoresis evidenced a polyclonal gammopathy without monoclonal spikes.
A biopsy of the tongue was not performed and therefore the possibility of mucin deposition remains questionable.
Moreover, the cutaneous manifestations improved with melphalan treatment but no details are given about the evolution of the tongue involvement.
Another case [Fudman et al] had a clinically significant involvement of the tongue: he was unable to protrude his tongue or move it freely.
The patient had a normal barium swallow although a manometric study disclosed a striated muscle dysfunction with low contraction amplitudes in the hypopharynx and upper esophagus.
Other features of gastrointestinal and hepatic involvement have rarely been described, therefore suggesting an occasional association rather than a specific manifestation of PM.

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Pulmonary involvement

Dispnea has been reported in 7/26 patients by Dinneen et al; in those who underwent pulmonary function tests 3 presented a restrictive pulmonary defect and 2 an obstructive pattern of lung involvement.
Decreased carbon monoxide diffusing capacity was also described in SMX  patients with dyspnea [Fudman et al, Harris et al]
Godby et al described a patient who developed pulmonary hypertension: post-mortem examination disclosed mucin deposition in the walls of the larger branches of the pulmonary artery and large veins.
Such mucin deposits were reduced by hyaluronidase digestion, indicating that they were primarily composed of hyaluronic acid.

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Ophtalmological involvement

Besides eyelid involvement with skin thickening, ectropion and lagophthalmos, few cases of corneal involvement have been described, with patients complaining of progressively blurred vision.
The first patient [Pusateri et al] noticed the simultaneous onset of bilateral blurred vision and cutaneous eruption.
Slit-lamp examination revealed sub-epithelial corneal opacities involving the entire cornea consisting of "irregularly shaped whorls of greysh-white material arranged in haphazard swirling pattern".
Deep stroma and Descemet's membrane were unaffected.
Stains for mucopolysaccarides and amyloid were negative while immuno-peroxidase stain demonstrated the presence of IgG and lambda chains.
The same pattern of corneal infiltrate described as "whorling plaques" has been reported by Milam et al and stained positive for the presence of immunoglobulins and negative for mucopolisaccarides (the patient had no monoclonal gammopathy).
A different pattern has been described [Goldin et al] consisting of the deposition of "linear, pointed, refractile crystals in the anterior to mid-stroma, rounder, fluffier opacities in the midstroma, and diffuse, larger aggregates in the posterior stroma".
These deposits were composed of hyaluronic acid and amyloid P and contained no immunoglobulins.
Two more cases of corneal opacities have been recently reported [Davis et al].
One had "thick, swirled pattern of epithelial opacities" and pathologic examination revealed superficial stromal deposition of acid mucopolysaccaride material and no amyloid. Stains for Ig were not done.

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Laringeal involvement

Rare cases of dysphonia have been reported.
Cosgarea et al described a patient with SMX who had a thickening of the vocal cords at indirect laryngoscopy, suggestive of a chronic pseudomyxomatous laryngitis.
The patient was treated with steroids, cyclophosphamide and finally with thiomucase (a mucopolysaccaridase) with a significant improvement of the cutaneous manifestations but no detail is given about the evolution of the laringeal involvement.
Another patient with vocal cord swelling has been reported [Leung et al] with no further informations about follow-up and response to isotretinoin treatment.

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Autopsy reports

The pathogenesis of the extracutaneous manifestations described in patients with SMX is still unclear.   Post-mortem evaluations have been performed to ascertain the presence of mucin within the involved tissues and organs.
The reports do not indicate significant visceral infiltration with inflammatory cells and/or mucin deposition although focal infiltration has occasionally been described in muscle, hearth, and kidney.

Reference	age (years) & sex	reported diagnosis	internal organ mucin deposition	other significant findings	cause of death
Montgomery, 1953	55 / M	LM	not found		hypertensive vascular disease
McCuistion, 1956	40 / M	LM	blood vessel adventitia in heart, kidney and adrenal glands	demyelinization and gliosis of the brain	bronchopneumonia
Perry, 1960	36 / M	LM	renal papillae	chronic pyelonefritis	bronchopneumonia & multiple cerebral infarcts
Rudner, 1966	51 / M	SMX	not found	coronary arteriosclerosis and myocardial infarction	acute bilateral subdural hemorrage
	55 / M	SMX	not found		artheriosclerotic heart disease
Colomb, 1974	76 / M		not found	cerebral atrophy	tuberculosis
Farmer, 1982	53 / M	PM	not found		gastric neoplasm
	67 / M	PM	not found		multiple thrombosis of cerebral vessels
Kantor, 1986	58 / M		not found	scleroderma renal disease	bacterial sepsis
Milam, 1988	39 / M	SMX	not found	demyelinization; necrotizing vasculitis in the kidneys	acute renal failure &  bronchopneumonia
Godby, 1998	35 / M	SMX	walls of pulmonary artery & veins; coronary arteries	gliosis and demyelinization	acute peritonitis

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Conclusions

A total number of 114 published cases of PM or SMX were reviewed for the present article.

• 101 patients were tested for the presence of a monoclonal gammopathy.

Prevalence and characteristics of the paraprotein
	number of patients	%
present	84	83.2
lambda light chains	54	53.3
kappa light chains	12	11.9
not specified	12	11.9
biclonal IgG + IgA	3	3.0
policlonal	3	3.0

• Muscle involvement was reported as dysphagia (31.6%) or as proximal weakness (27.2%) and most of the cases were confirmed by EMG and/or muscle biopsy.
• A high prevalence of pulmonary involvement was reported (16.7%) with dyspnea (at rest or more frequently with exercise), and respiratory function tests showed a restrictive or obstructive pattern of lung involvement or a reduced carbon monoxide diffusing capacity.
  Most of the reports do not indicate smoking habits, professional exposure to chemicals, nor the possibility of concurrent lung disorders due to ageing or past diseases.
• A neurologic involvement was reported in 14.9% of the published patients.
  In some cases it is difficult to rule out possible concomitant diseases and therefore the observed clinical patterns cannot be surely considered as part of the extracutaneous manifestations of PM and SMX.
  Nonetheless at least 10 cases of coma have been regarded as definite expression of a SMX encephalopathy.
• Joint involvement has been reported in 10.5% of the patients with very different clinical and/or radiological patterns, and for most of them a casual association cannot be ruled out.
• Sclerodactyly and the reduction of the oral aperture were present in 12.3% and 13.2% of the reported cases but this seems to be a lower estimate as many publications do not give a detailed clinical description.
  Raynaud's phenomenon was present in 8.8% of the patients, and was not necessarily associated to sclerodactyly.
• Carpal tunnel syndrome has been observed in 9.6% of the patients: this figure seems too high to be simply an occasional finding.
  Unfortunately no pathologic evaluation of the surgical specimens has ever been reported to confirm a pathogenetic link with the local deposition of GAGs or immunoglobulins.

Prevalence of extracutaneous manifestations
	number of patients	prevalence
dysphagia	36	31.6 %
myopathy	31	27.2 %
pulmonary involvement	19	16.7 %
neurologic involvement	17	14.9 %
decreased oral aperture	15	13.2 %
sclerodactyly	14	12.3 %
joint involvement	12	10.5 %
carpal tunnel syndrome	11	9.6 %
Raynaud's phenomenon	10	8.8 %

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  J Rheumatol 1989; 16: 837
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  Clin Rheumatol 1983; 2: 277
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  Arthritis Rheum 1986; 29: 913
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  Br J Dermatol 1979; 100: 727
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Riccardo Rondinone, M.D.
Division of Rheumatology
Via Giustiniani 2
35128  Padova,   ITALY
telephone 39498212190
e-mail ron@protec.it

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