A 49-year-old Caucasian female was previously diagnosed with systemic hypertension, hypothyroidism, and lactose intolerance. She had no previous musculoskeletal complaints. She noted transient skin lesions (rash) on her trunk and arms. Her physical examination was remarkable for polyarthritis of her ankles (Fig. 1) and wrists. Laboratory tests demonstrated a hemoglobin of 14.5 g/dl, white blood cells of 11,990 cells/ml, without atypical lymphocytes, platelets 267,000/ml, erythrocyte sedimentation rate of 54 mm/1st hour, C-reactive protein of 0.7 mg/l [normal range (nr) < 1 mg/l], AST 17 U/L (nr < 35 U/l), ALT 24 U/ml (nr < 35 U/l), creatine kinase 33 U/ml uIU/ml (nr < 35 U/l), thyrotrophic stimulating hormone 0.77 uIU/ml (nr 0.38–5.33 uIU/ml), and negative anti-thyroglobulin and anti-peroxidase antibodies. Serologies for CHIKV were positive with IgM 6.5 (normal range < 0.8) and negative for IgG. No antibodies to Zika, dengue, hepatitis A, B, and C, herpes simplex 1 and 2, HIV, HTLV I and II, toxoplasmosis, mononucleosis, syphilis were detected. Interestingly, antinuclear antibodies (ANA) were positive in a titer of 1:640 as well as anti-Ro/SS-A. The diagnosis of a subacute CHIKV infection was determined and a single dose of betamethasone depot was administered. No other antibodies were found including anti-dsDNA, anti-Sm, anti-U1RNP, anti-La, anti-CCP, rheumatoid factor, anti-Jo-1, anti-Scl70, lupus anticoagulant, IgG and IgM anti-anticardiolipin, IgG and IgM anti-beta-2-glycoprotein I, anti-neutrophil cytoplasm antibodies (ANCA); IgG and IgA anti-endomysium, anti-gliadin and anti-tissue transglutaminase; antiglutamate decarboxylase, anti-insulin, anti-parietal cell, anti-liver/kidney microsomal (LKM1), and anti-mitochondrial. Serum electrophoresis was interpreted as normal, without hypergammaglobulinemia and the total complement levels were normal (CH100—139 mg/dl). She denied xerostomia, xerophthalmia, parotiditis, and dry skin nor personal and family history for autoimmune diseases. ANA and anti-Ro antibodies were redone and confirmed the previous results. Schirmer test demonstrated 5 mm in left eye and 18 mm in right eye. Rose Bengal test showed a positive score of 1 in her right eye and 2–3 in her left one. A salivary scintigraphy revealed a moderate reduction of function of the left and normal result at the right gland, and the unstimulated salivary flow rate was < 0.1 ml per minute. The diagnosis of SS was determined based on the objective tests for sicca syndrome involving one eye (positive Schirmer test) (1 point), mouth (altered salivary flow rate) (1 point), and positive anti-Ro/SS-A (3 points) with a total of 5 points, fulfilling the classification criteria for this disease [8]. The patient refused a minor salivary gland biopsy. Hydroxychloroquine 400 mg/day was prescribed. Her ankle arthritis persisted and methotrexate 15 mg/week plus folic acid 5 mg/week were initiated and improvement was noted. She has a follow-up of 9 months and an arthritis remission was seen.
Moreover, searching for a molecular mechanism that might causally relate the concomitant emergence of CHIKV and SS, molecular mimicry between CHIKV and SS autoantigens was investigated. Specifically, SS autoantigens were obtained from UniProt database (https://www.uniprot.org/) using “Sjögren” as keyword. Only reviewed entries were analyzed. Then, the SS autoantigen primary sequences were dissected into pentapeptides overlapped by four amino acid residues. Each pentapeptide was analyzed for occurrences in the proteome of CHIKV, strain NCBITaxId371094, by using Pir Peptide Match program (https://research.bioinformatics.udel.edu/peptidematch/index.jsp) [16]. The specificity of the peptide overlaps between CHIKV and the human SS autoantigens was also analyzed. That is, infectious pathogens that have been associated with SS—namely: Coxsackievirus B4 (CVB4), Epstein–Barr virus (EBV), Hepatitis B virus (HBV), and Human cytomegalovirus (hCMV) [18]—were investigated for the presence of peptides shared between CHIKV and SS autoantigens.
Table 1 shows a significant peptide sharing between CHIKV and SS autoantigens [9,10,11,12,13,14,15,16,17] that lends support to the hypothesis that a CHIKV-induced autoimmune cross-reactivity might lead to the development of SS. In addition, Table 1 shows that the CHIKV versus SS autoantigens appears to be highly CHIKV-specific since only a few peptides shared between CHIKV and SS are also present in other infectious pathogens that have been associated with SS [18].
Table 1 Massive and specific peptide sharing between CHIKV and SS autoantigens: only a few peptides shared between CHIKV and SS are also present in other SS-related viruses