Clinical characteristics:
Clinical characteristics of the patients are summarized in Table 1. In this cohort (93% female, mean age 32.7, age range 8–80), types of dysautonomia included POTS (84%), OI (13%), IST (24%), NCS (7%), labile hypertension (4%), complex regional pain syndrome (4%) and neurogenic bladder (2%). Some patients had more than one type of dysautonomia. Common comorbidities included MCAS (78%), hEDS/HSD (35%), autoimmune thyroiditis (22%), celiac disease (9%), vitamin B12 deficiency (7%) and immunodeficiency (4%). One or more findings associated with aPL and/or Sjögren’s syndrome were found in most patients, including livedo reticularis (62%), migraine (91%, 53% with aura), Raynaud’s phenomenon (35%), leukopenia (35%), CNS white matter change (9%), thrombocytopenia (7%) and dry eye (75%). Forty-four percent of patients with dry eye with reliable Schirmer’s testing had a score of 5 mm or less. (Schirmer’s testing was considered unreliable if there was severe burning triggering a tear reaction). Monoclonal gammopathy of undetermined significance was seen in the 3 oldest patients, ages 62, 64 and 80, but no patient had Waldenstrom’s macroglobulinemia or multiple myeloma. Most patients had severe illness, with a mean functional ability score of 42% (able to get out of bed most of the time and can do more than just “survive”). One third of patients experienced one or more thrombotic events and 58% of patients who attempted pregnancy experienced morbidity, including miscarriage, stillbirth, pre-eclampsia, HELLP syndrome and/or intrauterine growth restriction.
Table 1. Clinical characteristics of the patients
Patients, n (%)
|
45 (100%)
|
Females
|
42 (93.3%)
|
Males
|
3 (6.7%)
|
Age, mean (SD)
|
32.7 (14.8)
|
Pre-treatment functional ability %, mean (SD)
|
42.1 (19.7)
|
Type of dysautonomia, n (%)
|
|
Postural orthostatic tachycardia syndrome
|
38 (84.4%)
|
Orthostatic intolerance
|
6 (13.3%)
|
Inappropriate sinus tachycardia
|
11 (24.4%)
|
Neurocardiogenic syncope
|
3 (6.7%)
|
Labile hypertension
|
2 (4.4%)
|
Complex regional pain syndrome
|
2 (4.4%)
|
Neurogenic bladder
|
1 (2.2%)
|
Comorbid Conditions, n (%)
|
|
Mast cell activation syndrome
|
35 (77.8%)
|
hEDS or HSD
|
18 (35.5%)
|
Autoimmune thyroiditis
|
10 (22.2%)
|
Celiac disease
|
4 (8.9%)
|
Thrombocytopenia
|
3 (6.7%)
|
Vitamin B12 deficiency
|
3 (6.7%)
|
Immunodeficiency
|
2 (4.4%)
|
Symptom Prevalence, n (%)
|
|
Raynaud’s phenomenon
|
16 (35.5%)
|
. Leukopenia (WBC<=4)
|
16 (35.5%)
|
Livedo reticularis
|
28 (62.2%)
|
Migraine
|
41 (91.1%)
|
Migraine with aura
|
24 (53.3%)
|
CNS white matter change
|
4 (8.9%)
|
Dry eyes
|
34 (75.5%)
|
Dry eyes + positive Schirmer’s testa
|
14 (43.7%)
|
Monoclonal gammopathy
|
3 (6.7%)
|
Thrombosis - any
|
15 (33.3%)
|
Thrombosis - arterial
|
7 (15.5%)
|
Thrombosis - venous
|
10 (22.2%)
|
Thrombosis - both arterial and venous
|
2 (4.4%)
|
Family history of antiphospholipid syndrome, n (%)
|
6 (13.3%)
|
History of pregnancy, n (% of females)
|
19 (45.2%)
|
Pregnancy morbidity, n (% of females with history of pregnancy)
|
11 (57.9%)
|
Miscarriage
|
6 (31.6%)
|
Stillbirth
|
2 (10.5%)
|
Preeclampsia
|
4 (21.0%)
|
HELLP syndrome
|
1 (5.3%)
|
Intrauterine growth restriction
|
1 (5.3%)
|
Abbreviations: SD standard deviation; HELLP hemolysis, elevated liver enzymes and low platelets; hEDS hypermobile Ehlers-Danlos Syndrome; HSD hypermobility spectrum disorder; CNS central nervous system. aShirmer’s test performed on 32 participants with dry eyes, reflected in % <=5mm, per American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) Sjogren’s guidelines.
Laboratory data:
Laboratory data are summarized in Table 2. The mean total IgM level was 389 ng/dl (range 236 - 1489). Persistently elevated aPL were found in 93% of patients and persistently elevated Sjögren’s antibodies were found in 67%. Most positive antibodies were of the IgM subtype.
Eight patients (18%) also tested positive for one of the anti-neuronal antibodies that have been associated with dysautonomia, including anti-MAG IgM (one patient), anti-GM1 IgM (one), anti-voltage gated potassium channel (two), anti-GAD 65 (one), low titer anti-ganglionic AChR (one), anti-fibroblast growth factor 3 receptor (one) and anti-voltage gated calcium channel antibodies (one).
The mean number of persistently elevated aPL per patient was 2.7 (range 0-5). The mean number of persistently positive antibodies per patient, including aPL, Sjogren’s, ANA and anti-neuronal antibodies was 4.7 (range 1-11) per patient.
While not included in the table because most patients did not undergo this testing, it should be noted that two patients had positive Lyme IgM antibody testing but negative Lyme IgM western blot and one patient had a positive Lyme IgM western blot but no response to prolonged Lyme therapy, suggesting false positivity due to the elevated total IgM.
Table 2. Laboratory Data
Laboratory results, n (%)
|
|
Elevated total serum IgM
|
45 (100%)
|
Positive ANA >=1:160
|
7 (15.5%)
|
Positive rheumatoid factor
|
0 (0.0%)
|
Elevated aPL or Sjogren’s antibodies
|
45 (100%)
|
Elevated aPL antibodies
|
42 (93.3%)
|
Lupus anticoagulant
|
7 (15.5%)
|
Anticardiolipin IgM
|
33 (73.3%)
|
Anticardiolipin IgG
|
2 (4.4%)
|
Anti-beta2-glycoprotein 1 IgM
|
2 (4.4%)
|
Anti-beta2-glycoprotein 1 IgG
|
1 (2.2%)
|
Anti-prothrombin-phosphatidylserine IgM
|
22 (48.9%)
|
Anti-prothrombin-phosphatidylserine IgG
|
0 (0.0%)
|
Anti-phosphatidylserine IgM
|
27 (60.0%)
|
Anti-phosphatidylserine IgG
|
1 (2.2%)
|
Anti-phosphatidylethanolamine IgM
|
17 (37.8%)
|
Anti-phosphatidylethanolamine IgG
|
0 (0.0%)
|
Anti-annexin IgM
|
1 (2.2%)
|
Anti-annexin IgG
|
0 (0.0%)
|
Elevated Sjogren’s antibodies
|
30 (66.7%)
|
Anti-Sjogren’s syndrome A IgG
|
5 (11.1%)
|
Anti- Sjogren’s syndrome B IgG
|
1 (2.2%)
|
Anti-salivary protein 1 IgM
|
19 (42.2%)
|
Anti-salivary protein 1 IgG
|
1 (2.2%)
|
Anti-salivary protein 1 IgA
|
1 (2.2%)
|
Anti-carbonic anhydrase VI IgM
|
22 (48.9%)
|
Anti-carbonic anhydrase VI IgG
|
6 (13.3%)
|
Anti-carbonic anhydrase VI IgA
|
2 (4.4%)
|
Anti-parotid specific protein IgM
|
15 (33.3%)
|
Anti-parotid specific protein IgG
|
2 (4.4%)
|
Anti-parotid specific protein IgA
|
1 (2.2%)
|
Elevated Anti-neuronal antibodiesa, n (%)
|
8 (17.8%)
|
Total number of elevated aPL per patient, mean (SD)
|
2.7 (1.4)
|
Total number of elevated antibodies per patient, including aPL, Sjogren’s, ANA and anti-neuronal antibodies, mean (SD)
|
4.7 (2.4)
|
Abbreviations: aPL antiphospholipid; ANA antinuclear antibodies; WBC white blood cells; Ig immunoglobulin. aincluding anti-ganglionic acetylcholine receptor antibodies, anti-glutamic acid decarboxylase-65 antibodies, anti-myelin associated glycoprotein IgM antibodies, anti-ganglioside GM1 IgM antibodies, anti-voltage gated calcium channel antibodies, anti-voltage gated potassium channel antibodies, and anti-fibroblast growth factor receptor 3 antibodies.
Treatment trials:
Results of treatment trials with immune modulatory therapy and antithrombotic therapy are summarized in Table 3.
Twelve patients were given a trial of immunoglobulin therapy (IG), either intravenous or subcutaneous. Three patients were unable to tolerate IG due to severe side effects. Six of 9 patients (67%) able to tolerate IG experienced a positive response, defined as >=20% improvement in their functional ability score. Two of 3 (67%) patients treated with rituximab were positive responders, including one who had failed a trial of IG. Thus, 8 of 11 (73%) patients tolerant of therapy were responsive to IG or rituximab. One of the other two patients who failed to respond to IG also failed to respond to rituximab and the other declined a trial of rituximab due to potential risks.
Seventy-eight percent of patients given a trial of antithrombotic therapy for symptoms that have previously been published to respond in some aPL-positive patients [12,13] experienced 50 to 100% improvement in one or more symptoms. All of these patients elected to continue this therapy indefinitely, due to the significant improvement in quality of life.
Table 3. Response to immune modulators therapy and antithrombotic therapy
Treated with immunoglobulin (IG), n
|
12
|
Tolerated IG
|
9 (75.0%)
|
Positive responsea
|
6 (50%; 66.7% of those who tolerated IG)
|
Treated with rituximab
|
3
|
Positive responsea
|
2 (66.6%)
|
Treated with antithrombotic therapy
|
18
|
Positive responseb
|
14 (77.8%)
|
Abbreviations: IG Immunoglobulin (subcutaneous or intravenous). aPositive response to immune modulatory therapy defined as >=20% improvement on functional ability scale. bPositive response to anti-thrombotic therapy defined as >=50% improvement in one or more symptom(s)