PMC8811255_01
Overview with timeline of clinical manifestations and treatments March 2018 to August 2021. Tx, therapy; PDN-dose, prednisolone dose (in mg/day); DX, current working diagnosis; MTX, Methotrexate; TCZ, Tocilizumab; ADA, Adalimumab; ANA, Anakinra; AZA, Azacytidine; CAN, Canakinumab; TOF, Tofacitinib; IFX, Infliximab; BMA, bone marrow aspirate; PMR, polymyalgia rheumatica; RA, rheumatoid arthritis; PsA, psoriatic arthritis; Hb, Hemoglobin (normal range, 135-168 g/L); MCV, mean corpuscular volume (normal range, 80-89 fl); Tc, Thrombocytes (normal range,150-450 G/L); CRP, C-reactive protein (normal < 3 mg/L); *Bone marrow aspirate.
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Measures of CRP, hemoglobin, MCV and thrombocytes are shown in detail in  Figure 1 ; minimum/maximum values in  Supplementary Table 1 . Seronegative rheumatoid arthritis (RA) was suspected and treatment with oral corticosteroids (CS) with up to 50 mg oral prednisone (PDN) daily and add-on methotrexate (MTX), 15 mg/week s.c. was initiated ( Figure 1 ). An initial hematologic workup with bone marrow assessment showed multilineage reactive changes and normal cytogenetics, which was insufficient for a definitive diagnosis of MDS ( Figure 1 ).
Pulmonary and esophageal affection on CT-scans. (A) multifocal nodular pulmonary infiltrates (arrows) on transverse (A1) and coronal (A2) high resolution CT scan. (B) diffuse pulmonary infiltrates (arrows) on transverse (B1) and coronal (B2) high resolution CT scan. (C) FDG-PET-CT scan: diffuse esophageal (arrowheads) tracer uptake and multiple pulmonary nodules (arrows).
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About one year later, the patient was hospitalized with pleurisy and nodular pulmonary infiltrates ( Figure 2A ). Treatment was switched to canakinumab (one application of 150mg s.c., without subsequent local reaction of the skin), which led to an immediate deterioration with markedly elevated inflammatory markers, recurrence of pleurisy and new diffuse pulmonary infiltrates ( Figure 2B ). An FDG-PET-CT scan revealed no signs of malignancy but showed significant esophageal tracer-uptake ( Figure 2C ), with no corresponding pathology detected on subsequent endoscopy of the upper gastrointestinal tract and MRI.
Cutaneous manifestations. (A) Pustulosis of the left arm. (B) Abdominal panniculitis after local application of anakinra. (C) Cervico-thoracic neutrophilic dermatosis. (D) Close up picture of cervico-thoracic neutrophilic dermatosis in (C). (E) Nodular phlebitis of the right forearm.
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The regular application of ANA led to a satisfactory relief of inflammatory symptoms and allowed considerable CS dose reduction, but provoked severe panniculitis at the injection sites ( Figure 3B ). This was followed by a trial of infliximab (IFX) up to 5mg/kg bodyweight monthly for two months, with no relevant treatment response and even development of nodular phlebitis of several veins of both arms ( Figure 3E ).
Histologic examinations. (A) Bone marrow cytomorphology: Pappenheim staining of a bone marrow aspirate is shown with typical vacuolizations in erythroid ( ) and myeloid progenitors ( ). Moreover, megaloblastic (*) and macroblastic (**) changes can be seen in the normoblasts (light microscope Zeiss, x40). (B) Bone marrow cytomorphology: Higher magnification of vacuolized myeloid progenitor (light microscope Zeiss, x100). (C, D) Histology of the skin: Neutrophilic dermatosis with neutrophilic perivascular and interstitial infiltrate with leukocytoclasia and few eosinophils involving the dermis.
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At that point, a new BMA, performed for staging of the MDS, confirmed the presence of the typical vacuolisation of the myeloid and erythroid progenitor cells ( Figures 4A, B ).