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\begin{document}

\title{Coexistence of scleroderma with multiple myeloma: a rare association}



\author[1]{Omar Alsamarrai}%
\author[1]{ghina haidar}%
\author[2]{Sana  Btrush}%
\author[2]{Ayham Alhusseini}%
\author[2]{Maysoun Kudsi}%
\affil[1]{Damascus University}%
\affil[2]{Damascus University Faculty of Medicine}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\textbf{Coexistence of scleroderma with multiple myeloma: a rare
association}

Omar Alsamarrai, M.D.\textsuperscript{1}, Ghina Haidar,
M.D.\textsuperscript{2}, Sana Btrush, M.D.\textsuperscript{3}, Ayham
Alhusseini, M.D.\textsuperscript{4}, Maysoun Kudsi, M.D,
PhD\textsuperscript{5}

\textsuperscript{1} Department of Neurology, Al Assad and Al Mouwasat
University hospitals, Faculty of Medicine- Damascus University,
Damascus, Syria

omarsamoraee@gmail.com

\textsuperscript{2} Department of Rheumatology, Al Assad and Al Mouwasat
University hospitals, Faculty of Medicine- Damascus University,
Damascus, Syria

gtghinahaidar@gmail.com

\textsuperscript{3} Department of Rheumatology, Al Assad and Al Mouwasat
University hospitals, Faculty of Medicine- Damascus University,
Damascus, Syria

Sana.btrush1996@gmail.com

\textsuperscript{4} Department of Neurology, Al Assad and Al Mouwasat
University hospitals, Faculty of Medicine- Damascus University,
Damascus, Syria.

ayham-94-h@hotmail.com

\textsuperscript{5} Rheumatology professor , Faculty of Medicine-
Damascus University, Damascus, Syria.

maykudsi@gmail.com

\textbf{Corresponding Author} : Omar Alsamarrai , Department of
Neurology, Al Assad and Al Mouwasat University hospitals, , Faculty of
Medicine- Damascus University, Almazah, Damascus, Syria. E-mail :
omarsamoraee@gmail.com .Tel: + 963 988212757

\textbf{Consent statement :} Written informed consent was obtained from
the patient to publish this report in accordance with the journal's
patient consent policy

\textbf{Abstract}

\textbf{Introduction:} Coexistence of scleroderma with multiple myeloma
is an unusual finding with unclear significance. Only 15 cases of MM
with scleroderma have been reported until now.

\textbf{Case presentation} : We report a case of a 58-year-old female
with 10-year history sceroderma, complaining from pallor and fatigue.
The initial workup showed a normocytic anemia with elevated ESR and
total proteins. On fruther investigation the gamma globulines were also
high and the bone marrow biopsy showed interstitial and focal increase
in plasma cells without bone marrow fibrosis. Skeletal survey showed
osteopenia, but no osteolytic lesion or fracture. The patient was
diagnosed as scleroderma with coexistence of immunoglobulin G (IgG) ,
kappa (\selectlanguage{greek}κ\selectlanguage{english}) MM.

\textbf{Conclusion:} In view of the possible coexistence of scleroderma
with MM, it is suggested that all patients with scleroderma should be
screened for monoclonal gammopathy and MM regarding their age. future
studies should be directed to determine the exact mechanism of these two
conditions association and the effect of MM treatment on SSc
improvement.

\textbf{Keywords} : Systemic Sclerosis (SSc),Multiple Myeloma ( MM),
Osteolytic lesion, Immunoglobulin G, \selectlanguage{greek}κ \selectlanguage{english}MM

\textbf{Background}

Scleroderma(SSc) is a rare connective tissue disorder of unknown
etiology characterized by thickness of the skin. The disease usually
affects patients between the ages of 30--50  (1). Scleroderma is
reported to be associated with Sjogren syndrome, rheumatoid arthritis
and systemic lupus erythematosus.~It is also associated with solid
tumors such as lung, breast, stomach and rectum .however, the
association with multiple myeloma (MM) has seldomly been reported (2).
To the best of our knowledge, only 14 cases of sceleroderma associated
with MM have been reported in the literature. Inflammation and
deregulation of immune system in this autoimmune disorder may cause
clonal expansions of plasma cells but such aberrations still remain
under investigation(2,3).

We report a case of a 58-year-old woman who presented with Systemic
sclerosis associated with multiple myeloma.

\textbf{Case presentation}

A 58-year-old female presented with pallor and fatigue for the last
month. She was diagnosed with sceroderma 10 years ago according to the
American College of Rheumatology criteria for SSc(4),and was treated
with methotrexate7.5mg/week for 5 years without adherence. Her past
medical history was significant for breast cancer 15 years ago that was
treated with surgery, chemotherapy, radiation and hormonal therapy for 5
years, with total remission.

On physical examination patient had thickened tight skin all over the
extremities (Figure 1), and telangiectasia on her face and
hands(Figure2,3).

Laboratory tests showed Haemoglobin 7.8 g/mL, total leucocyte count
5.7\selectlanguage{ngerman}×10\textsuperscript{9}/L and platelet count
258×10\textsuperscript{9}/L. The erythrocyte sedimentation rate was 122
in the 1\textsuperscript{st} hour and the C-reactive protein was
7.8mg/dl. Blood glucose, serum creatinine and electrolytes (including
calcium) were within the reference ranges. Serology immune profile
showed positive antinuclear antibodies (ANA) and SCL70 . The 25-Hydoxy
vitamin D was low (\textless{}5\selectlanguage{english} ng/mL; normal 9--37.6\selectlanguage{english} ng/mL)and the
parathyroid hormone level was normal (21.15\selectlanguage{english} pg/mL; normal 15--65\selectlanguage{english} pg/mL).
On serum protein electrophoresis, a dense monoclonal band of 3.03\selectlanguage{english} g/dL
.No monoclonal proteins were detected in urine.

Immunoglobulin subtype evaluation showed significant high levels of IgG
and Kappa light chain as demonstrated in (table 1)\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Immunoglobuline & \textbf{Results} & \textbf{Reference
range}\tabularnewline
\midrule
\endhead
Immunoglobuline G (IgG) & 3399 & 600-1600\tabularnewline
Immunoglobuline A (IgA) & 623.2 & 70-400\tabularnewline
Kappa chain & 764.14 & 174-370\tabularnewline
Lambda chain & 296.61 & 90-210\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1} : demonstrates Immunoglobulin subtype evaluation

Considering the patient's past history of breast cancer a PET Scan was
performed to look for recurrence , the patient was injected by 11
microkuri of FDG18, and scanned after 1 hour in 3 dimension directions,
the PET scan normal

A bone marrow biopsy showed interstitial and focal increase in plasma
cells (15\%) without bone marrow fibrosis in CD 138 staining.

On skeletal survey, there was diffuse osteopenia with osteoporotic
changes in all the vertebrae without osteolytic fractures. The patient
was diagnosed to have scleroderma coexisting with MM, and was treated
with thalidomide (100 mg/day) and dexamethasone (20 mg/day weekly).The
patient showed an improvement in skin thickening and increased range of
movements after 6 months of therapy.

\textbf{Discussion}

Scleroderma is an autoimmune connective tissue disease, usually affects
people of 30--50 years age group, with a female predominance
(1).Patients with scleroderma can have specific antibodies such as
antinuclear antibody, anticentromere or antitopoisomerase in their blood
which suggest autoimmunity.

Our patient is 58-year-old female with systemic sclerosis and positive
ANA and ScL 70.

Scleroderma is a disease with unknown etiology(1), but there may be a
history of a preceding infection in most cases(2); however, associations
have also been reported with diabetes, systemic lupus erythematosus,
rheumatoid arthritis, Sjogren syndrome, monoclonal gammopathy, and
MM(2,3).

There is possibility that inflammation , molecular deregulation events,
and the circulating factors inducing immunostimulation of B cells in
autoimmune disorders precede clonal proliferation of plasma cells and
lead to the emergence of MM. The second possibility of developing MM may
be related to the use of immunosuppressive drugs. In addition, a common
genetic susceptibility for developing both an autoimmune disease and MM
might also exist (2,3).

In our case the treatment of methotrexate could be a possible cause for
MM development.

In literature cases of scleroderma associated with monoclonal gammopathy
of undetermined significance have been reported. However, association of
scleroderma with MM is rare (Table 2).~Patients' age ranged from 37 to
76 years, with variable duration of developing MM after the diagnosis of
scleroderma. This duration ranges from 1 month to 40 years. Our patient
was diagnosed with MM after a period of 10 years of SSc diagnosis.

\textbf{Table~2:} Cases of systemic sclerosis with multiple myeloma\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Cases} & \textbf{Age/sex} & \textbf{Monoclonal protein} &
\textbf{Duration (years)} & \textbf{Therapy}\tabularnewline
\midrule
\endhead
\textbf{Korting~\emph{et al} \textsuperscript{5}} & 37/F & IgG \selectlanguage{greek}κ & 2 &
Improvement after myeloma therapy\tabularnewline
\textbf{Doyle~\emph{et al} \textsuperscript{6}} & 58/F 62/F & NA & 4 40
& NA\tabularnewline
\textbf{Ohta~\emph{et al} \textsuperscript{7}} & 64/M & IgG \selectlanguage{greek}κ & 11 &
Improvement after myeloma therapy\tabularnewline
\textbf{Hodak~\emph{et al} \textsuperscript{8}} & 74/F & IgG \selectlanguage{greek}κ & 4 &
Improved after 1.5 years of melphalan\tabularnewline
\textbf{Rimon~\emph{et al} \textsuperscript{9}} & 62/F & IgG \selectlanguage{greek}λ & 22 &
NA\tabularnewline
\textbf{Salisbury~\emph{et al}\textsuperscript{10}} & 76/F & IgA \selectlanguage{greek}κ & 0.1
& Improvement after 9 months of cyclophosphamide and
prednisolone\tabularnewline
\textbf{Nakanishi~\emph{et al} \textsuperscript{11}} & 50/M & IgG \selectlanguage{greek}κ & 3
& NA\tabularnewline
\textbf{Schmidt~\emph{et al} \textsuperscript{12}} & 46/M & IgG \selectlanguage{greek}λ & 22 &
NA\tabularnewline
\textbf{Pujol~\emph{et al} \textsuperscript{13}} & 74/M & IgA \selectlanguage{greek}κ & 15 &
Improvement after myeloma therapy\tabularnewline
\textbf{Valente~\emph{et al} \textsuperscript{14}} & 56/F & IgA \selectlanguage{greek}κ & 6 &
Improvement after melphalan and prednisolone\tabularnewline
\textbf{Bachleitner-Hoffman~\emph{et al} \textsuperscript{15}} & 73/F &
IgG & 24 & Improvement after vincristine, melphalan, cyclophosphamide
and prednisolone\tabularnewline
\textbf{Colovic~\emph{et al} \textsuperscript{16}} & 55/F & IgG \selectlanguage{greek}λ & 20 &
Improvement after 6 cycles of endoxan, thalidomide and
dexamethasone\tabularnewline
Smeeta Gajendra \textbf{\emph{etal} \textsuperscript{2}} & 24/M & IgA \selectlanguage{greek}κ
& 8 & Improvement after 9 months of thalidomide and
dexamethasone\tabularnewline
\bottomrule
\end{longtable}

In our case, diffuse osteopenia with osteolysis of phalanges on both
sides and osteoporotic change in vertebrae was observed but no
osteolytic lesions were seen in axial skeleton, unlike in MM, which is
characterized by the presence of osteolytic lesions of the axial
skeleton(2,3).

Plasma cells express osteoprotegrin (OPG) which blocks the interaction
between RANKL and RANK receptor on osteoclast surface leading to
impaired osteoclast resorption and preservation of bone structure(2).
Unfortunately, OPG levels could not be investigated in our patient.

SSc treatment includes non-steroidal anti-inflammatory drugs,
corticosteroids and immunosuppressants such as methotrexate,
azathioprine, mofetil mycophenolate, and cyclophosphamide. Nintedanib,
an antifibrotic agent, tocilizumab, an anti-interleukin-6 receptor
antibody, and rituximab, an anti-CD20 antibody were approved for
interstitial lung disease related to SSc and had showed improvement in
both modified Rodnan skin score(17).

Thalidomide is used for the treatment of MM, as it acts as an
anti-proliferative, antiangiogenic and inhibits myeloma tumor growth
(15-17).~ The previously reported cases showed that systemic sclerosis
symptoms were improved greatly by the treatment used for MM (when the
two conditions were associated) (18).

In our case the patient showed a substantial improvement of her symptoms
after 6 months of MM treatment

\textbf{Conclusion}

In view of the possible coexistence of scleroderma with MM, it is
suggested that all patients with scleroderma should be screened for
monoclonal gammopathy and MM regarding their age. Also, future studies
should be directed to determine the exact mechanism of these two
conditions association and the effect of MM treatment on SSc
improvement.

\textbf{Highlights}

-Coexistence of SSc with MM is an unusual finding with unclear
significance

-It is suggested that all patients with scleroderma should be screened
for monoclonal gammapathy and MM regardless their age.

\textbf{Contributors:} ~ O A, G H, S B,A A and A E prepared and wrote
the manuscript with the help of clinical information from M K. The final
draft was reviewed and edited by M K.

\textbf{Competing interests:} ~None.

\textbf{Patient consent:} ~Obtained.

\textbf{References}

1-Bukiri H, Volkmann ER. Current advances in the treatment of systemic
sclerosis. Curr Opin Pharmacol. 2022 Jun;64:102211. doi:
10.1016/j.coph.2022.102211. Epub 2022 Apr 18. PMID: 35447517; PMCID:
PMC9466985.

2-Smeeta Gajendra,~Richa Gupta,~Ritu Gupta,~and~Lalit
Kumar\textsuperscript{.} Coexistence of scleroderma with multiple
myeloma: a rare association. BMJ Case
Rep.~2013.~doi:~10.1136/bcr-2013-200639.PMCID:~PMC3794227.PMID:~24022902

3- Shimanovsky A, Alvarez Argote J, Murali S, Dasanu CA. Autoimmune
manifestations in patients with multiple myeloma and monoclonal
gammopathy of undetermined significance. BBA Clin. 2016 May 25;6:12-8.
doi: 10.1016/j.bbacli.2016.05.004. PMID: 27331023; PMCID: PMC4900299.

4-Frank van den Hoogen, etal.2013 classification criteria for Systenic
Slerosis. Arhtritis \& Rheumatism 2013.Volume65.N.11.PP:2737-2747.

5- Korting GW, Gilfrich HJ, Meyer zum Buschenfelde KH.~Scleroderma
adultorum and multiple myeloma.~\emph{Arch Dermatol Forsch}
~1974;2013:379--85.

6-~Doyle JA, Connolly SM, Hoagland HC.~Hematologic disease in
scleroderma syndromes.~\emph{Acta Derm Venereol} ~1985;2013:521--5

7-Ohta A, Uitto J, Oikarinen AI, et al.~Paraproteinemia in patients with
scleroderma. Clinical findings and serum effects on skin fibroblasts in
vitro.~\emph{J Am Acad Dermatol} ~1987;2013:96--107.

8-Hodak E, Tamir R, David M, et al.~Scleroderma adultorum associated
with IgG-kappa multiple myeloma---a case report~\emph{.} ~\emph{Clin Exp
Dermatol} ~1988;2013:271--4\emph{.}

9-Rimon D, Lurie M, Storch S, et al.~Cardiomyopathy and multiple
myeloma. Complications of scleroderma adultorum.~\emph{Arch Intern Med}
~1988;2013:551--3

10-Salisbury JA, Shallcross H, Leigh IM.~Scleroderma of Buschke
associated with multiple myeloma.~\emph{Clin Exp Dermatol}
~1988;2013:269--70

11-~Nakanishi H, Takehara K, Soma Y, et al.~Atypical scleroderma
associated with multiple myeloma.~\emph{Dermatologica} ~1989;2013:176--8

12-Schmidt KT, Gattuso P, Messmore H, et al.~Scleroderma and smoldering
myeloma.~\emph{J Am Acad Dermatol} ~1992;2013:319--21

13-~Pujol JA, Bueno M, Fuertes MA, et al.~Improvement of scleroderma
associated with IgA multiple myeloma alter chemotherapy.~\emph{Clin Exp
Dermatol} ~1995;2013:149--52.

14-Valente L, Velho GC, Farinha F, et al.~Scleroderma, acanthosis
nigricans and IgA/kappa multiple myeloma.~\emph{Ann Dermatol Venereol}
~1997;2013:537--9.

15-Bachleitner-Hofmann T, Machold K, Knobler R, et al.~Marked and
sustained improvement of systemic sclerosis following polychemotherapy
for coexistent multiple myeloma.~\emph{Clin Exp Rheumatol}
~2002;2013:85--8

16-Colovic M, Jurisic V, Bila J, et al.~FGF-R3 and OPG expression in
patient with multiple myeloma following systemic sclerosis: case report
and review of the literature.~\emph{Int J Hematol} ~2011;2013:228--31.

17- Ebata S, Yoshizaki-Ogawa A, Sato S, Yoshizaki A. New Era in Systemic
Sclerosis Treatment: Recently Approved Therapeutics. J Clin Med. 2022
Aug 8;11(15):4631. doi: 10.3390/jcm11154631. PMID: 35956246; PMCID:
PMC9369903.

18- Oliver SJ, Kaplan G.~Reduced fibrosis and normalization of skin
structure in scleroderma patients treated with
thalidomide.~\emph{Arthritis Rheum} ~1999;2013:S187.\selectlanguage{english}
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