On 2017 Sep 12, David Keller commented:

Pre-Existing Rheumatoid Arthritis Should Increase, Not Reduce, the Risk of Incident Parkinson Disease

The authors of this editorial ask "Would tamping down the immune system be a good thing for PD (Parkinson disease) symptoms, or would activation of the immune system be advantageous?"[1] They cite epidemiologic studies which showed "a higher risk of PD in patients with type 1 diabetes mellitus (T1DM) and Crohn disease (CD), among others [2]", in conflict with studies that showed a decreased risk of PD in patients with rheumatoid arthritis (RA). So, does the presence of RA increase or decrease the incidence of PD?

Genome-wide association studies (GWAS) found "enrichment" of loci associated with Parkinson disease conditional on the presence of loci associated with each of 7 autoimmune diseases, to varying degrees. The graphs in Figure 1 [3] demonstrate that for all 7 autoimmune diseases, the greater the population of SNPs associated with autoimmunity, the greater the enrichment of PD SNPs. The authors designate this as "leftward" deviation of the curves, although mathematically it is really UPWARD deviation from the straight line representing the null hypothesis. So, in genetic studies, all seven of the tested autoimmune diseases (T1DM, CD, Ulcerative Colitis, Celiac Disease, Psoriasis, Multiple Sclerosis and Rheumatoid Arthritis) were genetically associated with increased risk of incident PD.

How can genetic risk of PD increase directly with the genetic risk of RA, yet epidemiological studies demonstrate an inverse association of established RA disease on the incidence of PD? The authors of one such epidemiological study did not believe their own results, and hypothesized that "the decreased risk [of incident PD] among patients with RA might be explained by underdiagnosis of movement disorders such as PD in this patient group, or by a protective effect of treatment with anti-inflammatory drugs over prolonged periods." [4] In other words, early signs of PD, such as bradykinesia, could be masked in RA patients, in whom slow movement might be attributed to pain or joint destruction, and ibuprofen use could have further confounded their results.

The nonsteroidal antiinflammatory drugs (NSAID) have been studied extensively, and the only one which significantly reduces the risk of incident PD is ibuprofen.[5] A study by Sung and colleagues [6] concluded that pre-existing RA reduces the risk of incident PD, but they corrected their data for the use of any NSAID, rather than the use of ibuprofen, introducing systematic errors in their results, and potentially invalidating their conclusions. [7]

Can a destructive autoimmune disease like RA reduce the risk of incident PD, in contrast to 6 other autoimmune diseases, which raise risk for PD? Or, do symptom masking and the protective effects of ibuprofen explain the reduction in incident PD seen in patients with RA? In an unpublished reply to these arguments, Sung's group wrote: "[Keller's] criticism focuses on the issue whether [any] non-aspirin NSAID or ibuprofen only, has the truly protective effect against the development of PD", and agreed that "ibuprofen was associated with decreased risk of PD, but not aspirin or other NSAIDs" and concluded that "ibuprofen use should be considered as an important covariable in future correlational research in PD." [8]

References

1: McFarland NR, McFarland KN, Golde TE. Parkinson Disease and Autoimmune Disorders-What Can We Learn From Genome-wide Pleiotropy? JAMA Neurol. 2017 Jul 1;74(7):769-770. doi: 10.1001/jamaneurol.2017.0843. PubMed PMID: 28586798.

2: Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH. Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study. Inflamm Bowel Dis. 2016 May;22(5):1049-55. doi: 10.1097/MIB.0000000000000735. PubMed PMID: 26919462.

3: Witoelar A, Jansen IE, et al. for the International Parkinson’s Disease Genomics Consortium. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. JAMA Neurol. 2017;74(7):780–792. doi:10.1001/jamaneurol.2017.0469

4: Rugbjerg K, Friis S, Ritz B, Schernhammer ES, Korbo L, Olsen JH. Autoimmune disease and risk for Parkinson disease: a population-based case-control study. Neurology. 2009 Nov 3;73(18):1462-8. doi: 10.1212/WNL.0b013e3181c06635. Epub 2009 Sep 23. PubMed PMID: 19776374; PubMed Central PMCID: PMC2779008.

5: Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863-9. doi: 10.1212/WNL.0b013e31820f2d79. Epub 2011 Mar 2. PubMed PMID: 21368281; PubMed Central PMCID: PMC3059148.

6: Sung YF, Liu FC, Lin CC, Lee JT, Yang FC, Chou YC, Lin CL, Kao CH, Lo HY, Yang TY. Reduced Risk of Parkinson Disease in Patients With Rheumatoid Arthritis: A Nationwide Population-Based Study. Mayo Clin Proc. 2016 Oct;91(10):1346-1353. doi: 10.1016/j.mayocp.2016.06.023. PubMed PMID: 27712633.

7: Keller DL, Only ibuprofen is associated with reduced PD risk - controlling for use of any NSAID introduces error. PubMed Commons Comment, accessed on 9/12/2017 at the following URL: https://www.ncbi.nlm.nih.gov/pubmed/27712633#cm27712633_34408

8: Sung YF, Lin CL, Kao CH, and Yang TY. Reply to Keller's unpublished letter to Mayo Clinic Proceedings. Received by email on November 22, 2016.

On 2017 Sep 12, David Keller commented:

Pre-Existing Rheumatoid Arthritis Should Increase, Not Reduce, the Risk of Incident Parkinson Disease

The authors of this editorial ask "Would tamping down the immune system be a good thing for PD (Parkinson disease) symptoms, or would activation of the immune system be advantageous?"[1] They cite epidemiologic studies which showed "a higher risk of PD in patients with type 1 diabetes mellitus (T1DM) and Crohn disease (CD), among others [2]", in conflict with studies that showed a decreased risk of PD in patients with rheumatoid arthritis (RA). So, does the presence of RA increase or decrease the incidence of PD?

Genome-wide association studies (GWAS) found "enrichment" of loci associated with Parkinson disease conditional on the presence of loci associated with each of 7 autoimmune diseases, to varying degrees. The graphs in Figure 1 [3] demonstrate that for all 7 autoimmune diseases, the greater the population of SNPs associated with autoimmunity, the greater the enrichment of PD SNPs. The authors designate this as "leftward" deviation of the curves, although mathematically it is really UPWARD deviation from the straight line representing the null hypothesis. So, in genetic studies, all seven of the tested autoimmune diseases (T1DM, CD, Ulcerative Colitis, Celiac Disease, Psoriasis, Multiple Sclerosis and Rheumatoid Arthritis) were genetically associated with increased risk of incident PD.

How can genetic risk of PD increase directly with the genetic risk of RA, yet epidemiological studies demonstrate an inverse association of established RA disease on the incidence of PD? The authors of one such epidemiological study did not believe their own results, and hypothesized that "the decreased risk [of incident PD] among patients with RA might be explained by underdiagnosis of movement disorders such as PD in this patient group, or by a protective effect of treatment with anti-inflammatory drugs over prolonged periods." [4] In other words, early signs of PD, such as bradykinesia, could be masked in RA patients, in whom slow movement might be attributed to pain or joint destruction, and ibuprofen use could have further confounded their results.

The nonsteroidal antiinflammatory drugs (NSAID) have been studied extensively, and the only one which significantly reduces the risk of incident PD is ibuprofen.[5] A study by Sung and colleagues [6] concluded that pre-existing RA reduces the risk of incident PD, but they corrected their data for the use of any NSAID, rather than the use of ibuprofen, introducing systematic errors in their results, and potentially invalidating their conclusions. [7]

Can a destructive autoimmune disease like RA reduce the risk of incident PD, in contrast to 6 other autoimmune diseases, which raise risk for PD? Or, do symptom masking and the protective effects of ibuprofen explain the reduction in incident PD seen in patients with RA? In an unpublished reply to these arguments, Sung's group wrote: "[Keller's] criticism focuses on the issue whether [any] non-aspirin NSAID or ibuprofen only, has the truly protective effect against the development of PD", and agreed that "ibuprofen was associated with decreased risk of PD, but not aspirin or other NSAIDs" and concluded that "ibuprofen use should be considered as an important covariable in future correlational research in PD." [8]

References

1: McFarland NR, McFarland KN, Golde TE. Parkinson Disease and Autoimmune Disorders-What Can We Learn From Genome-wide Pleiotropy? JAMA Neurol. 2017 Jul 1;74(7):769-770. doi: 10.1001/jamaneurol.2017.0843. PubMed PMID: 28586798.

2: Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH. Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study. Inflamm Bowel Dis. 2016 May;22(5):1049-55. doi: 10.1097/MIB.0000000000000735. PubMed PMID: 26919462.

3: Witoelar A, Jansen IE, et al. for the International Parkinson’s Disease Genomics Consortium. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. JAMA Neurol. 2017;74(7):780–792. doi:10.1001/jamaneurol.2017.0469

4: Rugbjerg K, Friis S, Ritz B, Schernhammer ES, Korbo L, Olsen JH. Autoimmune disease and risk for Parkinson disease: a population-based case-control study. Neurology. 2009 Nov 3;73(18):1462-8. doi: 10.1212/WNL.0b013e3181c06635. Epub 2009 Sep 23. PubMed PMID: 19776374; PubMed Central PMCID: PMC2779008.

5: Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863-9. doi: 10.1212/WNL.0b013e31820f2d79. Epub 2011 Mar 2. PubMed PMID: 21368281; PubMed Central PMCID: PMC3059148.

6: Sung YF, Liu FC, Lin CC, Lee JT, Yang FC, Chou YC, Lin CL, Kao CH, Lo HY, Yang TY. Reduced Risk of Parkinson Disease in Patients With Rheumatoid Arthritis: A Nationwide Population-Based Study. Mayo Clin Proc. 2016 Oct;91(10):1346-1353. doi: 10.1016/j.mayocp.2016.06.023. PubMed PMID: 27712633.

7: Keller DL, Only ibuprofen is associated with reduced PD risk - controlling for use of any NSAID introduces error. PubMed Commons Comment, accessed on 9/12/2017 at the following URL: https://www.ncbi.nlm.nih.gov/pubmed/27712633#cm27712633_34408

8: Sung YF, Lin CL, Kao CH, and Yang TY. Reply to Keller's unpublished letter to Mayo Clinic Proceedings. Received by email on November 22, 2016.