Background/Purpose:   It has recently been shown that Fibromyalgia (FM) is commonly associated with clinical evidence of neuropathic pain language, laboratory evidence of small fiber and demyelinating neuropathy, and serologic evidence of a low-grade cytokinopathy.  All of these findings suggest the presence of immune dysfunction leading to an immune mediated neural injury in FM.  Any indication of a preexisting pro-inflammatory milieu in FM might help explain the presence of this immune dysfunctional state.  Since primary immune deficiency (PID) states are well known to predispose to autoimmunity we surveyed a series of FM subjects for evidence of selected immunoglobulin (Ig) deficiency.  We report our early findings here. 

Methods:   We retrospectively reviewed serum Ig concentration values on all FM subjects seen between July 2012 and December 2013 in an outpatient, rheumatology office setting.  No other diagnosis precluded inclusion in the study unless it was likely that it might predispose to Ig deficiency.  Charts on a total of 120 FM subjects were screened; 13 were excluded (e.g., family history of PID, SLE, Sjögren’s syndrome, prior irradiation or cancer chemotherapy, or use of a DMARD).  Data on 107 remaining FM subjects were reviewed; 38 (36%) had coincident RA (47 % of RA/FM subjects were positive for IgM RF).  Ig deficiency was defined as an Ig value of at least 2 standard deviations (SD) below the mean reported by our reference laboratory; all deficient specimens were tested in duplicate.  Ig abnormalities were confirmed by repeat analysis 6 – 9 weeks later.  

Results:  Our findings are listed below:

Serum Ig Deficiency in 107 FM Subjects Compared to Literature Based Controls

Immunoglobulin	Fibromyalgia Subjects
	No. with Ig  deficiency	No. without Ig deficiency	Prevalence of FM Ig Deficiency	Estimated Normal Prevalence †	P-value (2-tailed) ††
IgG Subclass 1	48	59	45%	1/1200	<0.0001
IgG Subclass 2	13	94	12%	1/1200	<0.0001
IgG Subclass 3	47	60	44%	1/1200	<0.0001
IgG Subclass 4	6	101	6%	1/1200	<0.0001
IgA	12	95	11%	1/500	<0.0001
IgM	16	91	15%	3/100	0.003
IgE	4	103	4%	2.5/100	0.34
Any Ig	70	37	65%	1/1200	<0.0001

† Schroeder HW, et al: Immunoglobulin Structure and Function. In Fundamental Immunology. 7^thEd.  Ed: Paul, WE.  Lippincott, New York 2013.   †† Analysis was by X² test.

Our data showed that 71% of the FM subjects deficient in IgG Subclass 1 were also deficient in IgG Subclass 3.  Thirty-one percent of those deficient in IgG subclass 2 were also deficient in IgG Subclass 4.  A coincident diagnosis of RA did not significantly affect the prevalence of Ig deficiency.  Of 56 FM subjects in whom Mannose Binding Lectin (MBL) was measured, 18 (32%) had levels <500 ng/ml, 9 (16%) had levels <100 ng/ml, and 8 (14%) had levels <50 ng/ml.  The Odds Ratio (OR) for an FM subject having any Ig deficiency, compared to literature based norms, was 784 (95% CI 108 to 5703).

Conclusion:  Our study shows that Ig deficiency, particularly IgG subclass deficiency, is a common accompaniment to FM.  It also strengthens the argument that FM may be a disorder associated with immune dysregulation.  The precise mechanism of this interaction remains unclear, but deserves further investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/unexpectedly-high-prevalence-of-immunoglobulin-deficiency-in-fibromyalgia/