A Rare Case of HLA2B27 Positive Presenting with Spondyloarthreditis and Enthesial Inflammation with Negative Rheumatoid Factor, ANA, who Responded to Methyl Prednisolone along with Hydroxychloroquine

Figure 2: Showing the Bone mineral density diagnosis system assesment for osteoporosis severity revealing presence of osteoporosis middle picture.

Magnetic Resonance Imaging (MRI) Sacroiliac Joints-no obvious discernible abnormality seen, along with earlier MRI of full lumbar, thoracic spine being normal. No disc problems were seen. Doppler studies showed no valvular abnormalities in the venous system.

Treatment

Treatment
After receiving a lot of non-steroidal anti-inflammatory drugs (NSAIDS), daphlon 500mg bd, foot stockings, crepe bandage with no relief to the patient, the initial treating rheumatologist was reluctant to start any specific therapy .With the total incapacitation we decided to administer injection depot medral 160mg in view of injectionmethyl prednisolone 120 mg injection being not available at that time period and then put her on wysolone 10mg daily, along with dabigatran 110mg daily and sulfasalazine 500mg bddespite negative Rheumatoid factor , but since sudden aggravation of pain was there again 1 month following depotmedral, methyl prednisolone 120mg intravenous bolus followed by replacement of sulfasalazine with Hydroxychloroquine 400mg bd was done besides continuation of wysolone 10mg, along with the anticoagulant dabigatran following which she has improved considerably with all incapacity finished and good quality of life (QOL), with movements improved, walking and working normally. She has been followed subsequently for 6 months and is pain free on same medicine now.

Discussion

HLA-B27 correlated conditions are HLA-B27 associated uveitis as well as members of the spondyloarthritides that are reactive arthritis, psoriatic arthritis, as well as Ankylosing Spondylitis (AS). HLA, basically belongs to the MHC Class 1 surface encoded by the MHCB gene on chromosome 6 awa is the maximum necessary gene which makes an individual susceptible to AS. HLA-B27 presents peptide antigens to T immunocytes of the human body defense processes as well as is believed to be significantly associated to AS as well as correlated inflammatory diseases. A review conducted involving greater than 7500 peptides that got presented by the 8 commonest HLA-B27- allotypes (HLA-B27-02- HLA-B27-09) pointed that there was binding as per consensus as well as selection motifs, demonstrated important similarities as well as variations among different HLA-B27- allotypes [1]. Further a spectrometry study did a review where a huge amount of HLA-B27-repository which might be more specific to origination as well as propagation [1]. Certain microbial peptides have similarity to the self peptides present within our body tissues as well as have the ability of stimulating response of certain HLA-B27-particular CD 8+T lymphocytes. There is a reaction of the T lymphocytes with these HLA-B27-peptide complexes resulting in autoreactivity as well as autoimmune disease [2,3]. That cartilage, specifically, the proteoglycan aggrecan, is the particular immunological target in SpA has been pointed [4], nevertheless, present studies over these peptides just got results that were not consistent. Additionally, rats possessing HLA-B27- particular CD 8+T lymphocytes still develop AS, that points that greater peptides which further need to be unrevelled [5]. Pul-D liberated pullulanase have the ability to interact with antibodies which associate HLA-B27 as well as myosin, whereas Pul-A components might interact with type I, III as well as IV collagens [6], that gives evidence for the reason molecular mimicry hypothesis might be right. Particular cross reactions stimulate the antibacterial antibodies which associate the HLA- molecules on immunocytes, chondrocytes as well as fibroblasts [7], that stimulate a cascade involving inflammatory reactions with the quantity of cytokines, complement proteins, proteinases as well as the similar formed [8]. The common spondyloarthropathies have the properties of implication of the axial spine, joints present in the periphery, as well as enthesial inflammation besides the non articular involvements of the uvea as uveitis, association of psoariasis, inflammation of the aortic root as well as inflammation of the intestine [9]. The correlation with HLA-B27 is greater than 90% of patients in the United Kingdom with Ankylosing Spondylitis (AS) [10], despite not all subtypes being correlated with disease [11]. Other HLA-B27 associations include reactive arthritis (67%) [10], IBD-associated spondyloarthritis (72%) [12], psoriatic arthritis-both peripheral and axial (24-90%) [13], juvenile enthesitis-related arthritis (76%) [14], and acute anterior uveitis (52%) [15]. Our patient did not have any uveitis, psoariasis or any associated inflammatory bowel disease (IBD). ECG was normal with normal BP but her marked varicose veins like symptoms with normal venous valves on Doppler point to enthesial inflammation in a case who had HLAB27 positive. No other family member had similar problem. Despite HLAB27 being positive, as well as raised hsCRP, in view of negative Rheumatoid factor (RF), antinucleic acids (ANA), no rheumatologist started any therapy. Since poor response has been observed with rituximab (pre B cell) and abatacept (costimulation blockade) [16,17] in terms of improving spondyloarthritides and pain relief they have not proven to be successful in terms of adaptive immunity. IL-17 as well as IL-23 inhibitors have shown some response in psoariasis associated problems but our patient did not have psoriasis [18], Similarly IL-1 inhibitors like anakinra [19] has been tried but still queries are there and TNF Inhibitors also have not worked [20]. Although lot of monoclonal antibodies [21,22] are being studied they turn out to be very expensive. A lot of controversy has been there regarding involvement of innate immune response or adaptive immunity in HLAB27 [23]. Here our patient is an example of overlapping spondyloarthrides with HLA-27 positive thus we decided to try drugs commonly utilized for RA with response to usual drugs used for Rheumatoid arthritis(RA) and our patient responded to methyl prednisolone followed by hydroxychloroquine and maintainance dose of wysolone along with simple oral anticoagulant like drug like dabigatran. This case exemplifies how many cases of HLAB27 positive spondyloarthropathies suffer with no proper therapy available currently although lot of trials are ongoing to study the etiopathogenesis be it involvement of microbes, arthrogenic peptide theory, homodimerization theory or ER mis-folding or UPR, GWAS involvement as well as other suggestions. Lot of work is being done on this to pinpoint if it is innate or adaptive immunity involvement and find out specific therapies for this intriguing problem [23].

References

1. Schittenhelm RB, Tc LKS, Wilmann PG, Dudek NL, Purcell AW. (2015) Revisiting the artritogenic peptide theory:quantitative not qualitative changesin the peptide repertoire of HLA B27allotypes. Arthritis Rheum.  67:702-13.
2. Faham M, Carlton V, Moorhead M, Zheng J, Klinger M, et al. (2017) Discovery of T cell receptor  beta  motifs  specific to  HLAB-27 positive  Ankylosing Spondylitis by deep repertoire sequence analysis. Arthritis Rheum. 69:774-84.
3. De Castro JAL. (2010) The HLA B-27building on the cornerstone. Arthritis Rheum. 63:362-69.
4. Wolfgang K, Kuhne M, Busch DH, Atagunduz P, Seipel M, etal. (2004) Identification of a novel human aggregan T-cell epitope T cell epitopes in HLAB-27 transgeni8c mice  associated with spondyloarthropathy. J Immunol .173:4859-866.
5. Lin A, Guo X, Inman RD, Sivak JM. (2015) Ocular inflammation in HLA-B27 transgenic mice reveals a potential role for MHC class I in corneal immune privilege. Mol Vis. 21:131-137.
6. Ramos M, Alvarez I, Sesma L, Logean A, Rognan D,  et al. (2002) Molecular mimicry of an HLAB-27-derived ligand  of arthritis linked subtypes of chlamydial proteins. J Biol Chem.  277:37573-7581.
7. Zhang L, Zhang Yj, Huang XL, Fang GS, Yang LY, et al. (2018) The association of HLA-B27 and Klebsiella pneumonia in Ankylosing Spondylitis: a systematic review. Molec Pathog. 117:49-54.
8. Ryu KH, Cho KA, Park HS, Kim JY, Woo SY,  et al. (2012) Tonsil derived mesenchymal stem cells , evaluation of biologic,immunologic and genetic factors for successful banking. Cytotherapy. 12:1193-1202
9. Stolwijk C, Essers I, van Tubergen A, Boonen A, Bazelier A, et al. (2015) The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study. Annals of the rheumatic diseases. 74(7):1373-1378.
10. Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, et al. (1996) HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Annals of the rheumatic diseases. 55(4):268-270.
11. Khan MA. (2013) Polymorphism of HLA-B27: 105 subtypes currently known. Current rheumatology reports. 15(10):362.
12. Brewerton DA, Caffrey M, Nicholls A, Walters D, Oates JK, et al. (1973) Reiter’s disease and HL-A 27. Lancet. 1302(7836):996-998
13. Brewerton DA, Caffrey M, Nicholls A, Walters D, James DC. (1974) HL-A 27 and arthropathies associated with ulcerative colitis and psoriasis. Lancet. 1(7864):956–958.
14. Thomson W, Barrett JH, Donn R, Pepper L, Ollier WER, et al. (2002)  Juvenile idiopathic arthritis classified by the ILAR criteria: HLA associations in UK patients. Rheumatology (Oxford). 41(10):1183-1189.
15. Brewerton DA, Caffrey M, Nicholls A, Walters D, James DC. (1973)  Acute anterior uveitis and HL-A 27. Lancet. 302(7836):994-996.
16. Wendling D, Dougados M, Berenbaum F, Brocq O, Schaeverbeke T, et al. (2012) Rituximab treatment for spondyloarthritis. A nationwide series: data from the AIR registry of the French Society of Rheumatology. J Rheumatol. 39(12):2327-2331.
17. Song IH, Heldmann F, Rudwaleit M, Haibel H, Weiss A, et al. (2011) Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study. Annals of the rheumatic diseases. 70(6):1108-1110.
18. Langley RG, Elewski BE, Lebwohl M, et al.  (2014) Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 371(4):326–338.
19. Griffiths CE, Strober BE, van de Kerkhof P. (2010) Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 362(2):118–128.
20.  Dick AD, Tugal-Tutkun I, Foster S, Zierhut, M, Liew Melissa SH, et al. (2013) Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology. 120(4):777–787.
21. Jesus AA, Goldbach-Mansky R. (2014)  IL-1 blockade in autoinflammatory syndromes. Annual Rev Med. 65:223–244.
22. Haibel H, Rudwaleit M, Listing J, Sieper J. (2005) Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Annals of the rheumatic diseases. 64(2):296-298.
23. Sibley CH. (2016) Autoinflammation and HLA-B27: more than an antigen. Occul Immunol Infl 24(4):460-69.