Comorbid Autoimmunity: Notes From the Field

Issue: August 2016

In the Cover Story of this issue of Healio Rheumatology, we explore comorbid autoimmunity. We ask complex questions that basically come down to this: What does the presence or absence of such disorders tell us in terms of the nature of autoimmune and possibly autoinflammatory disease?

Rheumatologists are familiar with the concept of multiple “autoimmune diseases” occurring in the same patient. In fact, it is part of the historical fabric of our specialty. Consider the syndromes of mixed connective tissue disease, polyangiitis overlap disorder, sclerodermatomyositis and Sjögren’s syndrome overlap with just about any disease that brings patients into our clinics and offices. In fact, we are not only inured to their presence, but we also approach patients expecting to encounter multiple autoimmune manifestations in order to optimize their care.

Defined Experience, Epidemiologic Evidence

At the same time, we are confident certain autoimmune diseases rarely occur together. When confronted with a patient with anti-citrullinated peptide antibodies (ACPA) and rheumatoid arthritis, how many rheumatologists assign high pretest probability of spondyloarthritis (SpA) when the patient notes increasing back pain? Similarly, in patients with SpA spectrum disease, do we concern ourselves with Sjögren’s syndrome overlap or small vessel vasculitis? The point is we practice based on our defined experience supported by epidemiologic evidence.

Let me share with you two conundrums from my clinical practice that have long bothered me. The first conundrum is the question of how common is autoimmunity. A few months ago, I commented that some estimates suggest up to 50 million people have autoimmune disorders. In practice, we meticulously rely on the detection of autoantibodies as the main tool in our diagnoses of a wide variety of autoimmune diseases. We eschew lab tests found to be abnormal in most of the population as non-specific and overly sensitive and thus not useful in practice.

Now, consider a growing bank of new evidence that suggests autoimmunity, as evidenced by the detection of antibodies against self, is more common than we previously thought. Think really common. One expression of this phenomenon is natural autoantibodies, which are IgM and ubiquitous and appear to have important homeostatic roles in diverse physiologic systems, according to a study by Silverman. Similarly using immune response profiling, IgG anti-self antibodies numbering in the thousands also can be identified. This suggests a far more complex role of autoantibodies than merely the purveyors of autoimmune disease. Also in support of this notion is everyone has B cells readily capable of producing rheumatoid factor under specific conditions. Autoantibodies also increase with age as part of the immunosenescence process.

You might say, “But these are autoantibodies against irrelevant targets.” What about when we ask the same question for autoantibodies known to be highly specific for disease, such as anti-neutrophil cytoplasmic antibodies (ANCA), an autoantibody considered highly specific for vasculitis? Consider the recent study by Kelsey which used epitope mapping to detect ANCA in many healthy individuals. Based on these observations, where does physiologic autoimmunity end and disease start and why?

Genetic Nature

My second conundrum stems from the implosion of our canonical thinking that the genetic nature of most autoimmune rheumatic diseases are polygenic, involving hundreds of diverse genes that interact with each other as well as our environment, according to a study by Cho. While genome-wide association studies have affirmed this in many disorders, there is now an emerging appreciation that some of “our diseases,” meaning what at least appear to be multi-organ inflammatory disorders associated with multiple autoantibodies, can be produced by any of a growing number of monogenic mutations. These monogenic diseases have features of both autoimmunity and autoinflammation.

I now wonder how many patients I have seen with such disorders during my long career and merely labeled them as overlap syndrome, idiopathic arteritis or atypical lupus. For example, we are evaluating a 14-year-old girl at our institution for a vasculitic disease of the brain and lungs characterized by lymphoplasmacytic infiltrates in which CLTA4 haploinsufficiency is now the number one rule-out and testing is pending.

Haploinsufficiency is characterized by a single functioning gene at a given locus and may or may not be symptomatic. CTLA4 haploinsufficiency, when symptomatic, is associated with widespread lymphocytic inflammation of multiple organs and may mimic vasculitis or a lupus-like state. Regardless of whether she is found to have this genetic disorder, the fact that it is now in our differential has changed my world view in approaching many such patients. It has recently been suggested that haploinsufficiency combined with incomplete penetrance may be one mechanism responsible for some cases of more common autoimmune diseases such as systemic lupus erythematosus or diabetes mellitus type 1, according to a study by Rieux-Laucat and colleagues.

Time of Rapid Advances

Where does this leave the practicing rheumatologist? Clearly it implies we are living in a time of rapid advances in understanding the nature and contributing factors to autoimmunity.

At the same time, it is a sobering reminder that we must commit ourselves to continuous learning in this space. This is essential for us to be confident in our ability to critically appraise new data regarding pathogenesis, diagnosis and treatment and, ultimately, to be more effective as clinical immunologists.

Thank you for reading this issue of Healio Rheumatology. I look forward to receiving your comments at calabrl@ccf.org or on Twitter @LCalabreseDO.

References:
Cho JH, et al. N Engl J Med. 2011;doi:10.1056/NEJMra1100030.
Kelsey R. Nat Rev Nephrol. 2013;doi:10.1038/nrneph.2013.71.
Rieux-Laucat F, et al. Science. 2014;doi:10.1126/science.1260791.
Silverman GJ. Ann N Y Acad Sci. 2015;doi:10.1111/nyas.12788.

For more information:
Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.

Disclosure: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi, Jansen and AbbVie; and is on the speakers bureau for Genentech, AbbVie and Bristol-Myers Squibb and Crescendo Bioscience.