A possible association of orthopedic metal implants and ASIA syndrome

Autoimmune disease following surgery with metal device placement, should prompt considering autoimmune/inflammatory syndrome induced by adjuvants, and their removal. Sir, Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a recently identified condition under debate [1, 2]. The exposure to adjuvants such as silicone [3], vaccines [4] and others may lead to an aberrant immune response, with arthralgia, myalgia and chronic fatigue being its common symptoms [5]. Diagnostic criteria have been proposed for ASIA [5], and the most frequent autoimmune disease related to it is undifferentiated connective tissue disease (UCTD) [5, 6]. Metal implants have been suggested in a few case reports as a trigger for ASIA [7, 8]. We describe herein two patients, one of whom developed UCTD and the other an overlap syndrome. Their disease developed at a relatively late age, within 18 months of a forearm fracture fixation surgery using titanium plate and locking screws. Both patients deteriorated in spite of immuno-suppressive treatment. Following extraction of the plate and screws, accompanied with medical treatment, they improved significantly. We presume that both patients developed ASIA syndrome as a result of exposure to orthopedic metal implants. The detailed case reports are described herein. The first was a 75-year-old female, previously diagnosed with a chronic kidney disease of unknown aetiology (baseline creatinine 2.1 mg/dl). In November 2016, she underwent surgery of her left radius bone following trauma using a DePuy Synthes titanium plate, locking screws and injectable bone graft (calcium sulfate). Shortly after the operation, the patient reported erythema and a constant burning and itching sensation around the fixation plate for nearly a month. In February 2018, the patient complained of swelling, redness and local warmth over the operated area. On April, 2018, she was admitted to the hospital complaining of redness and swelling around the surgical scar and a diffuse papular rash. A skin biopsy revealed superficial perivascular dermatitis with no signs of vasculitis. Lab results showed creatinine 8.1 mg/dl, and dialysis was ensued. During her hospitalization, acrocyanosis developed in all limbs, with subsequent gangrene. Lab results showed elevated creatinine kinase (ranging 470–9000 U/l), positive-anti-Sjögren-syndrome-related-antigen-A, with negative cryoglobulins and viral serology. Myositis-specific antibodies panel was also negative. A CT demonstrated pulmonary infiltrates, which were negative for malignancy as per lung biopsy. Capillaroscopy exhibited vasculopathy with no clear evidence of SSc. Neurological evaluation showed severe proximal myopathy, and bone technetium scanning demonstrated increased uptake on her left distal radius. Muscle biopsy was non-diagnostic. The clinical constellation was consistent with UCTD. On April 22, following spontaneous swelling of the left forearm, with a normal coagulation and platelet profile, she underwent surgery for evacuation of a haematoma. As of April 25, the patient was treated with methylprednisolone (1 g/day/5 days) followed by plasma exchange, with no response. Following patient request and clinical deterioration, the plate and screws were removed in May 2018 with a noticeable clinical improvement and a decline in creatine phosphokinase values from 9000 to 4000 U/l a week later, 2800 U/l 2 weeks later, and 530 U/l within a month. It should be noted that CYC treatment was initiated 1 week after surgery, but from our experience, an effect on creatinine kinase values was expected only after 4–8 weeks. She is now in complete remission under prednisone 5-mg treatment. The second case was a 65-year-old healthy female who, on 6 October 2017, underwent open reduction internal fixation surgery of the right distal ulnar bone fracture due to a fall. DePuy Synthes titanium plate and locking screws were used. Orthopedic follow-up in November 2017 displayed diffuse swelling of the right hand and joint stiffness. Since January 2017 RP was noticed, and a palpable tendon friction rub was felt over her right wrist extensors. During the period of January to February, 2018, she was evaluated for progressive weakness, right hand pain with contractures, skin thickening and RP. Furthermore, she reported dyspnea after minimal effort, difficulty in swallowing, regurgitation and an unintentional 3-kg weight loss. Lab results showed creatinine kinase ranging from 575 to 1023 U/l, a positive ANA and anti-PL7. CT demonstrated pericardial effusion, dilated esophagus and interstitial lung disease. Bone scanning showed an increased signal on the right forearm and hand. Stomach endoscopy and biopsy demonstrated bleeding gastric antral vascular ectasia. Capillaroscopy showed multiple microhemorrhages and pathological capillaries. A scleroderma-PM overlap syndrome was diagnosed. We treated her with IVIG, MTX, ciclosporin, steroids (3 months) and Rituximab therapy, with no significant clinical or laboratory response. Due to her deteriorating clinical state, it was decided to remove the implant on 15 May 2018, resulting in a mild clinical response and a decrease in creatine phosphokinase values to 250 U/l. Three months following the surgery, the patient had a clinical flair-up and her creatine phosphokinase levels increased to 600 U/l. I.v. CYC and Cellcept were prescribed to replace MTX. Five weeks later, she was treated with a second course of Rituximab therapy (1000 mg ×2). As of October 2018, the patient has shown constant clinical and laboratory improvement, and she is now in complete remission under Rituximab therapy and IVIG treatment. The authors would like to thank the patients for agreeing to share their experience for this report and Marianne Steinmetz for editing the manuscript. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest.