Background/Purpose

Fabry disease (FD) is an X-linked disorder caused by a deficiency of lysosomal alpha-galactosidase A resulting in accumulation of glycosphingolipids. Clinical manifestations include a small-fiber neuropathy associated with debilitating pain. Because enzyme therapy (ERT) is available, early diagnosis in FD is crucial. The objective of this study is to characterize the pain in male (M) and female (F) FD patients.

Methods

An observational, non-interventional, retrospective, multicentre, national study was performed in France between January 2013 and April 2014. This study was approved by the ethics committee (CNIL approval: 1588616). All FD patients were eligible. FD was confirmed in all cases by enzyme alpha-galactosidase A activity and/or gene mutation analysis. Characteristics of pain were reported by the patient and by a referent physician in each case. The Neuropathic Pain Symptom Inventory (NPSI) was assessed at time of evaluation and at the moment in life when “pain was at its worst”.

Results

A total of 79 patients were analyzed, median age 43 + 14 yrs.

Table 1: Summary of results

	Males	Females	p value
N (%)	33 (42)	46 (58)
Index case	21	7
Age at pain onset	10.9 + 8.3	19.3 + 15.4
Maximal intensity	Median 7 (quartiles 5,9)	Median 6 (quartiles 5,8)	NS
Frequency of crisis > 10/year	54.5%	34.8%	NS
Associated symptoms: (joint pain, fever, abdominal pain)	18, 16, 9	21, 15, 9
Aggravating factors (temperature change/humidity, effort/sport, infectious episodes)	22, 19, 20	33, 25, 20
Persistent burning pain	18	15
Pain at its worst	8.2 + 2.2	7.4 + 2.5	NS
Persistent burning pain	Median 3 (quartiles 0,5)	Median 5 (quartiles 2,6)	0.04
Persistent pain in adulthood	22	34	NS
Previous or current ERT	91%	50%	< 0.0001
Age at first infusion	31 + 11.1	42.1 + 15	< 0.01
Efficacy of carbamazepine (pain crisis)	21	10
Efficacy of physiotherapy (pain)	6	7
Depression	11	18
School attendance	66.7%	82.6%	< 0.01
Part-time work	3%	23.9%	< 0.01
Handicap expertise	51.5%	21.7%	< 0.01

Before diagnosis of FD, other causes of pain were considered (M: n=15; F: n=8): anxiety (n=25), growing pain (n=17), rheumatic fever (n=7), rheumatoid arthritis (n=1), Still disease (n=1). Raynaud’s phenomenon was present in 25 patients (30%). Only 18% of M and 15% of F had no pain according to the physician. The association of crisis and persistent pain was the most frequent phenotype (M: 51%, F: 43%). Pain crisis corresponded to burning sensation (M=F), tingling (M=F), electric discharge (M only). Pain crisis duration ranged from few minutes (one third) to few days (M: 18.2%, F: 11%). Other symptoms were more frequent in M than in F: sweating disorders (p=0.02), lymphedema (p=0.02), high creatinine level (p=0.04). Intra-familial other cases of pain in extremities were found with differences between genders: father’s pain only in F (p=0.002), children’s and cousin’s pain more frequently found in F (p=0.003 and p=0.002, respectively). NPSI questionnaire was performed in 75 cases. Agreement between patient and physician was good (kappa 0.73, CI95% 0.57-0.90). Patients with pain were treated with ERT in 69.4% of cases whereas patients without pain were treated with ERT in 61.5%. ERT was the most effective therapy on pain in only two males.  

Conclusion

Diagnosis and treatment of neuropathic pain are important in FD. Burning pain in the extremities, and frequent pain in relatives may be a tool for an early diagnosis. The higher frequency of chronic pain in females may imply clinical, psychological, and social components of pain. Treatment of pain in FD patients should not be limited to pharmacological therapies, but include personal and family management, to address psychosocial functioning.

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