The association between IIMs and cancer has been widely reported, with an increased risk by 2- to 7- fold in adults, so that malignancy screening is suggested for all adult patients with newly diagnosed inflammatory myositis [8]. Cancer-associated myositis (CAM) is typically defined as the development of a malignancy within 3 years of the diagnosis of myositis. Pathogenesis of CAM is still unclear, but a paraneoplastic nature has been proposed, given the cancer diagnosis and myositis onset temporal coincidence, their clinical course correlation, and common expression of myositis-specific autoantigens between cancer cells and regenerating muscle cells [9, 10]. While no significant difference was observed in the incidence of cancer among IIMs subgroups, recognized risk factors for CAM include male gender, older age at disease onset, extensive skin or muscle involvement, elevated inflammatory markers, negative ANA and/or MSAs and, interestingly, anti-SAE1, anti-NXP2, anti-HMGCR and anti-TIF1-γ antibodies positivity [10, 11], also referred to as cancer associated autoantibodies (CAAs). Adult patients with anti-TIF1-γ antibody showed the highest risk (17-fold higher compared to age- and sex-matched general population) and prevalence (40.7%) of CAM, with an estimated specificity for diagnosing CAM of 92% [12]. No correlation was found between different CAAs and certain type of cancer, prognosis (which is overall worse compared to myositis without cancer), and temporal relationship between myositis onset and cancer diagnosis [10].
In children, at least one myositis autoantibody can be identified in approximately 70% of JIIM patients [13]. Anti-TIF1-γ antibody is the most prevalent (22–36%) [4], and has been associated with more severe cutaneous disease, lipodystrophy, and chronic disease course [14], but not with CAM [6]. TIF1 family includes three 155-kDa, 140-kDa and 120 kDa proteins (TIF1-α, TIF1-β, and TIF-γ respectively), involved in several cellular pathways such as cell proliferation, apoptosis, and innate immunity [15]; in particular, high levels of TIF1-γ were found in both regenerating skeletal muscle cells [16] and tumor cells [17], supporting the hypothesis of a paraneoplastic mechanism causing CAM. Further studies are needed to explain the difference in CAM’s incidence between anti-TIF1-γ positive adult and children; the correlation between age and risk of cancer observed even among anti-TIF1-γ positive adult patients [18] could be part of the answer.
CAM is rare in children: an update by Morris [19] only found 12 pediatric cases over 45 years of literature up to 2008. Therefore, routine malignancy screening is not generally performed [20]. Nonetheless, as shown by our case, cancer can occur, defining a poorer prognosis especially if not recognized. Severe onset, with or without CAAs positivity, and anti-TIF1-γ antibody in particular, should always be considered in JIIMs and lead to perform a screening for malignancy. Anti-PM/Scl100 antibody is one of the most common MAAs in JIIMs, accounting for approximately 4% of cases; it is correlated with overlap myositis (OM) in adult patients, but data on associated clinical phenotype in children are limited [14, 21]. ANA testing does not necessarily identify a specific rheumatic disease if positive [2]; ANA positivity is found in approximately 70% of JIIM patients [22], especially if anti-TIF1-γ positive [14].
Another important issue to consider in this case is the presence of an underlying known spinal dysraphism that can be associated to cancer presence, as in our case. Benign teratomas have already been reported to be possibly associated with JIIMs, along with other paraneoplastic syndromes such as limbic encephalitis, seronegative polyarthritis, or autoimmune hemolytic anemia [23].
The treatment of CAM follows the rules of JIIM; as recently stated by SHARE recommendations [24], the mainstay of treatment is high-dose glucocorticoid (preferably methylprednisolone pulse 15–30 mg/Kg/dose for 3 days, followed by oral prednisolone 1–2 mg/Kg/day) initially in combination with methotrexate (15–20 mg/m2 weekly, preferably subcutaneously). Given the need of surgical intervention, in our case mycophenolate mofetil was preferred over methotrexate for its better profile in terms of infectious risk, being an effective and well tolerated option in JDM treatment as well [25]. IVIG can be added to first-line therapy of severe forms of JIIM, presenting with marked dysphagia or weakness [26]. Other treatment options, variably used for refractory disease in absence of head-to-head trials, include ciclosporin A, cyclophosphamide, azathioprine and biologics such as rituximab. In particular, in a trial with 200 adult and juvenile patients suffering from PM, DM or JDM and treated with rituximab, 83% reached a clear improvement [27], with the presence of MSAs predicting a more rapid response [28]. The severity of our patient suggested to be very aggressive in early treatment (steroids, IVIG, mycophenolate and rituximab) even if a teratoma was found and then successfully surgically removed. Steroids tapering should be considered only when clinical improvement is documented; a steroid-tapering regimen was recently proposed by PRINTO group [29], suggesting to gradually reach a prednisone dose of 1 mg/Kg/day by month 2, then the safer dose of 0.2 mg/Kg/day by month 6, and to maintain such dose up to month 12, when the dose should be halved twice more until steroid suspension at month 24. Withdrawal of disease-modifying drug should be considered once the patient is in remission and off steroids for a minimum of 1 year [24].
Overall mortality for JIIMs accounts for approximately 4%; clinical subgroup (JCTM>JPM > JDM), weight loss and dysphagia at illness onset are predictors of mortality [30]. A monocyclic course, with medication suspension within 2 years, is reported in 25% of patient, with another 25% having a polyphasic course; anti-TIF1-γ antibody positivity and severe illness onset carry a greater risk of chronic course, observed in the remaining 50% of patients [31]. Most of adult patients with CAM obtain remission after removal of malignancy, but in some cases myositis recur even without a relapse of cancer, probably because of a self-perpetuating, although cancer-triggered, immune response [12].
Severe onset of a JIIM, especially if anti-TIF1-γ antibody positive, should prompt suspect of a CAM and lead to a screening for malignancy.
