Abstract

Melioidosis is an important differential diagnosis in Indian patients presenting with febrile osteoarticular disease, particularly in association with diabetes mellitus, environmental exposure or visceral abscesses. Infection with Burkholderia pseudomallei may manifest as septic arthritis, osteomyelitis or disseminated infection and can be misclassified as tuberculosis or inflammatory rheumatic disease. Definitive diagnosis requires microbiological confirmation, while management comprises source control, intensive parenteral antimicrobial therapy and prolonged eradication treatment. Other infections encountered in India produce overlapping articular and systemic phenotypes. Leprosy may present with rheumatoid-like polyarthritis, tenosynovitis or vasculitic manifestations; brucellosis with sacroiliitis and spondylodiscitis; and tuberculosis with indolent synovitis or Poncet disease. Pneumocystis jirovecii pneumonia is an important differential diagnosis of hypoxaemic respiratory deterioration during immunosuppressive therapy, particularly when autoimmune pneumonitis or drug-induced lung injury is suspected. Infective endocarditis and visceral leishmaniasis may generate misleading autoantibody profiles. Strongyloidiasis is relevant predominantly as an immunosuppression-associated complication. Diagnostic evaluation should integrate epidemiological exposures, detailed cutaneous and neurological examination, synovial sampling, targeted microbiological testing and histopathology. Autoantibody positivity and glucocorticoid responsiveness are insufficient to establish autoimmune aetiology. Recognition of these clinically heterogeneous presentations facilitates timely antimicrobial treatment, appropriate immunosuppressive decisions and avoidance of preventable morbidity, while acknowledging that infection and established autoimmune disease may coexist.

Main article

Melioidosis: osteoarticular and disseminated infection

Melioidosis, caused by Burkholderia pseudomallei, should be considered in Indian patients with febrile monoarthritis, osteomyelitis or multifocal suppuration. Diabetes mellitus, agricultural exposure and contact with contaminated soil or floodwater increase clinical suspicion. Chronic kidney disease and immunosuppressive therapy are additional predisposing factors. Osteoarticular involvement may coexist with pneumonia or visceral abscesses, whereas chronic infection can resemble tuberculosis. In a Vellore cohort of 114 culture-confirmed cases, diabetes was the predominant risk factor and chronic presentations exceeded acute disease.^{[1, 2]}

Diagnostic evaluation requires blood cultures and culture of synovial fluid, pus or tissue. The microbiology laboratory should be informed because identification and specimen processing require appropriate biosafety precautions. Imaging should delineate adjacent osteomyelitis and additional infective foci. Treatment comprises drainage or debridement when indicated, intensive intravenous ceftazidime or meropenem, and prolonged oral eradication therapy, usually trimethoprim-sulfamethoxazole. Osteoarticular infection requires extended treatment, with trimethoprim-sulfamethoxazole additionally recommended during the intensive phase.^[2]

Leprosy: inflammatory arthritis and reactional states

Leprosy may present with symmetrical polyarthritis, tenosynovitis or swollen hand-foot syndrome, mimicking rheumatoid arthritis. Type 2 lepra reactions (erythema nodosum leprosum) can produce systemic inflammation and vasculitic features. Indian rheumatology series describe presentations without conspicuous cutaneous lesions. Sensory impairment, peripheral nerve thickening, neuropathy and erythematous nodules should prompt targeted evaluation. Slit-skin smears and skin histopathology with appropriate acid-fast staining support diagnosis. Rheumatoid factor or antinuclear antibody positivity does not exclude leprosy, and glucocorticoid responsiveness lacks specificity because reactional inflammation may also improve.^{[3, 4]}

Brucellosis: infectious sacroiliitis and spondylodiscitis

Brucellosis should enter the differential diagnosis of sacroiliitis, spondylodiscitis or peripheral arthritis in patients with livestock exposure or consumption of unpasteurised dairy products. Fever, diaphoresis and focal spinal pain warrant consideration of infection before classification as axial spondyloarthritis. Imaging localises disease but is not aetiologically definitive. Obtain blood cultures and targeted Brucella serology, interpreted against exposure history and clinical probability. Laboratory notification is essential because of aerosol-associated occupational transmission. Confirmed disease requires combination antimicrobial therapy, with prolonged regimens for spinal involvement.^{[5, 6]}

Tuberculosis: direct infection versus reactive arthritis

Osteoarticular tuberculosis may present as chronic monoarthritis, tenosynovitis or spondylodiscitis. Synovial fluid or tissue should undergo mycobacterial culture, nucleic acid amplification testing and, for tissue, histopathological examination. Negative results do not exclude paucibacillary infection; tuberculin testing and interferon-gamma release assays cannot establish active osteoarticular tuberculosis. Poncet disease is a distinct, sterile, nonerosive oligoarthritis or polyarthritis associated with active tuberculosis elsewhere. It is a diagnosis of exclusion, supported by resolution following antituberculous therapy, rather than evidence of direct synovial infection.^{[7, 8, 9]}

Pneumocystis pneumonia: an opportunistic pulmonary mimic

Pneumocystis jirovecii pneumonia (PCP/PJP) is an opportunistic fungal infection that may mimic connective tissue disease-associated pneumonitis or drug-induced lung injury. In immunosuppressed patients, fever, nonproductive cough, hypoxaemia and bilateral ground-glass opacities should prompt investigation. Respiratory specimens should undergo microscopy and polymerase chain reaction testing; molecular positivity requires clinical interpretation because colonisation may occur. In patients with established interstitial lung disease, superimposed infection must be differentiated from acute exacerbation. Clinical deterioration should not automatically trigger escalation of immunosuppression. Prophylaxis should be considered according to glucocorticoid dose and duration, concomitant immunosuppressive therapy and individual risk factors.^{[10, 11, 12]}

Infective endocarditis: a vasculitic phenotype

Infective endocarditis may produce glomerulonephritis and antineutrophil cytoplasmic antibody positivity, mimicking systemic vasculitis. Persistent constitutional symptoms, a cardiac murmur or pre-existing valvular disease warrant blood cultures and echocardiography. Serological findings must be interpreted within the clinical phenotype before initiating intensive immunosuppression.^[13]

Parasitic infections: selected differential diagnoses

Visceral leishmaniasis can mimic a systemic lupus erythematosus flare; prolonged fever, splenomegaly and cytopenias in patients with endemic exposure warrant investigation despite positive autoimmune serology. Parasitological or molecular confirmation may be required when initial investigations are inconclusive. Strongyloides stercoralis is principally relevant because glucocorticoids can precipitate hyperinfection; absence of eosinophilia does not exclude infection. Targeted screening before immunosuppression is appropriate in epidemiologically at-risk patients.^{[14, 15, 16]}

Diagnostic approach

Investigation should be syndrome-directed and exposure-informed. Prompt arthrocentesis, appropriate cultures and selective tissue sampling take precedence over indiscriminate serological panels. Synovial crystals do not exclude concomitant infection. Obtain microbiological specimens before antibiotics when feasible, without delaying treatment in sepsis. Reassess presumed inflammatory disease when clinical distribution, systemic features or therapeutic response are discordant. Infection and autoimmunity may coexist; antimicrobial and immunosuppressive decisions therefore require individualised multidisciplinary assessment.^{[9, 12]}

References

1. Koshy M, Jagannati M, Ralph R, et al. Clinical manifestations, antimicrobial drug susceptibility patterns, and outcomes in melioidosis cases, India. Emerg Infect Dis. 2019;25(2):316-320.

2. Centers for Disease Control and Prevention. Clinical overview of melioidosis.

3. Prasad S, Misra R, Aggarwal A, et al. Leprosy revealed in a rheumatology clinic: a case series. Int J Rheum Dis. 2013;16(2):129-133.

4. Rath D, Bhargava S, Kundu BK. Leprosy mimicking common rheumatologic entities: a trial for the clinician in the era of biologics. Case Rep Rheumatol. 2014;2014:429698.

5. Gokhale YA, Ambardekar AG, Bhasin A, et al. Brucella spondylitis and sacroiliitis in the general population in Mumbai. J Assoc Physicians India. 2003;51:659-666.

6. Centers for Disease Control and Prevention. Clinical overview of brucellosis. Accessed 8 September 2026.

7. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official ATS/IDSA/CDC clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64(2):e1-e33.

8. Sharma A, Pinto B, Dogra S, et al. A case series and review of Poncet’s disease, and the utility of current diagnostic criteria. Int J Rheum Dis. 2016;19(10):1010-1017.

9. Ravn C, Neyt J, Benito N, et al. Guideline for management of septic arthritis in native joints (SANJO). J Bone Jt Infect. 2023;8:29-37.

10. Shi Y, Chen R, Sun H, et al. Characteristics and prognostic analysis of Pneumocystis jirovecii pneumonia in connective tissue diseases patients with interstitial lung disease: a retrospective study. Clin Rheumatol. 2025;44:1653-1663.

11. Dhanalakshmi S, Thambu David S, Gupta R, et al. Effectiveness of a real-time PCR for diagnosis of Pneumocystis pneumonia in immunocompromised patients – experience from a tertiary care center, India. J Mycol Med. 2022;32(2):101241.

12. Fragoulis GE, Nikiphorou E, Dey M, et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2023;82(6):742-753.

13. Veerappan I, Prabitha EN, Abraham A, Theodore S, Abraham G. Double ANCA-positive vasculitis in a patient with infective endocarditis. Indian J Nephrol. 2012;22(6):469-472.

14. Garg S, Kundu M, Dwivedi AND, et al. Visceral leishmaniasis or systemic lupus erythematosus flare? Case Reports Immunol. 2012;2012:523589.

15. Centers for Disease Control and Prevention. Clinical overview of Strongyloides.

16. Centers for Disease Control and Prevention. Clinical care of Strongyloides.