Autoimmune Disease in Chronic Granulomatous Disease (CGD): A Diverse Spectrum.

Abstract CGD is an immunodeficiency caused by defects in phagocyte oxidase with increased infections. A major characteristic is extensive granuloma formation associated with infection. However, unusual autoinflammatory processes have been reported in CGD patients that may be autoimmune disease. We outline the spectrum of autoimmune disorders in CGD, making a case for these patients actually having an autoimmune disorder, rather than this being extremes of CGD granuloma formation. The most common autoimmune disease candidate in CGD is inflammatory bowel disease affecting almost 20% of CGD patients, satisfying diagnostic criteria established for Crohn's disease. X-linked CGD carriers and patients can develop discoid lupus. There are many reports about Crohn's disease and discoid lupus in CGD. We previously reported in detail 2 CGD patients with sarcoidosis (Pediatrics 2006 Mar;117(3):e590–5) making note of this here, but do not re-describe the cases. Here we present 3 additional cases of CGD patients with other unusual autoinflammatory processes responsive to immunesuppression, that extend the spectrum of autoimmune diseases observed in CGD. Patient #1: X-linked CGD patient presenting at age 14yrs with acute swelling, pain and redness of the left thigh secondary to deep venous thrombosis. Several months later while on warfarin 3·5mg/d daily with INR of 3, he developed extensive intracerebral sinus thrombosis, and subsequent further extension of clots in his left calf. A trial of oral prednisone at 0.5mg/kg/day was commenced. Within 24 hours, symptoms improved dramatically. Prednisone was tapered, with intermittent increases for symptom flares, to current maintenance of 5mg/d. Patient #2: X-linked CGD at age 9mo presented with respiratory distress and a pericardial effusion without fevers, trauma or infection. The pericardial effusion resolved with combined therapy of antibiotics and oral prednisone. 6 months later, the pericardial effusion recurred, a repeat infectious work-up was negative, and he promptly responded to oral prednisone alone. This pattern recurred every few months without precipitating events until he was 4 years of age and then had a recurrence at age 10yrs. Patient #3: Female with p47phox-deficient CGD who at age 15yrs developed arthralgias that progressed to involve elbows, knees, metacarpal-phalangeal, and proximal phalangeal joints bilaterally. Erythematous maculopapules were present on arms and forehead, with bilateral swelling in metacarpal-phalangeal and proximal interphalangeal joints, as well as development of rheumatoid nodules. A positive rheumatoid factor serology was found. Treatment with non-steroidal anti-inflammatory medications and minocycline resulted in short-lived improvement, but remission was achieved with etanercept. The 3 patients above who have not been previously reported, extend the unusual spectrum of autoimmune diseases associated with CGD. We raise the possibility that CGD may be a co-factor in the overt development of autoimmune diseases in patients with an underlying genetic predisposition, rather than this being merely extremes of the spectrum of granuloma formation specific to CGD. This represents a paradigm shift, and has significant implications for diagnosis and management. Maintaining a high index of suspicion for autoimmune disorders in patients with CGD will minimize unnecessary invasive procedures, and allows early institution of appropriate therapy reducing risks of long-term complications.