A case of overlap syndrome successfully treated with canakinumab: A new treatment

approach for refractory dermatomyositis

Abstract:

Introduction: Juvenile dermatomyositis (JDM) is a rare and heterogeneous disease. High

dose of corticosteroids remain the cornerstone of the therapy along with other
immunosuppressive therapies.
Aim: Here we present a patient with severe JDM and poliartricular JIA successfully treated
with canakunimab.

Case: A 12 years old female patient diagnosed with JDM and polyarticular JIA- overlap
syndrome due to having typical rashes for dermatomyositis, muscle weakness and
polyarthritis. She was resistant to conventional immunosuppressive therapies for years. Her
clinical and laboratory findings improved significantly after starting canakinumab therapy.

Conclusion: This is the first case having overlap syndrome treated with canakinumab
successfully. There is no data on the efficacy of canakinumab treatment in juvenile
dermatomyositis in the literature. More studies are needed on this subject.
Introduction
Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in the
childhood period (1). It is characterized by proximal muscle weakness and pathognomonic
skin rashes such as Gottron’s papules and the heliotropic rash (1,2). Skin ulceration,
calcinosis, major organ vasculopathy (gut, cardiac etc), dysphagia and respiratory
involvement have been proposed as predictors of a severe disease course in JDM. There are,
however, no serological or genetic tools currently available to predict who will suffer these
extramuscular complications (3). Arthritis is another common manifestation of JDM with a
reported prevalence of 23–64% of cases. It may occur early in the course of the disease, and
is usually non-erosive. Overlap syndromes (OS) can include the some findings of
dermatomyositis / polymyositis and systemic lupus erythematosus, rheumatoid arthritis,
systemic sclerosis, etc. OS is more frequent in females than males (female/male ratio is 1:9),
and generally associated with anti-PM-Scl, U1RNP and Ku autoantibodies (4).

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease characterized by the

presence of arthritis in children under 16 years of age for more than 6 weeks in the absence of
any other known causes (5). Polyarticular JIA is defined as the appearance of arthritis in 5 or
more joints in the first 6 months of the disease. It is further divided into two subgroup as
rheumatoid factor (RF) positive or RF negative (5).

Overlap myositis is defined as coexistence of myositis and another connective tissue

disease. Myositis is usually mild and polycyclic in patients with OS (6). Although overlap
myositis generally shows a milder course with favorable treatment response, here we present
a child with severe dermatomyositis and poliartricular arthritis successfully treated with
canakunimab.

Case report

A 12 years old female patient admitted to our clinic with the complaints of skin rash, swelling
of joints, weakness, and difficulty in walking for 8 years. On her physical examination,
erythematous skin lesions on the face and extremities, heliotropic rash, severe muscle
weakness and arthritis in bilateral ankle, knee, wrists, metacarpophalangeal and
interphalangeal joints were detected (Fig 1). CBC revealed leukocytosis (22.8000 / mm3),
neutrophilia (19.600 / mm3), mild anemia (hemoglobin: 10.80 gr / dl) and thrombocytosis
(560.000 / mm3). Erythrocyte sedimentation rate (ESH) was 98 mm / h and C reactive protein
(CRP) was 12 mg / dl on admission. Creatine kinase (CK) and aldolase levels were normal.
Antinuclear antibody (ANA) and ANA profile was negative; serum levels of C3, C4,
rheumatoid factor and anti- CCP antibody were normal. Increased muscle echogenicity was
detected in her both upper and lower leg by ultrasonography. A biopsy sample obtained from
the muscle of right upper arm showed that increased HLA expression in sarcolemma and
prominent mononuclear cell infiltration in perivascular area were compatible with JDM. The
patient was treated with prednisolon, methotrexate, and etanercept for four years in another
rheumatology center. Despite these treatments, skin findings, joint complaints and muscle
weakness did not improve and contractures were developed in her many joints. For these
reasons, various immunosuppressive treatments including cyclophosphamide (500mg/m2),
infliximab (5mg/kg-7dose), rituximab (375 mg/m2, weekly, for 4 weeks), high dose IVIg (2
gr/kg/dose, 8 times), mycophenolate mofetil (500 mg/day), and tocilizumab (12mg/kg), were
applied at different time intervals to improve her joint and muscle findings during 5 years.
Since all these treatments were unhelpful to control her disease, canakinumab had been
started at the doses of 8 mg/kg monthly bases for the last 6 months. Her skin and joint
symptoms receded and she gained muscle strength. Not only clinical findings of her, but also
acute phase proteins turned to normal.
Discussion

Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The

ligands and receptors of IL-1 family are strongly associated with both acute and chronic
inflammation (7). It has been reported that IL-1 can affect almost every cell type and has an
effect in concert with other cytokines (8). As a main result of IL-1 secretion, T and B
lymphocytes are activated and many cytokines are released (9). Monotherapy blocking IL-
1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease
severity, including reversal of inflammation-mediated loss of sight, hearing and organ
function. Anti-IL-1β therapy is mainly used in autoinflammatory diseases whereas the use of
immunosuppressive drugs in autoimmune diseases is more preferred (7). There is no data
related to canakinumab treatment in polyarticular JIA or JDM. In this case, it had been
observed that clinical and laboratory findings of the patient improved prominently after the
use of canakinumab. From the pathogenetic point of view, autoimmune and autoinflammatory
diseases are characterized by a chronic activation of immune system, which eventually leads
to tissue inflammation in genetically predisposed individuals. Nevertheless, the specific
effectors of the damage are different in the two groups of diseases: in autoinflammatory
diseases the innate immune system directly causes tissue inflammation, whereas in
autoimmune reactions the innate immune system activates the adaptive immune system
which, in turn, is responsible for the inflammatory process  (10). This fact may explain that
effectivity of canakinumab in JDM and polyarticular JIA which have been accepted as
autoimmune disease. The coexistence of dermatomyositis and rheumatoid arthritis has been
reported in adults but not reported in children so far (11,12,13). Our patient developed the
symptoms of JDM together with polyarticular JIA, as match the criteria of overlap syndrome.

Steroids (prednisone, methylprednisolone), hydroxychloroquine, methotrexate,

azathioprine, cyclosporine, and IVIG in different combination therapy regimens have been
used in treatment of JDM succesfully (14). Biological treatments have provided important
advances in the treatment of chronic arthritis in both children and adults. Biological
treatments have been developed against many cytokines or receptors such as; tumor necrosis
factor, IL-1, IL-6, B cell surface antigen -CD20 and the CTLA molecule (14). IL-1 receptor
antagonist (Anakinra) was used in adulthood refractory inflammatory myopathies successfully
(15). There is no data in the literature on the use of canakinumab therapy in adulthood or
juvenile inflammatory myopathies and polyarticular JIA. Since we could not get a good
response to previous treatments in our case, canakinumab was administered, and a satisfying
response was obtained.

In conclusion; suppression of the IL-1 inflammatory pathway may be effective in

treatment of JDM and polyarticular JIA combined overlap syndrome. Early and accurate
treatment is important in reducing the risk of associated morbidity and poor outcomes. The
use of IL-1 blockers at early stage of inflammatory myositis may prevent the long-term
complications of corticosteroids.

Conflict of interest: None.