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CASE REPORT
Scleroderma-Like Illness as a Presenting Feature of Multiple
Myeloma and Amyloidosis
Candice Marie Casim Reyes, MD,* Alla Rudinskaya, MD,* Robert Kloss, MD,*
Michael Girardi, MD,† and Rossitza Lazova, MD†
Abstract: A 31-year-old woman with a history of bilateral carpal
tunnel surgery complained of worsening hand pains and swelling.
Subsequently, she presented for rheumatologic evaluation with gen-
eralized arthralgias, symmetric polyarthritis of the hands and feet,
shiny skin with tightness and thickening, tender periungual ery-
thema, malar rash, and photosensitivity. The only laboratory abnor-
mality found then was a positive antinuclear antibody. Her joint
symptoms were responsive to low-dose prednisone and hydroxy-
chloroquine. However, the skin tightness progressed proximally and
centrally and developed around the mouth. At that point, more
specific autoimmune work-up showed negative relevant antibodies,
and repeat antinuclear antibody tests turned out negative.
Later, she reported dysphagia and hoarseness, and ecchymotic
rashes appeared on the face and forearm. Biopsy of the forearm
lesion showed leukocytoclastic vasculitis. Staining for amyloid was
negative. Subsequently, she was found to have hypogammaglobu-
linemia and Bence-Jones proteinuria; the progression of her skin
symptoms provoked a repeat skin biopsy with special stains that
demonstrated amyloidosis. Bone marrow biopsy showed ⬎75%
plasma cells, skeletal survey revealed multiple lytic lesions, and a
diagnosis of multiple myeloma with associated amyloidosis was
made. Despite the initial features of connective tissue disease in this
young woman, a steadfast workup revealed the source of her
problem.
Key Words: scleroderma-like, amyloidosis, multiple myeloma
(J Clin Rheumatol 2008;14: 161–165)
Systemic amyloidosis is well-known for its ability to in-
volve various organs and imitate other diseases, poten-
tially leading to a delayed diagnosis. Skin lesions are not
uncommon in amyloidosis but scleroderma-like changes are
rare. The term Skleroderma amyloidosum was first used by
Gottron in 1932 to describe sclerosing skin changes resem-
bling scleroderma in patients with primary systemic amyloid-
osis.
1
Since then, scleroderma-like lesions have been de-
scribed in patients with systemic amyloidosis,
2,3
multiple
myeloma,
4
or in those with both.
1,5
However in most of these
cases, there were clues that prompted a search for amyloid or
myeloma. Amyloidosis in the skin has also been reported to
occur in those with established systemic sclerosis,
6 –10
inde-
pendent of multiple myeloma.
We describe the case of a young woman whose initial
rheumatologic presentation turned out to be a manifestation
of multiple myeloma with amyloidosis.
CASE PRESENTATION
KS was 31-years-old when she developed bilateral
carpal tunnel syndrome for which she underwent bilateral
surgical release in 2001, with good results. In 2002, she had
gradually worsening pain and swelling in the hands and feet
for 6 months. In February 2003, she presented to a rheuma-
tologist with generalized arthralgias and symmetric polyar-
thritis affecting predominantly the metacarpophalangeal and
proximal interphalangeal joints, shoulders, wrists, and feet.
She had a malar rash and reported a transient sun-sensitive
rash on her forearms. The patient had shiny and tight skin in
the hands, and tender periungual and palmar erythema (Figs.
1A, B), without sclerodactyly. There were no symptoms of
Raynaud phenomena. Nailfold capillaroscopy was not done.
At that time, ANA was positive (1:160) in a nucleolar pattern.
ESR was normal at 18 mm/h, and CRP was slightly elevated
at 12 mg/L.
Further laboratory tests revealed no anemia or leuco-
penia, chemistries, complement, anti-neutrophilic cytoplas-
mic antibody levels were normal and hepatitis panel was
negative. Considerations included early SLE, scleroderma,
and overlap syndrome. Her joint symptoms were respon-
sive to prednisone (5 mg daily) and hydroxychloroquine
(200 mg twice daily). However, her skin manifestations
persisted. More specific autoimmune work-up was nega-
tive, including antibodies to dsDNA, Smith, SCL-70, cen-
tromere, cardiolipin, ribonuclear protein antibodies, rheu-
matoid factor, and cyclic citrullinated peptide. Repeat
ANA test was negative.
Over the next 5 to 8 months from initial rheumatologic
presentation in 2003, the tight, shiny, and thickened skin
progressed proximally and centrally from the hands (both
palmar and dorsal aspects) towards the arms, chest, and neck.
There were gradually progressing flexion contractures of the
fingers. There were no digital ulcers or pitting, and no nail
From the *Internal Medicine, Danbury Hospital, CT; and †Yale University
School of Medicine, New Haven, CT.
Reprints: Candice Marie Casim Reyes, MD, 1 Fairfield Ave. Unit A4,
Danbury, CT 06810. E-mail: Candice.reyes@danhosp.org.
Copyright © 2008 by Lippincott Williams & Wilkins
ISSN: 1076-1608/08/1403-0161
DOI: 10.1097/RHU.0b013e3181775a15
JCR: Journal of Clinical Rheumatology • Volume 14, Number 3, June 2008 161
changes. A sensation of tightness around the mouth devel-
oped. Intermittent dysphagia to solids and hoarseness ensued,
with unrevealing gastrointestinal and ear nose and throat
workup. She had no symptoms of heartburn, chest pain, or
dyspnea. Bilateral shoulder arthritis, hand pains, and stiff-
ness became prominent and persistent joint symptoms.
New ecchymotic, purpuric lesions appeared on the right
forearm and face. Multiple bruises in the legs were also
seen, along with skin thickening and edema in the feet. In
July 2003, biopsy of the forearm lesion showed paucicel-
lular leukocytoclastic vasculitis. The working diagnosis at
that point was overlap syndrome with features of sclero-
derma, rheumatoid arthritis, SLE, and leukocytoclastic
vasculitis. Scleroderma was being favored given the pro-
gression of skin symptoms and dysphagia. In January
2004, 6 months after the initial biopsy, an area of more
prominent induration from the left hand was biopsied
showing nonspecific fibrosing dermatitis with no diagnos-
tic changes of scleroderma. One month thereafter, another
indurated lesion from the left palm was biopsied revealing
fibrosing dermatitis and features suggestive of scleromyx-
edema and amyloid; however, Congo red staining did not
show apple-green birefringence.
Further work-up revealed a normal computed tomog-
raphy scan of the chest, echocardiography, and pulmonary
function tests. Renal ultrasound was normal, done as part of
an evaluation for mild proteinuria. In April 2004, serum and
urine protein electrophoresis respectively revealed hypogam-
maglobulinemia (gamma component of 0.49, IgG 539 mg/dl,
IgA 32 mg/dl, IgM 31 mg/dl, with an intense discrete band in
the alpha-2 region corresponding to increased concentration
of monoclonal free lambda light chains), and lambda type
Bence-Jones proteinuria. However, considering her young
age, persistently normal complete blood count and ESR, lack
of bone pains or constitutional symptoms, and lack of hyper-
calcemia, a primary bone marrow disorder was considered
unlikely and bone marrow biopsy was deferred until a few
months later.
Progression of skin symptoms prompted referral to
another dermatologist, who performed 2 punch skin biopsies
in September 2004 on the areas with the most prominent
induration (posterior neck and left upper arm). In both biop-
sies (Figs. 2 and 3), there was amorphous eosinophilic ma-
terial in the dermis and focally extending to the subcutaneous
fat. Congo Red and Crystal Violet stains for amyloid were
positive. Apple-green birefringence was seen under polarized
light on sections stained with Congo Red. Further, hemato-
logic evaluation was then pursued. Bone marrow aspirate
done in October 2004 revealed ⬎75% plasmacytosis with
abundant atypical plasma cells, with diffuse infiltration on
biopsy (Fig. 4); stains were negative for amyloid. Flow
cytometry was consistent with a lambda light chain restricted
plasma cell dyscrasia. No clonal abnormality was detected in
the mitotic population in cytogenetic studies. Skeletal survey
revealed multiple lytic lesions. At this time, there was very
limited mouth opening due to skin tightness. Macroglossia
had also become evident, which contributed to impaired oral
FIGURE 1. A, dorsal view hands with periungual erythema,
edema, ecchymoses, atrophic nail changes, and tight, shiny
skin. B, diffuse palmar erythema, patchy erythema on volar
aspects of fingers, ecchymosis, and edema; no telangiectasia
or sclerodactyly.
FIGURE 2. Deposits of amorphous eosinophilic material in
the dermis consistent with amyloid (H&E; ⫻100).
Casim Reyes et al JCR: Journal of Clinical Rheumatology • Volume 14, Number 3, June 2008
© 2008 Lippincott Williams & Wilkins162
intake and cosmetic changes. Her nails exhibited atrophic
changes, extensive ecchymoses, and swelling of the lower
extremities were evident, along with her previously described
skin lesions. A diagnosis of multiple myeloma and amyloid-
osis was then established.
Subsequently, the patient received 3 cycles of VAD in
November 2004. In March 2005, she underwent tandem
high-dose chemotherapy and autologous stem-cell transplant,
7 months apart, after periods of induction and mobilization.
Eventually, there was marked decrease in total serum free
lambda light chain levels, and her soft tissue amyloidosis
improved significantly. Electrophoresis consistently showed
no discrete bands suggestive of monoclonal gammopathy
after her 2 transplants. In the succeeding months posttrans-
plant, the patient had marked physical and functional im-
provement. There is continued decrease in macroglossia, and
in the tightness in the skin around the mouth. Significantly
less tightness, swelling, and erythema are also obvious in the
skin of the hands, legs, and feet.
DISCUSSION
Amyloidosis results from abnormalities in protein fold-
ing that leads to deposition of insoluble fibrils in the tissues,
which may be manifested by impaired organ function and
alteration of tissue structure. Virtually any organ may be
affected and thus can mimic a multitude of diseases. Classi-
fication is based on the identity of the fibril-forming protein,
with AL (light chain amyloidosis, primary idiopathic amy-
loidosis, or amyloidosis associated with multiple myeloma)
being the most common. All amyloid fibril deposits share the
beta-pleated sheet ultrastructure and typically impart an ap-
ple-green birefringence with Congo red. This latter finding
was not clearly demonstrated on the patient’s initial skin
biopsies, promoting confusion as to her diagnosis.
Systemic sclerosis or scleroderma is a chronic, multi-
system disorder characterized by thickening of the skin and
internal organs due to diffuse fibrosis. There are 2 subsets,
diffuse cutaneous, and limited cutaneous scleroderma. Over-
production and deposition of extracellular matrix, vascular
damage, and immune activation are prominent features.
Scleroderma has a worldwide distribution and affects all
races. Incidence increases with age with peak in 3rd to 5th
decades. Women are affected 3 times as often as men.
Raynaud phenomena is a common symptom of scleroderma,
occurring in 95% of patients.
11
It is the initial manifestation
of disease in 70% of patients with scleroderma, particularly in
limited cutaneous systemic sclerosis, and represents the most
frequent clinical aspect of microvascular involvement. Nail-
fold capillaroscopy is a valuable method to analyze micro-
vascular abnormalities in autoimmune diseases; when abnor-
mal, this may be predictive of evolution to scleroderma.
Architectural disarray, giant capillaries, hemorrhages, loss of
capillaries, and avascular areas are present in ⬎95% of
patients with overt scleroderma.
11,12
In our case, symptoms pointing to scleroderma in-
clude her young age at onset (age 31), prominent symp-
toms of skin tightness and thickening with progression
proximally from the hands towards the arms, neck, chest,
and the skin around the mouth, findings typical of diffuse
cutaneous scleroderma. The histologic findings from the
skin biopsies were inconclusive. However, other points fa-
voring scleroderma are the positive ANA with nucleolar
staining, dysphagia, and arthralgias/arthritis. Thus a clinical
suspicion for scleroderma was reasonable.
Points against scleroderma are the following: absence
of Raynaud phenomenon, negative Scl-70, anticentromere
antibodies, the low titer of ANA, skin lesions atypical of
scleroderma, and absence of sclerodactyly and telangiectasia.
Raynaud phenomenon is almost uniquely present in sclero-
derma, thus the absence of this finding, or a normal capil-
laroscopy, should prompt a search for another disease.
Scleroderma-like skin changes can be seen in other sys-
temic disorders or from exposures to a variety of drugs, toxins.
Scleredema, scleromyxedema, overlap syndromes (rheumatoid
arthritis, Mixed Connective Tissue Disease, SLE), endocrine
disorders such as diabetes mellitus and hypothyroidism,
nephrogenic systemic fibrosis, amyloidosis, eosinophilic fas-
ciitis, chronic graft-versus-host disease, drug-induced sclero-
FIGURE 3. Congo red stain highlights the amyloid in the
dermis (⫻100).
FIGURE 4. High power view showing atypical plasma cells,
including binucleate forms; classic spoke-wheel appearance
of nucleus.
JCR: Journal of Clinical Rheumatology • Volume 14, Number 3, June 2008 Scleroderma of Multiple Myeloma and Amyloidosis
© 2008 Lippincott Williams & Wilkins 163
derma (bleomycin, pentazocine), and environmental expo-
sures (organic solvents, petroleum distillates). These conditions
should thus always be considered in the appropriate setting and
in questionable cases.
The diffuse palmar erythema, patchy erythema on the
fingers, scattered ecchymoses, and swelling of the hands and
feet are atypical for scleroderma. However, in the first few
months of scleroderma disease, an inflammatory stage may
be seen with arthralgia and soft tissue swelling rather than
skin induration as the most prominent features. In our patient,
these atypical skin lesions persisted throughout most of her
course whereas the induration progressed independently, and
such prompted a search for an alternative diagnosis.
Subsequent skin biopsies revealed nodular amyloidosis.
Retrospectively, the evolution of the patient’s symptoms
could be explained by amyloidosis. When the gastrointestinal
tract is affected by amyloidosis, the most common sites of
mucosal infiltration are the duodenum (100%), stomach
(95%), colorectum (91%), and esophagus (72%) as seen in
one series with endoscopic and biopsy studies.
13
Chronic
intestinal dysmotility could occur with the myopathic, infil-
trative stage of the disease and patients could have stasis
syndromes such as dysphagia,
14
a symptom present in our
patient. Although the patient’s intermittent dysphagia could
connote the esophageal dysmotility frequently seen in sclero-
derma, there was no heartburn and no findings on esophago-
gastroduodenoscopy suggestive of gastroesophageal reflux
disease. Furthermore, the patient’s musculoskeletal symp-
toms could have been manifestations of amyloidosis. Carpal
tunnel syndrome is common with amyloid hand involvement,
typically bilateral and symmetric, as in this patient.
15
Ar-
thropathy in AL amyloid is low-grade, subacute, progressive,
symmetric, with predilection for the shoulders, knees, wrists,
metacarpophalangeal and proximal interphalangeal joints,
with the joints being mildly tender or nontender, and with
little morning stiffness.
16
Soft tissue swelling could be prom-
inent because of nodular hypertrophied synovium directly
infiltrated by amyloid. Infiltration of muscles by amyloid is
generally associated with systemic involvement, and macro-
glossia is characteristic of AL amyloid. This patient had
evident macroglossia only later in the course of her disease,
around the time that the diagnosis was being made.
Sclerotic skin changes could be found in both scleroderma
and systemic amyloidosis, but in the latter, slightly raised, waxy
papules or plaques usually with clustering in the axillae, anal,
and inguinal regions are typical, and may also be seen in the
face, neck, and mucosal areas. Clinical skin involvement occurs
in 25% of patients with AL amyloidosis manifesting as pete-
chiae, ecchymoses, papules, plaques, nodules, tumors, bullae,
alopecia, and scleroderma-like thickening.
2
The distribution of
skin changes in this patient was atypical for amyloidosis and was
initially more suggestive of scleroderma.
The changes of paucicellular leukocytoclastic vasculitis
in the biopsy from July 2003 cannot be clearly explained.
This is a condition that may be associated with malignancy
including lymphoproliferative diseases, exposures to drugs,
chemicals, infections, and autoimmune connective tissue dis-
eases like scleroderma and SLE.
Multiple myeloma represents a malignant monoclonal
expansion of plasma cells. It occurs in all races, slightly more
frequent in males, with peak of occurrence around the 5th–
6th decades. Prominent symptoms may include bone pain or
fracture, renal failure (25%), susceptibility to infection, ane-
mia (80%), hypercalcemia. The ESR is usually elevated.
Classically, marrow plasmacytosis is ⬎10%, and lytic bone
lesions may be found.
17
Of patients with multiple myeloma,
15%-20% have amyloidosis; clinically overt organ dysfunc-
tion due to amyloidosis is present in 5% to 7%.
18
Among
patients with AL amyloidosis, 13% have multiple myeloma.
2
Amyloid arthropathy may occur in about 0.1 to 6% of
patients with multiple myeloma.
19
Proteinuria may be present in scleroderma, systemic
amyloidosis, and multiple myeloma. In one report, nearly
75% of patients with primary amyloidosis present with pro-
teinuria.
20
The patient’s protein electrophoresis showed hy-
pogammaglobulinemia and lambda-type Bence-Jones pro-
teinuria. Although the protenuria could have been a clue to
her underlying hematologic condition, her young age, lack of
constitutional symptoms, and absence of suggestive labora-
tory abnormalities lessened the suspicion for a primary bone
marrow disorder. All these factors contributed to the delay in
pursuing a bone marrow biopsy and skeletal survey.
Interestingly, despite this patient having almost com-
plete replacement of bone marrow with abnormal plasma
cells, the patient had no anemia throughout most of her
course. Her chemistries and ESR were persistently normal.
Despite diffuse lytic lesions in skeletal survey, she had no
hypercalcemia. Hence, there were no clear signs and symp-
toms to have suggested multiple myeloma. Primary amyloid-
osis was diagnosed based on histologic examination of skin
biopsies showing deposits of amyloid in the dermis. The
association of multiple myeloma and amyloidosis then be-
came evident in this case.
ACKNOWLEDGMENTS
The authors thank Dr. David Trock for his assistance in
the preparation of this paper.
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JCR: Journal of Clinical Rheumatology • Volume 14, Number 3, June 2008 Scleroderma of Multiple Myeloma and Amyloidosis
© 2008 Lippincott Williams & Wilkins 165
