**10. Conclusions**

96 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

150 mg/m² i.v.

**General remarks:**

(e.g., PPIs)

150 mg/m² i.v.

week

experience (personal communication with Jan-Inge Henter)

intravenous immunoglobulin; PPI – proton pump inhibitor.

once weekly every alternating (with Dexamethasone) second

alternating (with etoposide) second week

\* – etoposide dose recommendations for adults are not validated proposal, but based on clinical

HLH - hemophagocytic lymphohistiocytosis; CSF – cerebrospinal fluid; CyA – cyclosporine A; IVIG -

Table 9. The HLH-2004 immunochemotherapy protocol for management of hemophagocytic

(week 3–8)

twice weekly in 2 weeks followed by once weekly administration

10 mg/m² p.o. daily in 2 weeks (week 1–2) 5 mg/m² p.o. daily in 2 weeks (week 3–4) 2.5 mg/m² p.o. daily in 2 weeks (week 5–6) 1.25 mg/m² p.o. daily in 1 week (week 7) tapering and discontinuation during week 8

IVIG (0.5 g/kg) once every 4 weeks

Methotrexate injections are recommended

pulses of 10 mg/m² p.o. for 3 consecutive days, given every

dose aiming CyA concentration at trough of 200 µg/l (adults 100–200 µg/l)

**Initial therapy (weeks 1–8) aiming remission** 

**Continuation therapy (≥ week 9) after achieved HLH remission until alloSCT or** 

**discontinuation** 

lymphohistiocytosis

**therapy** 

**of HLH** 

**Children Adults\*** 

**Etoposide**

Caution! Adults usually do not tolerate as high etoposide doses as children, therefore dose reduction is indicated as proposed above **Dexamethasone**

**Cyclosporine A** 3 mg/kg p.o. twice daily during the first week of therapy, followed by dose aiming CyA concentration at trough of 200 µg/l (week 2–8) Caution! Adults usually do not tolerate as high CyA concentrations as children, and CyA concentrations of 100–200 µg/l may be acceptable

1. Maximal initial supportive care is suggested, inclusive: appropriate broad-spectrum antibiotics (until culture results); prophylactic co-trimoxazole (equivalent to 5 mg/kg of trimethoprim 3 times weekly); an oral antimycotic therapy; antiviral therapy in patients with ongoing viral infection; and

2. Gastroprotection due to the high steroids doses is recommended

3. If after 2 weeks there is clinical evidence of progressive neurological symptoms or if abnormal CSF (pleocytosis and elevated proteins) has not improved, 4 weekly intrathecal

**Etoposide**

**Cyclosporine A**

week **Dexamethasone**

50–100 mg/m² i.v.

once weekly every alternating (with Dexamethasone) second

50–120 mg/m² i.v.

(week 3–8)

twice weekly in 2 weeks followed by once weekly administration

> Autoimmune-associated hemophagocytic syndrome/macrophage activation syndrome is a life-threatening hyperinflammatory syndrome which remains a major cause of morbidity and mortality in patients with autoimmune/autoinflammatory diseases. Awareness of AAHS/MAS, its symptoms and diagnostic criteria should be made mandatory among all physicians, especially those providing care to patients with autoimmune/autoinflammatory diseases. There are no validated diagnostic criteria making early MAS diagnosis difficult in part owing to strong similarities between MAS and sepsis. The treatment of MAS remains highly variable across clinical centers. Nevertheless, the frontline treatment of AAHS/MAS usually involves corticosteroids with or without intravenous immunoglobulin. In some patients with corticosteroid-refractory MAS, administration of cyclosporine A circumvents refractoriness. If there is no response to the aforementioned treatments a use of etoposide is recommended. The progress in understanding the pathophysiology behind MAS and identification of the pathways associated with the early stages of this syndrome bring hope to the idea of developing new biomarkers and treatments for clinical practice.

## **11. Acknowledgments**

This work was supported by ALF resources (the agreement on clinical research between the Stockholm County Council and Karolinska Institutet). The authors thank Mr. J. Hubert and Mr. F. Kasina for linguistic assistance.

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**6** 

*USA* 

**Ocular Myasthenia Analysis of Diagnostic** 

*Department of Neurology & Psychiatry, Saint Louis University, St. Louis, MO* 

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by antibodies directed towards the skeletal muscle nicotinic acetylcholine receptor (AChR), the muscle specific kinase (MuSK), and perhaps as yet undefined antigens, which compromise neuromuscular transmission (Figure 1) (Vincent et al. 2001; Conti-Fine et al. 2006). The disorder has a distinct predilection for the ocular muscles - the extraocular muscles (EOM), which move the globe, and the levator palpebrae that elevates the eyelid (Kusner et al. 2006). MG may produce weakness of any skeletal muscle to varying degrees with the potential for a broad range of clinical presentations (Seybold 1999; Kuks and Oosterhuis 2003); however, almost all patients will have ocular manifestations during the disease course, and a large subset will have manifestations restricted to the ocular muscles, so-called ocular myasthenia (OM) (Kusner et al. 2006). Diagnostic tests for OM include clinical evaluations, serum autoantibodies, and electrophysiological evaluation, all of which differ in their diagnostic predictive value depending on whether a patient has generalized MG or OM (Roh et al. 2011). Treatment for OM includes well-studied modalities; however, none that are supported by rigorous, controlled trials. This analysis will discuss the ocular manifestations, diagnostic testing, and treament of OM, with a focus on the current evidence to support

MG has a prevalence of 20-400 per million based on large population studies, and OM comprises approximately 20% of all cases (Somnier et al. 1991; Phillips et al. 1992; Christensen et al. 1993; Phillips and Torner 1996; MacDonald et al. 2000; Casetta et al. 2010). The classic statement of the disease being of old men and young woman is true with an age distribution being bimodal with incidence peaks in the 20's for women and 40's for men (Phillips and Torner 1996; Grob 1999; Mantegazza et al. 2003; Vincent et al. 2003; Matsuda et al. 2005). OM is more likely to present at a later age and is more often seen in men (Gilbert and Savino 2007). In Asian populations, OM is more common and has a distinct predilection for a juvenile onset, quite different from that observed in European and American populations (Chiu et al. 1987; Hawkins et al. 1989; Wong et al. 1992). One study from South Africa found that OM in the black population was more likely to be treatment resistant than

clinical decision-making (Luchanok and Kaminski 2008).

**1. Introduction** 

**2. Epidemiology** 

in the white (Heckmann et al. 2007).

 **and Treatment Options** 

Austin Hake and Henry J. Kaminski

