Paraneoplastic syndromes, rheumatical

Rheumatologic paraneoplastic syndromes are rare, but represent an important differential diagnosis to classical rheumatologic and other rheumatologic accentuated clinical pictures (e.g. systemic scleroderma/dermatomyositis). Early recognition of the syndromes, if necessary taking into account additional laboratory and other examination findings, allows early detection of an underlying malignancy and, if necessary, curative therapy.

• Paraneoplastic Arthritis (PA): Paraneoplastic arthritis is particularly difficult to detect because, in addition to polyarthritis, positive rheumatoid factor is present in up to 23% and positive anti-citrullinated proteins (ACPAs) are present in 11% of patients (Kisacik B et al 2014). Asymmetric joint involvement (91%) in male patients and poor treatment response to disease-modifying anti-rheumatic drugs (DMARDS) suggest a paraneoplastic etiology.
• Palmary fasciitis with polyarthritis (PFPAS): The rare PFPAS syndrome, compared to paraneoplastic arthritis, forms a clearly demarcated appearance due to associated inflammation of the palmar/plantar fascia. The diffuse inflammation of the palmar fascia, tendon sheaths, joints of the fingers and wrists, rapidly leads to a (scleroderma-like) flexion contracture of the hands (woody hands). The clinical course shows analogies to Dupuytren's contracture. Originally, palmar fasciitis/polyarthritis syndrome was associated with ovarian cancer (> 50% of patients). However, it is now associated with several other malignancies e.g., adenocarcinoma of the lung, non-small cell carcinoma of the lung (Okumura H et al. 2022; Manger B et al. 2014; Sheehy C et al. 2007).
• Pancreatic panniculitis with polyarthritis (PPP): PPP refers to a syndrome in which polyarthritis is associated along with panniculitis. PPP often occurs in patients with pancreatitis and severely elevated lipase levels (Narváez J et al 2010). Knee, ankle, hand, and metacarpophalangeal joints are most commonly affected. In acinar cell carcinoma of the pancreas, PPP with high lipase levels is common. Here, PPP syndrome is associated with a poor prognosis (Zundler S et al. 2016).
• Remitting seronegative symmetrical synovitis with pitting edema (RS3PE): Clinically, RS3PE patients present with usually acute, bilateral, massive, pillow-like swellings of the dorsum of the hands and/or feet, with associated synovitis of the hand and finger joints (the rheumatologic components are often masked). The edema is deeply depressible and shows prompt improvement on glucocorticoids and NSAIDs. Other joints affected, but less commonly, include the MTP and small toe joints, elbow, shoulder, hip, knee, and ankle joints. Low-dose corticosteroids result in very good treatment response. Poor response to therapy is indicative of the presence of paraneoplastic RS3PE, which is present in approximately 30% of these patients (Li H et al. (2015). Serologically, elevated serum matrix metalloproteinase 3 (MMP-3) levels were detected in patients in a Japanese cohort (Li H et al. (2015).
• Tumor-induced osteomalacia (TIO): The syndrome is caused by rare mesenchymal osseous tumor entities (40%) or soft tissue tumors (55%), with approximately 8% being malignant (Jiang Y et al. (2012). Tumor cells release fibroblast growth factor 23 (FGF 23), which leads to increased phosphate secretion by binding to receptors of proximal renal tubule cells (Hautmann AH et al 2015). Laboratory chemistry reveals hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase, and a normal to decreased 1,25-dihydroxycholecalciferol level. Clinically, there is bone pain, spontaneous fractures, muscle weakness, and fatigue.
• Hypertrophic osteoarthropathy (Marie-Bamberger) (HOA): This classic paraneoplasia is particularly caused by thoracic malignancies (lung carcinoma/Izumi M et al 2010). Increased production of vascular endothelial growth factor(VEGF) leads to differentiation of the periosteum into osteoblasts (Martinez-Lavin M (2007). This leads to the typical drumstick fingers, toes, arthritis, arthralgias, bone pain especially in tibia and femur due to osteoproliferations which can be visualized by imaging techniques (scintigraphy and positron emission tomography ).
• Malignancy-associated myositis (CAM): Inflammatory myopathies (IIM) comprise a heterogeneous group of muscle diseases (Lundberg IE et al. 2017) and are associated with a variable risk of malignancy. The subgroup of dermatomyositides is associated with a markedly increased risk of malignancy, unlike the other IIMs, some of which are poorly defined (Qiang JK et al 2016). The malignancy risk of dermatomyositis patients with evidence of anti-TIF1γ antibodies is increased 27-fold (Trallero-Araguás E et al. (2012). TIF-1γ ubiquitinates the tumor suppressor gene p53, thereby downregulating it, leading to decreased apoptosis of tumor cells. The increased presence of TIF-1γ in skin and muscle cells supports its ethiopathogenetic significance. Antibodies to nuclear matrix protein 2 (NXP2) are also associated with an approximately 4-fold increased risk of malignancy compared to the normal population (Albayda J et al.2017). The absence of specific antibodies in IIM patients is also associated with an increased risk of malignancy (Trallero-Araguás E et al. 2012). There is evidence supporting blind screening of IIM patients and clear algorithms for screening in IIM patients (Selva-O'callaghan A et al. 2018). The greatest likelihood of malignancy is 1 year after and 1 year before symptom onset, and extends to approximately 3 to 5 years before/after symptom onset (Sigurgeirsson B et al. 1992).

Evidence of a rheumatic paraneoplastic syndrome .

• atypical constellation of symptoms
• unusual age of onset
• unusual joint involvement pattern
• unusually high humoral inflammatory activity
• B-symptomatology
• severe distal edema
• palmar or plantar fasciitis
• poor response of rheumatologic symptoms to glucocorticoids, NSAIDs or immunosuppressants
• In myositis: detection of anti-TIF-1γ, anti-NXP-2 autoantibodies,
• Pronounced muscle involvement (very high creatine kinase levels),
• pronounced, even unusual and therapy-resistant skin symptoms (possibly partial manifestations of the paraneoplastic symptom constellation).

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