A 33-year-old patient was diagnosed in 2006 with stage IIIa nodular sclerosing Hodgkin lymphoma, treated with 12 different therapeutic regimens due to multiple relapses, including successively ABVD, radiotherapy, cisplatin containing regimen and autologous stem cell transplantation after BEAM conditioning regimen (year 4) (Additional file 1: Figure S1). He relapsed again, and was treated successively by bendamustin, FMS tyrosine kinase inhibitor, ICE, holoxan; bendamustin, and a first allogeneic stem cell transplantation from one of his HLA-matched sister (year 9) (conditioning regimen: Fludarabine 30 mg/m2 day 1-5; busulfan 3.2 mg/kg day 3 and 4; antithymocyte globulin 2.5 mg/kg day 5 and 6. 98% donor-type chimerism was achieved after this first allo-SCT.
He unfortunately relapsed, and successively received vinblastine, navelbin, brentuximab, gemcitabine, and 8 injections of Nivolumab every 2 weeks (3 mg/kg; pre-approval access, French authorization), from March to June 2016 (year 10) followed by a second allogeneic SCT from another HLA-haplo-identical sibling donor (conditioning: TBI 2 Gy on day 1; Cyclophosphamide 14.5 mg/kg/day day 2 and 3; Fludarabine 30 mg/m2/day, day 2 to 6). Full chimerism was reached 1 month after the haplo-SCT.
Clinical and radiographic resolution of cHL were reached, but in October 2016, he was hospitalized for an acute interstitial pneumonia associated with hepatic cytolysis and cutaneous eruption consisting of interspersed erythematous plaques with central vesiculo-bullous elements lacking Nikolsky's sign on trunk, shoulders, abdomen and legs. There were remaining patches of unaffected skin (Fig. 1). Mucosal (oral, ophthalmic and genital) lesions were also observed, with localized ulcerations and erosions. Bacteriological investigations including bronchoalveolar lavage were negative. Antibiotics were initiated but blood cultures returned negative. Subsequently, he presented with acute hypoventilation requiring invasive mechanical ventilation. Cerebral CT-scan and magnetic resonance imaging (MRI) were performed and did not reveal any cerebral abnormality. Lumbar puncture was performed, indicating normal white-cell count and protein/glucose levels. An electromyogram was performed, favoring myositis. 
Hepatic cytolysis and cholestasis progressed (maximal values: ASAT: 942 UI/lL, x 25.4 normal range; ALAT: 1 166 UI/L, x14.9 normal range; bilirubin 629 micromol/L, x37 normal range). Further complications occurred, including acute renal failure requiring hemodialysis, diarrhea and moderate colitis. Although some of these adverse events were compatible with severe GVHD, others were uncommon and highly evocative of immune checkpoint blockers-induced immune-related adverse events.
The patient exhibited endocrine complications, with acute pancreatitis (Balthazar C) and hypothyroidism (TSH 59 IU/L). Moreover, troponin was elevated (4 microg/L) without any evidence of myocardial infarction; ECG (Fig. 2) showed regular rhythm at a rate of 55 bpm with normal QRS complex duration (< 0.12 s) and morphology. There were regular atrial waveforms seen at a rate of 70 bpm, and of same morphology with an isoelectric baseline between each atrial waveform. PP interval was constant with no relationship between the P waves and QRS, demonstrating atrioventricular dissociation. AS atrial rate was faster (70 bpm) than the ventricular rate (55 bpm). Complete heart block was diagnosed while subsequent junctional escape rhythm axis was normal at +45  (positive and equivalent QRS voltage in leads I and aVF). Beat to beat QRS complex amplitude remained constant along the trace, T wave amplitude and morphology as well (no electric alternans). There was no argument for left ventricular hypertrophy as RV2 + SV5 < 35 mm. Slope of ST segment was normal (no down or up-sloping ST segment depression). The QT/QTc intervals were normal (600 ms/428 ms). Additional transthoracic echocardiography confirmed an acute myocarditis. 
Eventually, these multisystemic injuries were hypothesized to result from cumulated immune-related adverse events induced by Nivolumab and/or exacerbated GVHD. The patient successively received mycophenolate mofetil, steroids (1 to 2 mg/kg) and polyvalent immunoglobulins, without any improvement leading to death.
A skin biopsy was analyzed by HES coloration (Fig. 3a, b) after hospitalization, 3 months after the second allograft. The stratum corneum was thickened, the epidermis contained diffused inflammatory cells, and there was an epithelial intercellular oedema. Numerous inflammatory cells accumulated along the dermoepidermal junction, leading to its liquefaction. Necrotic keratinocytes were frequently seen, without typical satellite cell necrosis. One section stained with periodic acid Schiff (PAS) did not show any infectious agent (not shown). Immunohistochemistry revealed the presence of numerous CD3 + lymphocytes, with similar proportions of CD4 + and CD8 + lymphocytes (Fig. 3c-e). PD-L1 was found to be expressed in the inflamed dermoepidermal junction and in the epidermis both on immune cells and on keratinocytes (Fig. 3f, g). 
In the liver biopsy (collected 4 months after the second allograft) there was moderate inflammation, with discrete lymphocytic infiltration. An important cholestasis was seen, associated with foam cells. There was no vein endotheliitis. PD-L1 was found to be expressed on inflammatory cells, as well as on Kupffer and endothelial cells (Additional file 2: Figure S2).
A muscular biopsy was performed 3 months after the haplo-SCT, and showed foci of endomysial inflammation (Fig. 4a, b). There was evidence of acute necrotizing myositis characterized by several foci of necrotic muscle fibers, macrophage activity and some regenerative fibers (Fig. 4b arrows highlight some basophilic fibers with nuclear internalizations). There was massive lymphoid-histiocytic infiltration of muscle fibers (Fig. 4b). The infiltrating cells were mostly CD3 + , although some CD68 + macrophages were present (Fig. 4e, f). In the endomysium, CD4 + lymphocytes were in higher density than CD8 + (Fig. 4g, h). There was a high expression of both HLA class I and HLA class II molecules at the surface of infiltrating cells and a diffuse sarcolemic expression. The expression of both HLA molecules was also sarcoplasmic in the inflammatory foci (Fig. 4c, d), confirming the diagnosis of myositis. PD-L1 was found to be expressed in the inflamed area, both on immune cells and myocytes (Fig. 4i-k).