46-Year-Old Man With Lower Back Pain

Abstract

A 46-year-old man originally from Vietnam with no known long-term medical conditions presented to a primary care clinic for evaluation of gradually progressive, left-sided, lower back pain accompanied by resolving flulike symptoms. He had a history of episodic back pain dating to his mid-20s, but the cause had never been determined. Unlike his prior episodes, on this occasion he first noticed the discomfort after what he thought was a flulike illness, characterized by fevers, chills, myalgia, malaise, and headache, as well as a 6.8-kg unintended weight loss. Although his constitutional symptoms had largely resolved in the week before his presentation, his lower back pain continued to worsen and began radiating to the perineum. His pain increased when he lay flat and was partially alleviated when he walked. The pain was generally worst at night and was accompanied by morning stiffness. He reported no focal weakness, bowel or bladder dysfunction, saddle anesthesia, or history of uveitis, psoriasis, inflammatory bowel disease, or sexually transmitted infections. On physical examination, he was afebrile, and other vital signs were within normal limits. He had marked tenderness to palpation of the left sacroiliac (SI) joint. Results of a FABER (flexion, abduction, external rotation) test were positive on the left side, and a straight leg raise yielded negative results bilaterally. There were no cutaneous lesions, enthesitis, or ocular findings. His neurologic, cardiopulmonary, abdominal, and geniturinary tract examination findings were also unremarkable. Despite a trial of nonsteroidal anti-inflammatory drugs, the patient’s pain persisted for the next several weeks, and follow-up was arranged. At that time, his symptoms and physical examination findings were largely unchanged. Laboratory studies revealed the following (reference ranges given parenthetically): white blood cell count, 7.3 × 109/L (3.5-10.5 × 109/L); erythrocyte sedimentation rate, 34 mm/h (0-22 mm/h); and C-reactive protein, 13.2 mg/dL (<8 mg/dL). Results of an HLA-B27 antigen test were positive.1.Given the information obtained thus far, which one of the following raises the posttest probability of ankylosing spondylitis most substantially?a.HLA-B27 positivityb.Features of inflammatory lower back painc.Elevated acute-phase reactantd.No response to nonsteroidal anti-inflammatory drugse.Sudden onset of lower back pain To better standardize the diagnosis of ankylosing spondylitis, several classification criteria have been developed, including the modified New York, Amor, and Assessment of SpondyloArthritis International Society criteria. The sensitivity and specificity of the individual parameters within these criteria vary vastly. Owing to this variability, likelihood ratios (LRs) have been assigned to the clinical and laboratory parameters to assist in determining disease probability before ordering more advanced studies.1Rudwaleit M. van der Heijde D. Khan M.A. Braun J. Sieper J. How to diagnose axial spondyloarthritis early.Ann Rheum Dis. 2004; 63: 535-543Crossref PubMed Scopus (521) Google Scholar In this case, the most appropriate option is HLA-B27 positivity, which confers a positive LR of 9. The inflammatory lower back pain (LR, 3.1) and elevated acute-phase reactants (LR, 2.5) also increase the likelihood of ankylosing spondylitis but to a lesser degree. Taken together, the presence of just these 3 variables increases the posttest probability to 78%, assuming a pretest probability of 4.6%, which is the reported rate of ankylosing spondylitis in primary care patients who have long-term lower back pain.2Underwood M.R. Dawes P. Inflammatory back pain in primary care.Br J Rheumatol. 1995; 34: 1074-1077Crossref PubMed Scopus (162) Google Scholar Patients with ankylosing spondylitis are expected to have a good response to nonsteroidal anti-inflammatory drugs rather than no response. The back pain experienced by those who have ankylosing spondylitis is generally long-term rather than short-term and has an age at onset of less than 45 years. The patient continued to experience lower back pain despite 2 weeks of conservative therapy and requested stronger pain relief and further evaluation.2.Which one of the following would be the most appropriate next step in evaluating the etiology of this patient’s lower back pain?a.Defer imaging unless back pain continues for 6 weeks despite conservative therapyb.Plain radiographyc.Immediate magnetic resonance imaging (MRI) of the pelvis/lumbosacral spined.Computed tomography (CT) of the spinee.Corticosteroid injection In the presence of substantial risk factors for ankylosing spondylitis and a failed trial of conservative therapy, imaging is the most appropriate next step, and the question becomes which study to obtain. Unlike imaging for myofascial back pain, ankylosing spondylitis imaging should not be delayed for an additional 6 weeks. Plain radiography is the criterion standard and is generally indicated because it is very sensitive for established disease that has caused damage to the SI joint. It has the additional benefits of greater accessibility and lower cost compared with MRI. However, MRI has greater capacity for assessing active inflammation and early sacroiliitis, but its role in evaluating long-term disease is still unclear. For this reason, many argue that plain film radiography is always indicated.3Braun J. Sieper J. Ankylosing spondylitis.Lancet. 2007; 369: 1379-1390Abstract Full Text Full Text PDF PubMed Scopus (1376) Google Scholar A CT scan may result in improved detection of long-term damage at the SI joint compared with radiography, but it is not used routinely because of the increased radiation exposure. Immediately sending the patient for corticosteroid injections would further delay diagnosis and treatment. Plain radiography of the pelvis revealed irregular widening of the left SI joint. Much milder widening was noted in the right SI joint also. With concern for sacroiliitis related to ankylosing spondylitis, the patient was referred to rheumatology specialists. Given his recent history of fevers and chills and asymmetric widening of the SI joint evident on radiography, the decision was made to obtain MRI, which revealed severe left sacroiliitis with erosive changes and reactive edema within the adjacent soft tissues. There was confluent T1 marrow replacement in the adjacent iliac bone and sacrum, along with marked T2 hyperintense thickening and peripheral enhancement of the left S3 nerve root.3.On the basis of the patient’s MRI and clinical findings, which one of the following is the most appropriate next step?a.Obtain blood culturesb.Obtain blood cultures and start empirical broad-spectrum antibioticsc.Biopsy of the SI joint under CT guidanced.Screen for hepatitis B and human immunodeficiency virus (HIV); if results are negative, start tumor necrosis factor inhibitore.Screen for rheumatoid factor and anti-citrullinated protein antibodies This patient has severe sacroiliitis, and differentiating infectious sacroiliitis from sacroiliitis associated with an axial spondyloarthritis is of paramount importance. On MRI, the patient has erosive intra-articular changes at the SI joint, and bone marrow edema—common features of both entities. However, the imaging findings of unilateral sacroiilitis, sacral distribution of bone marrow edema, and periarticular muscle edema greatly increase suspicion of infection.4Kang Y. Hong S.H. Kim J.Y. et al.Unilateral sacroiliitis: differential diagnosis between infectious sacroiliitis and spondyloarthritis based on MRI Findings.AJR Am J Roentgenol. 2015; 205: 1048-1055Crossref PubMed Scopus (28) Google Scholar The next task becomes a targeted microbiologic confirmation of the pathogen. Blood cultures have much lower yield than CT-guided biopsy. If an infection is confirmed, starting antibiotics would be appropriate but premature at this time and would decrease the yield of biopsy. Although anti–tumor necrosis factor agents can slow progression to permanent structural damage in ankylosing spondylitis, starting it before infection has been ruled out is inappropriate. Finally, screening for rheumatoid factor and anti–citrullinated protein antibodies does not address the immediate and serious concern of infection suggested by MRI. Examination of this patient’s biopsy samples revealed chronic and granulomatous inflammation. No evidence of malignancy was found, and results of Grocott-Gomori methenamine silver stain were negative. A special stain for acid-fast bacilli yielded positive results, and cultures from the joint fluid and tissue eventually grew Mycobacterium tuberculosis (TB) complex. Quantiferon testing for TB was positive, with a TB antigen value of 10.72 IU/mL. Of note, this patient had immigrated to the United States from Vietnam with his wife and children 6 months before his initial presentation. At that time, he was evaluated by the Department of Homeland Security for standard communicable diseases of public health relevance. A tuberculin purified protein derivative skin test was administered, producing a reaction size of 10 mm. This test was followed by chest radiography, which revealed no evidence of active pulmonary TB. To our knowledge, he did not receive treatment for latent TB.4.For the described HIV-negative patient from Vietnam without a history of bacille Calmette-Guérin vaccination or known TB exposures, which one of the following is the threshold at which a tuberculin purified protein derivative skin test result should be considered positive?a.2.5 mmb.5 mmc.7 mmd.10 mme.15 mm Interpretation of tuberculin skin testing on the basis of risk factors is important and is commonly tested on licensing and board certification examinations. Had the patient been HIV-positive, immunosuppressed, or had recent contact with active TB disease, the threshold would be reduced to 5 mm. The correct threshold is 10 mm for a recent immigrant (<5 y) from a country with a high TB prevalence. An induration of 15 mm or more is positive for TB regardless of TB risk factors. Previous bacille Calmette-Guérin vaccination can cause false-positive tuberculin skin test results.5Lewinsohn D.M. Leonard M.K. LoBue P.A. et al.Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children.Clin Infect Dis. 2017; 64: 111-115Crossref PubMed Scopus (401) Google Scholar The patient was referred to infectious disease specialists who reported his case to local county public health officials. We initiated directly observed therapy with rifampin, isoniazid, ethambutol, and pyrazinamide. Orthopedic surgery specialists also evaluated the patient but did not believe that surgical irrigation and debridement was indicated. Before initiating therapy, we obtained baseline measurements of serum aminotransferase, bilirubin, alkaline phosphatase, and creatinine levels and a platelet count, all of which were within normal limits. Additionally, the patient underwent screening for HIV, which yielded negative results. Because ethambutol would be included in his treatment, visual acuity and red and green color discrimination were tested as well. Two weeks after treatment initiation, culture results indicated pan-susceptibility, and ethambutol was therefore discontinued, with continuation of rifampin, isoniazid, and pyrazinamide. Four weeks into treatment, the patient’s back pain had decreased; however, he returned to the clinic with numbness and tingling in both hands. Isoniazid-related neuropathy was suspected, and pyridoxine (vitamin B6) therapy was initiated. Despite this measure, his neurologic symptoms continued, prompting discontinuation of pyrazinamide in favor of reinitiation of ethambutol, along with continued rifampin and isoniazid.5.Given that this patient had no baseline laboratory or visual abnormalities, which one of the following should be regularly assessed for the duration of his treatment?a.Liver functionb.Serum creatininec.Platelet countd.Signs of visual disturbancese.Sputum specimen for acid-fast bacilli smear and culture, at monthly intervals Baseline evaluation of hepatic function, renal function, platelet count, and testing of visual acuity and red and green color discrimination should be performed for all patients before initiation of anti-TB therapy. Patients then require monthly clinical assessments for adverse effects of the medications, including questioning for hepatotoxicity, which may manifest with nausea, emesis, or right upper quadrant pain. Should a patient be at increased risk of hepatic toxicity, as from alcohol abuse or chronic hepatitis, for example, liver function should be monitored routinely to ensure that the liver disease does not worsen. The same is true for those who have baseline kidney disease or thrombocytopenia. All patients, regardless of their initial laboratory test results, should be questioned at monthly intervals about visual symptoms which may result from ethambutol. During treatment of patients who have active pulmonary TB, sputum specimens for acid-fast bacilli smears and cultures should be obtained monthly until results are negative for 2 consecutive months, but smears and cultures are not performed routinely for patients with extrapulmonary TB.6Nahid P. Dorman S.E. Alipanah N. et al.Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis.Clin Infect Dis. 2016; 63: e147-e195Crossref PubMed Scopus (583) Google Scholar Repeated MRI at 6 months revealed marked improvement in the inflammatory and reactive changes surrounding the joint but interval worsening of the destructive changes within the joint that occurred as a consequence of infection. These destructive changes were thought to represent a delayed radiographic response, given the normalization of inflammatory markers and clinical improvement. Three-drug therapy with ethambutol, rifampin, and isoniazid was therefore continued for 9 months total, at which time results of repeated clinical, laboratory, and imaging evaluations were reassuring, allowing discontinuation of therapy. Mycobacterium tuberculosis remains a global health priority, with 9.6 million new cases and 1.5 million TB-related deaths in 2014 alone.7World Health Organization, Global Tuberculosis Programme. Global tuberculosis report. http://www.who.int/tb/publications/global_report/gtbr15_main_text.pdf. Accessed April 26, 2017.Google Scholar The numbers are particularly tragic because the condition is treatable and often curable with early recognition. The diagnosis, however, requires a high index of suspicion, as TB has long been known for its ability to imitate other disorders. Most cases of TB in the United States occur in foreign-born individuals.8Sia I.G. Wieland M.L. Current concepts in the management of tuberculosis.Mayo Clin Proc. 2011; 86: 348-361Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar A critical clue in this case was the patient’s recent immigration from Vietnam, a country designated by the World Health Organization as one of 22 countries with a “high burden,” a label given to places with 100 or more TB cases per 100,000 population. Countries in the top 5 for number of incident cases are India, Indonesia, China, Pakistan, and South Africa. In total, 86% of cases occur in patients from Asian and African regions. Awareness of the atypical manifestations is of growing importance in industrialized countries where extrapulmonary TB accounts for an increasing proportion of the total cases. Currently, nearly 20% of all TB cases in US national surveillance data are extrapulmonary, with a contribution of 11% from bone and joint sites.9Peto H.M. Pratt R.H. Harrington T.A. LoBue P.A. Armstrong L.R. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006.Clin Infect Dis. 2009; 49: 1350-1357Crossref PubMed Scopus (481) Google Scholar Osteoarticular TB can present in any skeletal location, but the aerobic, acid-fast bacilli have a predilection for areas with abundant vascularity, including the spine and long bones of weight-bearing joints such as the knee and hip. Unlike infections from other microbes, osteoarticular TB tends to present in a subacute to chronic fashion. Pain and swelling may be the only signs of infection and may precede inflammatory features such as erythema and warmth by weeks.10Pigrau-Serrallach C. Rodriguez-Pardo D. Bone and joint tuberculosis.Eur Spine J. 2013; 22: 556-566Crossref PubMed Scopus (171) Google Scholar Even constitutional symptoms and fever may not be present. Patients with skeletal TB are unlikely to have primary pulmonary involvement at the same time; rather, it is usually due to reactivation of latent TB. An interesting consideration in the presented case is the patient’s long-standing history of lower back pain with inflammatory features suggestive of ankylosing spondylitis. A body of literature indicates that patients with rheumatologic conditions are at increased risk of infection because of their immunocompromised state, even before the initiation of medication that can further suppress their response to infection.11Franco-Paredes C. Diaz-Borjon A. Senger M.A. Barragan L. Leonard M. The ever-expanding association between rheumatologic diseases and tuberculosis.Am J Med. 2006; 119: 470-477Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar In addition, skeletal TB has been described in association with systemic lupus erythematosus, rheumatoid arthritis, and even superimposed on gouty arthritis. However, given that our patient is of Southeast Asian descent, it should be noted that the distribution of HLA-B27 antigen is the lowest in equatorial areas and that certain subtypes of HLA-B27 antigen may not be associated with ankylosing spondylitis in Asians.12Khan M.A. HLA-B27 and its subtypes in world populations.Curr Opin Rheumatol. 1995; 7: 263-269Crossref PubMed Scopus (225) Google Scholar, 13Yang T. Duan Z.H. Wu S.S. et al.Association of HLA-B27 genetic polymorphisms with ankylosing spondylitis susceptibility worldwide: a meta-analysis.Mod Rheumatol. 2014; 24: 150-161Crossref PubMed Scopus (22) Google Scholar One possibility is that his HLA-B27 antigen positivity was a “red herring.” Testing with the Mantoux tuberculin skin test or interferon gamma release assay can help indicate whether a patient has a cellular immune response to TB. Further laboratory testing does not aid in the diagnosis of active extrapulmonary TB, as the white blood cell count and inflammatory markers may be normal or only mildly elevated. As discussed previously, imaging characteristics can be suggestive of bone and joint infections, but definitive diagnosis requires biopsy and cultures. On the biopsy sample, smear microscopy for acid-fast bacilli and nucleic acid amplification testing are useful for rapid detection of M tuberculosis, but confirmation with mycobacterial cultures and drug susceptibility testing are essential for diagnostic and therapeutic purposes. Emerging nuclear acid amplification testing methods (ie, GeneXpert MTB/RIF™ [M tuberculosis/rifampin]) can detect resistance to rifampin and other agents within a matter of hours, but complete susceptibility testing still relies on conventional mycobacterial cultures, which may take weeks. Treatment for extrapulmonary TB should be coordinated with local public health officials and in consultation with local or regional authorities. Treatment for all forms of pan-susceptible, active TB is administered in 2 phases—an 8-week initiation phase, typically consisting of treatment with pyrazinamide, rifampin, ethambutol, and isoniazid, followed by a longer continuation phase. Extrapulmonary pan-susceptible disease is generally treated with a continuation phase of 4 to 7 months, although this period is extended to 12 months for TB meningitis or other advanced disease.6Nahid P. Dorman S.E. Alipanah N. et al.Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis.Clin Infect Dis. 2016; 63: e147-e195Crossref PubMed Scopus (583) Google Scholar Directly observed therapy is critical to minimize the chances of treatment failure, relapse, and emergence of drug resistance. Rates of relapse for TB sacroiliitis depend on treatment selection, duration, isolate susceptibility, adherence to therapy, and clinical characteristics, and they are estimated only imprecisely in the current literature. Surgical intervention is frequently necessary, particularly in cases of TB sacroiliitis.14Gao F. Kong X.H. Tong X.Y. et al.Tuberculous sacroiliitis: a study of the diagnosis, therapy and medium-term results of 15 cases.J Int Med Res. 2011; 39: 321-335Crossref PubMed Scopus (10) Google Scholar However, for patients with pan-sensitive TB sacroiliitis who receive adequate therapy, favorable outcomes with no relapse can be expected.